Using Light to Guide T Lymphocytes to Attack Tumors

Solid tumors have a whole bag of tricks to avoid the immune system. Fortunately, new therapies aim at these strategies to sensitize the patient’s immune system to the tumor. A new study from the University of Rochester Medical Center laboratory has discovered a simple, practical way that uses light and optics to turn killer immune cells to the tumors.

The lead author of this study, Minsoo Kim, Ph.D., works as a professor of Microbiology and Immunology, and is also an investigator at the Wilmot Cancer Institute. This work from Kim’s laboratory were published in the online journal Nature Communications. Kim described the method devised in his laboratory as similar to “sending light on a spy mission to track down cancer cells.”

A new therapy for treating hard-to-crack cancers is called immunotherapy. Immunotherapy does not utilize radiation or chemotherapy, but instructs the patient’s T lymphocytes to attack the cancerous cells. For example, CAR T-cell therapy removes the patient’s T cells, grows them in the laboratory, genetically engineers them to recognize, attack and kill the cancer, and then reintroduces these cells back into the patient. This is one type of immunotherapy. While this ingenuous technique shows remarkable promise, the immune system can overreact or under-react sometimes. Also, slippery cancers can find ways to hide from marauding T cells. Likewise, aggressive tumors often have mechanisms by which they suppress the immune system and surround themselves with a kind of “no-go” zone that prevents any immune cells from coming near the tumor. These immunosuppressive microenvironments that surround the malignant tumor keeps T cells out.

While it is true that T cells can be engineered to be more efficient killers, unleashing such supercharged T cells into the body can produce a tempest of toxicities. Is there a safer way?

Kim and his colleagues tried to find a kinder, gentler way to crack the tumor. They used a two-prong approach. First, Kim and others discovered that light-sensitive molecules could effectively guide T cells toward tumors. Kim and his coworkers even discovered that a molecule from algae called “channelrhodopsin” (CatCh) that is light-sensitive, could be introduced into immune cells by genetically engineering them with viruses. This technology is so novel that the university’s technology transfer office has filed for patent protection on the invention. Secondly, Kim collaborated with University of Rochester optics and photonics experts to design a Light Emitting Diode (LED) chip that could be implanted and shine light on the tumor.

Next, the Kim group fitted their mice with a small battery pack that sent a wireless signal to the implanted LED chip. When the ears of the mice were implanted with aggressive melanoma cells taken from a patient, the chip remotely shines light on the implanted tumor and surrounding areas. The light-guided T cells ran headlong to the tumor, ignoring the no-go zone where they killed the implanted tumor.

Even more interestingly, the LED chip with the battery pack were used in many control mice and no toxic side effects were observed. In the tumor-implanted mice, the light-guided T cells completely destroyed the implanted melanoma was destroyed without dangerous side effects.

In the future, Kim wants to determine if the wireless LED signal can deliver light to tumors deep within the body instead only on the surface. Also, can light shined into deep areas of the body still guide the T cells to the tumor to attack the tumor.

Kim cautiously emphasized that while his discovery is exciting, it is only meant to be combined with immunotherapy to make it safer, more effective, and traceable. Perhaps with additional improvements, Kim’s optical method might allow doctors to see, in real-time, if cancer therapies are reaching their target. Currently when patients receive immunotherapy, they must wait for several weeks and then have imaging scans to determine if the treatment worked.

“The beauty of our approach is that it’s highly flexible, non-toxic, and focused on activating T cells to do their jobs,” Kim said.

Hitting Acute Myeloid Leukemia Where It Hurts

Research teams from Massachusetts General Hospital and the Harvard Stem Cell Institute have teamed up to devise a new strategy for treating acute myeloid leukemia (AML). This new strategy is an outgrowth of new findings by these research groups that have identified an enzyme that plays a central role in the onset of AML.

During blood cell development in the bone marrow, hematopoietic stem cells divide to produce daughters cells, one of which remains a stem cells and the other of which becomes a progenitor cell. The progenitor cells can either differentiate toward the lymphoid lineage, in which it will become either a B-lymphocyte, T-lymphocyte, or a Natural Killer cell, or a myeloid precursor that can give rise to neutrophils, megakarocytes (that produce platelets), monocytes, eosinophils, or red blood cells. However, the means by which myeloid cells are formed in the bone marrow of AML patients is abnormal, and the myeloid precursor cells do not differentiate into a specific white blood cells, but, instead, remain immature and proliferate and crowd out and suppress the development of normal blood cells.

David Scadden, MD, director of the MGH Center for Regenerative Medicine (MGH-CRM), co-director of the Harvard Stem Cell Institute (HSCI), and senior author of this Cell paper, had this to say about AML: “AML is a devastating form of cancer; the five-year survival rate is only 30 percent, and it is even worse for the older patients who have a higher risk of developing the disease.” Dr. Scadden continued: “New therapies for AML are extremely limited – we are still using the protocols developed back in the 1970s – so we desperately need to find new treatments.”

What genetic changes cause these developmental abnormalities that lead to AML? As it turns out, a wide range of genetic changes occur in AML (see Medinger M, Lengerke C, Passweg J. Cancer Genomics Proteomics. 2016 09-10;13(5):317-29; and Prada-Arismendy J, Arroyave JC, Röthlisberger S. Blood Rev. 2016 Sep 2. pii: S0268-960X(16)30060-1). In this paper, however, the authors proposed that the effects on differentiation had to transition through a few shared events. Using a method created by lead author David Sykes of the MGH-CRM and HSCI, the team discovered that a single dysfunctional point in the developmental pathway common to most forms of AML that could be a treatment target.

Previous studies had demonstrated that expression of the HoxA9 transcription factor, a transcription factor that must be inactivated during normal myeloid cell differentiation, is actually quite active in the myeloid precursors of 70 percent of patients with AML.  Unfortunately, no inhibitors of HoxA9 have been identified to date.  Therefore, Scadden and others used a different, albeit freaking ingenious, approach to screen small molecules that were potential Hox9A inhibitors based not on their interaction with a particular molecular target but on whether they could overcome the differentiation blockade characteristic of AML cells.

First, they induced HoxA9 overexpression in cultured mouse myeloid cells to design a cellular model of AML.  They also genetically engineered these cultured cells to glow green once they differentiated into the mature white blood cell types.  These groups screened more than 330,000 small molecules to find which would produce the green signal in the cultured cells.  The green glow indicated that the HoxA9-induced differentiation blockade had been effectively overcome. Only these 330,000 compounds, only 12 induced terminal differentiation of these cells, but 11 of then acted by suppressing a metabolic enzyme called DHODH.  DHODH, or dihydroorotate dehydrogenase, is a biosynthetic an enzyme that is a member of the pyrimidine biosynthesis pathway, which catalyzes the oxidation of dihydroorotate to orotate.

This is a shocking discovery because the DHODH enzyme is not known to play any significant role in myeloid differentiation.  Corroboratory experiments demonstrated that inhibition of DHODH effectively induced differentiation in both mouse and human AML cells.

The next obvious step would be to use known inhibitors of DHODH in mice with AML.  They were able to identify a dosing schedule that reduced levels of leukemic cells and prolonged survival that caused none of the adverse effects of normal chemotherapy.  Even though six weeks of treatment with DHODH inhibitors did not prevent eventual relapse, treatment for up to 10 weeks seemed to have led to long-term remission of AML.  This remission included reduction of the leukemia stem cells that can lead to relapse.  Similar results were observed in mice into which human leukemia cells had been implanted.

“Drug companies tend to be skeptical of the kind of functional screening we used to identify DHODH as a target, because it can be complicated and imprecise. We think that with modern tools, we may be able to improve target identification, so applying this approach to a broader range of cancers may be justified,” says Scadden, who is chair and professor of Stem Cell and Regenerative Biology and Jordan Professor of Medicine at Harvard University. Additional investigation of the mechanism underlying DHODH inhibition should allow development of protocols for human clinical trials.

Scadden noted that this manuscript describes six years of work and, also, is a true reflection of the collaborative nature of science in pursuit of clinically relevant therapies.

Pancreatic Cancers Treated Better By Breaking Up Scar Tissue

Despite advances in cancer treatment, tumors of the pancreas remain among the most difficult to treat. To date, pancreatic cancers remain largely resistant to immune-based therapies, despite the successes of immunotherapies in treating lung cancers and melanomas.

A new study from Washington University School of Medicine in St. Louis that was published in the journal Nature Medicine, has shown that immunotherapy against pancreatic cancer can shrink these tumors if they are given in combination with drugs that break up the fibrous scar tissue in these tumors.

Physicians at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital are using the strength of these data to conduct a phase 1 clinical trial in patients with advanced pancreatic cancer. This clinical trial will test the safety of this drug combination when given alongside standard chemotherapy.

“Pancreatic tumors are notoriously unresponsive to both conventional chemotherapy and newer forms of immunotherapeutics,” said senior author David G. DeNardo, PhD, an assistant professor of medicine. “We suspect that the fibrous environment of the tumor that is typical of pancreatic cancer may be responsible for the poor response to immune therapies that have been effective in other types of cancer.”

Pancreatic cancers are unusual among cancers since they characteristically consist of large swaths of scar tissue. These balls of fibrous tissue that surround the tumor create a protective environment for cancer cells. These scar tissue-based capsules prevent the immune system accessing the tumor cells and also limit the exposure of these tumors to chemotherapies that have been administered through the bloodstream. DeNardo and his colleagues used a mouse model of pancreatic cancer to determine if disrupting these fibrous capsules could sensitize pancreatic tumors to chemotherapy regimens.

Pancreatic tumors are surrounded by a protective “nest” made of fibrotic scar tissue and the cells that manufacture it (red). A new study demonstrates that disrupting this fibrous tissue makes immune therapy and chemotherapy more effective in attacking tumors of the pancreas. (Image: DeNardo Lab)

“Proteins called focal adhesion kinases are known to be involved in the formation of fibrous tissue in many diseases, not just cancer,” DeNardo said. “So we hypothesized that blocking this pathway might diminish fibrosis and immunosuppression in pancreatic cancer.”

Focal adhesion kinase (FAK) is a protein (encoded by the PTKs gene) that controls cell adhesion and cell motility. Inhibiting FAK activity in breast cancer cells makes them less likely to spread to other organs (see Chan, K.T., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200809110). Small molecules have been designed that can readily inhibit FAK, and DeNardo and his colleagues used FAK inhibitors against pancreatic cancer in combination with immunotherapy.

In their mouse study, an investigational FAK inhibitor was administered to mice in combination with a clinically approved immune therapy that activates the patient’s own T-cells so that they can effectively attack tumor cells.

Mice that had pancreatic cancer survived no longer than two months when given either a FAK inhibitor or immune therapy alone. If the FAK inhibitors were added to standard chemotherapy, the tumor response improved over chemotherapy alone. However, the three-drug combination that consisted of FAK inhibitors, immune therapy and chemotherapy, displayed the best outcomes in laboratory studies and more than tripled survival times in some mice. Some were still alive without evidence of progressing disease at six months after treatment and beyond.

The success of this mouse study provided a strong rationale for testing this drug combination in patients with advanced pancreatic cancer, according to oncologist Andrea Wang-Gillam, MD, PhD, an associate professor of medicine, who was involved with this research.

“This trial is one of about a dozen we are conducting specifically for pancreatic cancer at Washington University,” she said. “We hope to improve outcomes for these patients, especially since survival with metastatic pancreatic cancer is typically only six months to a year. The advantage of our three-pronged approach is that we are attacking the cancer in multiple ways, breaking up the fibers of the tumor microenvironment so that more immune cells and more of the chemotherapy drug can attack the tumor.”

New Gene Therapy Treatment Stops Deadly Brain Cancer in its Tracks

Brain cancers called Diffuse Intrinsic Pontine Gliomas (DIPGs) are often a death sentence. These aggressive, fast-growing, drug-resistant tumors are deadly and they originate from glial cells in the brain.

However a recent report published in the journal Cancer Cell details an experimental gene therapy that stops DIPGs in their tracks. This study included researchers from several different institutions, but was led by scientists at Cincinnati Children’s Hospital Medical Center. The study examined human cancer cells and a mouse model of DIPG.

DIPGs seem to require a gene called Olig2 (which encodes a transcription factor) to grow and survive. The majority of gliomas express the protein encoded by the Olig2 gene and removing this gene halts tumor growth and liquidating Olig2-producing cells inhibits tumor formation. This collaborative team designed a technique scientists found a way to use a gene therapy to shut down Olig2 expression.

“We find that elimination of dividing Olig2-expressing cells blocks initiation and progression of glioma in animal models and further show that Olig2 is the molecular arbiter of genetic adaptability that makes high-grade gliomas aggressive and treatment resistant,” said Qing Richard Lu, PhD, lead investigator and scientific director of the Brain Tumor Center at Cincinnati Children’s. “By finding a way to inhibit Olig2 in tumor forming cells, we were able to change the tumor cells’ makeup and sensitize them to targeted molecular treatment. This suggests a proof of principle for stratified therapy in distinct subtypes of malignant gliomas.”

DIPGs originate from supporting brain cells called oligodendrocytes. Oligodendrocytes make the insulation that surrounds the axons of various nerves in the central nervous system. Olig2 expression appears at the early stages of brain cell development, and is also present in the early-stage dividing and replicating cells in tumors. Olig2 also participates in the transformation of normal oligodendrocyte progenitor cells (OPCs) into cancer cells that divide uncontrollably. Olig2 also facilitates the adaptability of gliomas that helps them evade chemotherapeutic regimens. Indeed, clinically speaking, DIPGs may initially respond to chemotherapeutic agents, but they tend to quickly adapt to these drugs and develop high-levels of resistance to them.

Lu and his colleagues and collaborators eliminated Olig2-positive dividing cells from DIPG tumors that were still in the early stages of tumor formation. Lu and his colleagues used an ingenious technique to remove Oligo2 expression: by genetically engineering a herpes simplex virus-based vector, they delivered a suicide gene (Thymidine kinase) into replicating Olig2-positive cancer cells. Since herpes simplex viruses (HSVs) have the ability to grow in neurons that do not divide a great deal, the HSV-vectors are well suited to this purpose. After infecting the early DIPG cells with the HSV vectors, they administered an anti-herpes drug already in clinical use, ganciclovir (GCV), which kills any cells that have the thymidine kinase gene. The Olig2-deleted tumors were not able to grow.

In follow-up work, Lu and his colleagues observed a fascinating fate for the Olig2- tumors. These cells differentiated into astrocyte-like cells that continued to form tumors, but expressed the epidermal growth factor receptor (EGFR) gene at high levels. EGFR is an effective target for several chemotherapy drugs. In repeated tests in mouse models, Olig2 inhibition consistently transformed the glioma-forming cells into EGFR-expressing astrocyte-like cells. Then these tumors were treated with an EGFR-targeted chemotherapy drug called gefitinib. These treatments stopped the growth of new tumor cells and tumor expansion.

According to Dr. Lu, with additional testing, verification, and, of course, refinement, this experimental therapy that he and his colleagues have designed, could help prevent the recurrence of brain cancer in patients who have undergone initial rounds of successful treatment. Lu also added that these new treatments would probably be used in combination with other existing therapies like radiation, surgery, other chemotherapies and targeted molecular treatments.

Lu and his team will continue their research with other human cell lines and “humanized” mouse models of high-grade glioma. Such mouse models use genetically engineered mice that can grow brain tumors derived from the tumor cells of specific human patients. These tumor cells come from the tumors of patients whose families have donated biopsied tumor samples for research. This allows researchers to test different targeted drugs in their therapeutic protocol that may best match the genetic makeup of tumors from specific individuals.

The entire research team cautions the experimental therapeutic approach they describe will require extensive additional research. Therefore, this type of treatment is years away from possible clinical testing. Having said that, Lu said the data are a significant research breakthrough, since this study identifies a definite weakness in these stubborn cancers that almost always relapse and kill the patients who get them.

Pancreatic Cancer Stem Cells Could Be “Suffocated” by an Anti-Diabetic Drug

A new study by researchers from Queen Mary University of London’s Barts Cancer Institute and the Spanish National Cancer Research Centre (CNIO) in Madrid shows that pancreatic cancer stem cells (PancSCs) are very dependent on oxygen-based metabolism, and can be “suffocated” with a drug that is already in use to treat diabetes.

Cancer cells typically rely on glycolysis; a metabolic pathway that degrades glucose without using oxygen. However, it turns out that not all cancer cells are alike when it comes to their metabolism.

PancSCs use another metabolic process called oxidative phosphorylation or OXPHOS to completely oxidize glucose all the way to carbon dioxide and water. OXPHOS uses large quantities of oxygen and occurs in the mitochondria. However, this is precisely the process that is inhibited by the anti-diabetic drug, metformin.

Ever crafty, some PancSCs manage to adapt to such a treatment by varying their metabolism, and this leads to a recurrence of the cancer. However, this English/Spanish team thinks that they have discovered a way to prevent such resistance and compel all PancSCs to keep using OXPHOS. This new discovery might open the door to new treatments that stop cancer stem cells using oxygen and prevent cancers from returning after conventional treatments. A clinical trial is planned for later next year.

Dr Patricia Sancho, first author of the research paper, said: “We might be able to exploit this reliance on oxygen by targeting the stem cells with drugs that are already available, killing the cancer by cutting off its energy supply. In the long-term, this could mean that pancreatic cancer patients have more treatment options available to them, including a reduced risk of recurrence following surgery and other treatments.”

PancSCs become resistant to metformin by suppressing a protein called MYC and increasing the activity of a protein called PGC-1α. However, this resistance mechanism of PancSCs can be abolished if a drug called menadione is given. Menadione increases the amount of reactive oxygen species in mitochondria. Additionally, resistance to metformin can be prevented or even reversed if the MYC protein is inhibited by genetic or pharmacological means. Therefore, the specific metabolic features of pancreatic Cancer Stem Cells are amendable to therapeutic intervention and can provide the basis for developing more effective therapies to combat this lethal cancer.

Pancreatic cancer is still one of the most difficult cancer types to treat. It rarely causes symptoms early on and does not usually trigger diagnosis until its later and more advanced stages. Unfortunately, many patients do not live longer than a year after being diagnosed. These cancers are also becoming more common due to obesity, which increases the patient’s risk for metabolic syndrome and diabetes, which are pancreatic cancer risk factors. Limited treatment options and a failure to improve survival rates mean that finding new treatment strategies is a priority.

PancSCs could be an important but as yet overlooked piece of this puzzle, since they compose only a small proportion of the tumor. PancSCs also have the potential to make new tumors, even if all the other cells are killed, and are prone to spreading around the body (metastasis). Therefore killing these PancSCs is a better way to treat such dangerous cancers.

Bone Marrow Pretreatment with Hypomethylating Agents Improves Progression-Free Survival in Leumemia Patients

When patients have certain types of leukemia, they can be cured if they receive a bone marrow transplant from a healthy donor. The immune cells from the donated bone marrow will then attack the cancer cells vigorously, and the leukemia will slip into remission.

Such a strategy is called an “allogeneic bone marrow transplant,” and it is an effective way to treat some types of leukemia. However, this technique is risky and it usually involves some patient-related mortality. The problem is getting the transplanted cells to survive.

A new study from the University of Texas MD Anderson Cancer Center in Houston, Texas has examined over eighty patients who have received allogeneic bone marrow grafts for chronic myelomonocytic leukemia (CMML). Stefan O. Ciurea and his colleagues have identified a new pre-treatment that seems to decrease the degree of tumor relapse.  Their study was published in the Biology of Blood and Bone Marrow Transplantation.

83 consecutive patients with some form of CMML received an allogeneic bone marrow transplants between April 1991 and December 2013 were examined in detail. They asked if pre-treatment of the bone marrow stem cells with chemicals called “hypomethylating agents” before transplant improved progression-free survival.

Seventy-eight patients received “induction treatment” before transplant, 37 received hypomethylating agents and 41 received cytotoxic chemotherapy. Patients treated with a hypomethylating agent had a significantly lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03). However, the transplant-related mortality 1 year post-transplant did not significantly differ between these groups (27% and 30%, respectively; p=0.84). The lower relapse rate resulted in a significantly higher 3-year progression-free survival rate in patients treated with a hypomethylating agent (43%) than in those treated with other agents (27%; p=0.04).

This study supports the use of hypomethylating agents before allogeneic stem cell transplantation for patients with CMML to achieve remission and improve progression-free survival of patients. Of course future studies are needed to confirm these findings, but they suggest that pretreating bone marrow stem cells with hypomethylating agents prior to transplanting them will beef the cells up and help them life longer to fight tumors.

Biomaterial Sponge-Like Impant Traps Spreading Cancer Cells

Prof Lonnie Shea, from the Department of Biomedical Engineering at the University of Michigan and his team have designed a small sponge-like implant that has the ability to mop up cancer cells as they move through the body. This device has been tested in mice, but there is hope that the device could act as an early warning system in patients, alerting doctors to cancer spread. The sponge-like implant also seemed to stop rogue cancer cells from reaching other areas where they could establish the growth of new tumors. Shea and others published their findings in the journal Nature Communications.

According to Cancer Research UK, nine in 10 cancer deaths are caused by the disease-spreading to other areas of the body. Stopping the spread of cancer cells, or metastasis, is one of the ways to prevent cancers from becoming worse. Complicating this venture is the fact that cancer cells that circulate in the bloodstream are rare and difficult to detect.

Shea’s device is about 5mm or 0.2 inches in diameter and made of a “biomaterial” already approved for use in medical devices. So far, this implant has so far been tested in mice with breast cancer. Implantation experiments showed that it can be placed either in the abdominal fat or under the skin and that it tended to suck up cancer cells that had started to circulate in the body.

The implant mimicked a process known as chemoattraction in which cells that have broken free from a tumor are attracted to other areas in the body by immune cells. Shea and others found that these immune cells are drawn to the implant where they “set up shop.” This is actually a natural reaction to any foreign body, and the presence of the immune cells also attracts the cancer cells to the implant.

Initially, Shea and others labeled cancer cells with fluorescent proteins that caused them to glow under certain lights, which allowed them to be easily spotted. However, they eventually went on to use a special imaging technique that can distinguish between cancerous and normal cells. They discovered that they could definitively detect cancer cells that had been caught within the implant.

Unexpectedly, when they measured cancer cells that had spread in mice with and without the implant, they showed that the implant not only captured circulating cancer cells, but it also reduced the numbers of cancer cells present at other sites in the body.

Shea, said that he and his team were planning the first clinical trials in humans fairly soon: “We need to see if metastatic cells will show up in the implant in humans like they did in the mice, and if it’s a safe procedure and that we can use the same imaging to detect cancer cells.”

Shea and his coworkers are continuing their work in animals to determine what the outcomes if the spread of the cancer spread was detected at a very early stage, which is something that is presently not yet fully understood.

Lucy Holmes, Cancer Research UK’s science information manager, said: “We urgently need new ways to stop cancer in its tracks. So far this implant approach has only been tested in mice, but it’s encouraging to see these results, which could one day play a role in stopping cancer spread in patients.”

U of Penn Group Releases Hopeful Results of CAR T-Cells Trial

Chimeric Antigen Receptor T-Cells (CART-cells) are a type of genetically engineered type of immune cell that represents one of the most promising avenues of cancer therapy. Such treatments can induce sustained remissions in patients with stubborn disease.

Studies with CART-cells have been tested in patients with relapsed and stubborn chronic lymphocytic leukemia (CLL). Now a new publication by Porter and others reports the results of a clinical trial that examined CART-cells as a treatment for blood-based cancers. This study reports that infused CART-cells were functional up to 4 years after treatment. Patients also achieved completely remission, and no patient who achieved complete remission relapsed, and no minimal residual disease was detected, suggesting that in a subset of patients, CAR T cells may drive disease eradication.

Patients enrolled in this study suffered from CLL and had a poor prognosis. The CART-cells employed in this study targeted the molecule CD19. Porter and others report the mature results of the treatment of 14 patients with relapsed and refractory CLL.

The patient’s own T-Cells were extracted from circulating blood, and genetically engineered to express a CD19-directed receptor. Patients received doses of 0.14 × 10[8] to 11 × 10[8] CTL019 cells. Patients were monitored for toxicity, response, expansion, and persistence of circulating CTL019 T cells.

The overall response rate in these heavily pretreated CLL patients was 8 of 14 (57%), and there were 4 complete remissions (CR) and 4 partial remissions (PR). The expansion of the CAR T-cells in culture correlated with clinical responses; the better the engineered T-cells grew in culture the better they performed in the Patient’s bodies. Furthermore, the CAR T-cells persisted and remained functional beyond 4 years in the first two patients achieving Complete Remission. None of the patients who experienced Complete Remission have relapsed.

All the patients who responded to the treatment developed “B cell aplastic” (abnormally low B-cell levels) and experienced cytokine release syndrome, which was part and partial of T cell proliferation.

Minimal residual disease was not detectable in patients who achieved Complete Remission, suggesting that disease eradication may be possible in some patients with advanced CLL.

Expanding and Activating a Cancer Patient’s Own T-Cells to Treat Their Cancer

A research team from UH Seidman Cancer Center in Cleveland, Ohio have designed a protocol for culturing activated T-cells from melanoma patients in order to expand and use the patient’s own T-cells to fight their cancer. This research, which may lead to treatments that save lives someday, was published in the Journal of Immunotherapy and will hopefully lead to clinical trials.

T-cells are a type of white blood cell in our bodies. These cells are born in the bone marrow, and they play a central role in orchestrating the immune response against foreign entities that enter our bodies. There are several different types of T-cells; some of the help other cells get revved up to fight an infection, others attack and destroy virus-infected cells, some suppress inappropriate immune responses, and others do a host of other interesting, and in some cases, poorly understood things. One function of T-cells is to identify and attack cancer cells. The problem is that T-cells from our own bodies often have trouble identifying cancer cells as truly foreign entities and deserve the T-cells ire.

Patients who suffer from a deadly type of skin cancer known as melanoma have T-cells coursing through their blood vessels that can trigger a protective immune response against the disease, according to a new study out of University Hospitals Case Medical Center Seidman Cancer Center and Case Western Reserve University School of Medicine. This new study demonstrates that T-cells isolated from lymph nodes of patients with melanoma can be expanded in number and activated in a laboratory-based cell culture system. These laboratory-grown T-cells can then be intravenously administered back into these same patients to treat their cancer.

Julian Kim, MD, Chief Medical Officer at UH Seidman Cancer Center, led the research team that did this fascinating study. According to Dr. Kim., he and his colleagues developed a completely novel technique that allowed them to successfully generate large numbers of activated T-cells that could be reintroduced back into the same patient to stimulate their immune system to attack or destroy their cancer.

“This study is unique in that the source of T-cells for therapy is derived from the lymph node, which is the natural site of the immune response against pathogens as well as cancer,” said Dr. Kim who also serves as a Professor of Surgery at Case Western Reserve University School of Medicine and the Charles Hubay Chair at UH Case Medical Center. “These encouraging results provide the rationale to start testing the transfer of activated T-cells in a human clinical trial.”

In the Kim laboratory at the School of Medicine, Kim and his team developed a new method to grow T-cells from cancer patients and then activate them in a two-week cell culture system. The extracted the immune cells from lymph nodes that were exposed to growing melanoma in the patient’s body. Instead of trying to activate these tumor-sensitized T-cells in the body, the lymph nodes were surgically removed in order to activate and grow the T-cells in a tightly regulated environment in the laboratory. This novel approach to cancer treatment, which is termed “adoptive immunotherapy,” is only offered at a few institutions worldwide.

After these T-cells from melanoma patients were expanded and activated by exposing the cells to bits of proteins known to be on the surfaces of the melanomas, they were sicced on melanoma cells in culture.  These activated T-cells dutifully and efficiently killed the melanoma cells.  Well that’s all fine and good in culture, but could the cells to this in a living organism?  Do answer this question, Kim and others transplanted human melanomas into special laboratory mice that could grow human tumor tissue effective and then gave these mice intravenous infusions of the activated T-cells. These tumor-infested mice typically died from these transplanted tumors, but the mice treated with the patient-specific, activated T-cells survived in a concentration-dependent fashion.  In order words, the more activated T-cells the mice were given, the longer they lived and the better their bodies were able to fight the transplanted tumors.

The promising findings of this study have led to the recent launch of a new Phase I human clinical trial at UH Seidman Cancer Center in patients with advanced melanoma. “The infusion of activated T-cells has demonstrated promising results and is an area of great potential for the treatment of patients with cancer,” said Dr. Kim. “We are really excited that our method of activating and expanding T-cells is practical and may be ideal for widespread use. Our goal is to eventually combine these T-cells with other immune therapies which will result in cures. These types of clinical trials place the UH Seidman Cancer Center at the forefront of immune therapy of cancer.”

Kim and his team have also been investigating the possibility of using lymph nodes from patients with pancreatic cancer to develop additional T-cell therapies. Kim and his coworker would like to expand their program to eventually study other tumor types including lung, colorectal and breast cancers.

Regulating Gene Expression Pushes Tumors into Remission

A study published online by the journal Science Translational Medicine discusses a new experimental treatment for a rare, deadly leukemia (blood cancer) that can send the disease into remission even in those patients for whom the standard therapy has failed. Such a treatment can buy patients more time to have a stem cell transplant that could save their lives. This study was only a small pilot study, but these findings are potentially revolutionary.

“It was unbelievable, really, seeing a patient who had already failed Campath [the drug typically used to treat the disease] literally going back into remission,” said Thomas P. Loughran Jr., MD, the director of the University of Virginia Cancer Center, who also served as one of the lead researchers of this study. “We were able to get every single patient back into remission.”

This new approach for battling T-cell prolymphocytic leukemia combines immunotherapy, which boosts the body’s immune system, with the manipulation of gene activity. Such a strategy might cast the mold for treatments for not only T-cell prolymphocytic leukemia, but other cancers as well. “There’s been a revolution in the last few years seeing success with immunotherapy, and people speculated that perhaps if you combined epigenetic and immunotherapy, that might be even more spectacular,” Loughran said. “This is proof of principle that this might be true.”

The pilot study, led by Loughran at UVA and Elliot Epner, MD, at Pennsylvania State University College of Medicine, looked at eight patients with T-cell prolymphocytic leukemia, which is an aggressive cancer that is extremely difficult to treat. T-cell prolymphocytic leukemia is also extremely rare and appears mostly in older men.

Cancer cells in patients with T-cell prolymphocytic leukemia have a cell-surface protein called CD52. By using an antibody to CD52, in the form of a drug called alemtuzumab (a monoclonal antibody to CD52), some patients can be driven into complete remission that lasts, for the most part, between 6-12 months. Alemtuzumab binds to CD52 and directs white blood cells to destroy them (see here).  However, if patients do not receive a bone marrow transplant, the cancer will come back and the cells will not be as sensitive to alemtuzumab. The reason for this resistance is that the cancer cells have down-regulated the expression of CD52. In this reports, patients were given drugs that prevent genes from being silenced (known as histone deacetylase inhibitors). The data from this study shows that the co-administration of epigenetic agents can overcome resistance to alemtuzumab, since the histone deacetylase inhibitors prevented the cancer cells from down-regulating their CD-52 genes.

Although this experimental approach did not cure the patients, it did send them all into remission. Furthermore, it works as well as predicted; patients could be re-treated and receive the same benefit each time. These treatments gave patients vital time as they looked for a suitable bone marrow/stem cell donor. Patients with T-cell prolymphocytic leukemia must have disease that is in remission in order to first receive the transplant.

There are limitations to this approach. Mounting toxicity limits how many times the treatment can be administered. Secondly, the suppression of the immune system can lead to infections and other complications. But the treatment has made a significant difference for all those patients who participated in this study. One patient was expected to live only four months but survived 34. Three others were still alive at the time the researchers were compiling the trial results.

The drugs used in the treatment are already commercially available, meaning doctors could, in theory, administer the treatment without further testing. Loughran, however, believes there needs to be additional study, hopefully in larger trials, but the rarity of the disease makes recruiting subjects difficult. Loughran encourages patients with the disease to consider seeking treatment at UVA. “We’d be very glad to see them here, if they want to come see us,” he said.

Treating Colon Cancer By Activating Damaged Genes

What if doctors could turn cancer cells into healthy cells? It would change everything about how we treat cancer. Researchers may have discovered a way to do that in colorectal cancer.

What if we could turn the clock back on cancer cells and return them to their healthy status?   A new study in animals might have accomplished exactly that.

A research team from the Memorial Sloan Kettering Cancer Center has reactivated a defective gene in mice with colorectal cancer.  This gene, adenomatous polyposis coli, or Apc, is commonly defective in colorectal cancer cells.  Approximately 90 percent of colorectal tumors have a loss-of-function mutation of this gene.

At the onset of this research project, The Sloan Kettering group suppressed the expression of the Apc gene in mice.  The Apc gene encodes a protein that regulates an important cell signaling pathway known as the Wnt signal pathway.  Suppression of Apc activates the Wnt signaling pathway, which helps cancer cells grow and survive.

Afterwards, they reactivated the Apc gene, which returned Wnt signaling to its normal levels and the cancerous tumors stopped growing, and normal intestinal function was restored in four days. By two weeks after Apc was reactivated, the tumors were gone and there were no lingering signs of no signs of cancer relapse during the six-month follow-up.

The same approach turned out to be effective in mice with colorectal cancer tumors that result from activating mutations in the Kras gene and loss-of-function mutations in the p53 gene.  In humans, about half of colorectal tumors have these mutations

This study was published in the prestigious international journal, Cell, by Scott Lowe and his colleagues.  “Treatment regimens for advanced colorectal cancer involve combination chemotherapies that are toxic and largely ineffective, yet have remained the backbone of therapy over the last decade,” said Lowe.

Apc reactivation might very well be the way to improved treatment for colorectal cancer.  It is doubtful it will be helpful in other types of cancer, but in the future, it might become so.  “The concept of identifying tumor-specific driving mutations is a major focus of many laboratories around the world,” said Lukas Dow, Ph.D., of Weill Cornell Medical College, who is the first author of this study.

“If we can define which types of mutations and changes are the critical events driving tumor growth, we will be better equipped to identify the most appropriate treatments for individual cancers,” said Dow.

Colorectal cancer begins in the colon or rectum, and it remains the second-most prevalent cause of cancer death in developed countries.

According to the Surveillance, Epidemiology, and End Results Program, in 2012, there were 1,168,929 people living with colon and rectal cancer in the United States.

Estimates postulate that there will be 132,700 new cases of colorectal cancer in the United States in 2015, and about 49,700 people will lose their lives to this disease. Worldwide, colorectal cancer is the cause of approximately 700,000 deaths each year.

Internist and gastroenterologist Dr. Frank Malkin expressed optimism regarding genetic research into colorectal cancer.  He said in an interview with the medical news service, Healthline: “They’ve identified a suppressor gene that can turn a tumor on and off. It can suppress the cancer and destroy it rapidly. That’s very promising.”

Cancers are normally treated with a combination of surgery, chemotherapy, and radiation.  These rather harsh treatments can take a lasting toll.  Easier and more effective treatments could change the lives of cancer patients.

Michelle Gordon, D.O., FACOS, FACS, finds it encouraging. “If this treatment is to be believed, all current modalities will be obsolete.”

However, Malkin and Gordon both cautioned that it is simply too early to bring this strategy to the clinic to treat human patients.

“There are so many unknowns when taking a mouse model to humans,” Gordon told Healthline. “This may be the foundational step that will lead to curing most colorectal cancers. This study can provide hope to future generations of colorectal cancer [patients], but I believe a cure is decades away.”

Researchers know Apc mutations initiate colorectal cancer, but they are unsure if Apc mutations are involved in promoting tumor growth after the cancer has developed.

The next step in this work will examine the ability of Apc reactivation to affect tumors that have spread or metastasized to distant locations in the body.  Lowe and his colleagues are also hard at work to determine precisely how Apc works.  That will help scientists develop safe treatments that change cancer cells into normal cells. Such a drug could make colorectal cancer treatment easier, faster, and safer.

How this research will impact other types of cancer remains unclear.  “Cure rates for colorectal cancers are better than they used to be, especially when treated in the early stages,” said Malkin.  Nevertheless, it is still far better to stop tumors before they start.

According to Malkin, the number of colon cancer cases has dropped dramatically since routine colonoscopy screening began. A colonoscopy allows doctors to find and remove polyps before they turn cancerous.  Malkin also looks forward to genetic research that will identify those at greater risk for colorectal cancers.

“Right now, we’re using colonoscopy to screen people over 50, most who don’t have the genetic predisposition and will never get colorectal cancer,” he said. “We don’t yet have the genetic studies that would help us identify high-risk patients so we don’t have to screen everyone.”

I must admit that I remain skeptical as to whether or not this will work.  The reasons for my skepticism lie in the fact that tumor cells in the colon are the result of a series of mutations in cells that cause the cells to overgrow and eventually become invasive.  Colorectal carcinoma cells have mutations in several genes and not just Apc.  Apc reactivation worked in these mice because this was the only gene affected in these animals.  In a cancerous human colon, the cancer cells have a variety of mutations.  Kurt Vogelstein’s work at Johns Hopkins has shown this in great detail.  If Lowe could demonstrate the efficacy of his treatment in mice with humanized immune systems that have been infected with human colorectal carcinoma cells, then I will believe that this technique could work in human patients.  For now, I remain skeptical.

Marrow-Infiltrating Lymphocytes Safely Shrink Multiple Myelomas

Medical researchers at the Johns Hopkins Kimmel Cancer Center have published a report that appeared in the journal Science Translational Medicine in which they describe, for the first time, the safe use of a patient’s own immune cells to treat the white blood cell cancer multiple myeloma. There are more than 20,000 new cases of multiple myeloma and more than 10,000 deaths each year in United States. It is the second most common cancer originating in the blood.

The procedure under investigation in this study is called utilizes a specific type of tumor-targeting T cells, known as marrow-infiltrating lymphocytes (MILs). “What we learned in this small trial is that large numbers of activated MILs can selectively target and kill myeloma cells,” says Johns Hopkins immunologist Ivan Borrello, M.D., who led the clinical trial.

According to Borrello, MILs are the foot soldiers of the immune system that attack invading bacteria or viruses. Unfortunately, they are typically inactive and too few in number to have a measurable effect on cancers.

Experiments conducted is Borrello’s laboratory and in the laboratory of competing and collaborating scientists have shown that when myeloma cells are exposed to activated MILs in culture, these cells could not only selectively target the tumor cells, but they could also effectively destroy them.

To move this procedure from the laboratory into the clinic, Borrello and his collaborators enrolled 25 patients with newly diagnosed or relapsed multiple myeloma. Only 22 were able to receive this new treatment, however.

The Hopkins team extracted and purified MILs from the bone marrow of each patient and grew them in the laboratory to increase their numbers. Then they activated the MILs by exposing them to microscopic beads coated with immune activating antibodies. These antibodies bind to specific cell surface proteins on the MILs that induce profound changes in the cells. This induction step wakes the MILs up and readies them to sniff out tumor cells. These laboratory-manipulated MILs were then intravenously injected back into each patient (each of the 22 patients with their own cells). Three days before these injections of expanded MILs, all patients received high doses of chemotherapy and a stem cell transplant, which are standard treatments for multiple myeloma.

One year after receiving the MILs therapy, 13 of the 22 patients had at least a partial response to the therapy (their cancers had shrunk by at least 50 percent) Seven patients experienced at least a 90 percent reduction in tumor cell volume and lived and average of 25.1 months without cancer progression. The remaining 15 patients had an average of 11.8 progression-free months following their MIL therapy. None of the participants experienced serious side effects from the MIL therapy.

According to Borrello, several U.S. cancer centers have conducted similar experimental treatments (adoptive T cell therapy). However, only this Johns Hopkins team has used MILs. Other types of tumor-infiltrating cells can be used for such treatments, but Borrello noted that these cells are usually less plentiful in patients’ tumors and may not grow as well outside the body.

In nonblood-based tumors, such as melanoma, only about half of those patients have T cells in their tumors that can be harvested, and only about one-half of those harvested cells can be grown. “Typically, immune cells from solid tumors, called tumor-infiltrating lymphocytes, can be harvested and grown in only about 25 percent of patients who could potentially be eligible for the therapy. But in our clinical trial, we were able to harvest and grow MILs from all 22 patients,” says Kimberly Noonan, Ph.D., a research associate at the Johns Hopkins Universithttp://www.fiercevaccines.com/special-reports/gvax-pancreasy School of Medicine.

This small trial helped Noonan and her colleagues learn more about which patients may benefit from MILs therapy. As an example, they were able to determine how many of the MILs grown in the lab were specifically targeted to the patient’s tumor and whether they continued to target the tumor after being infused. They also found that patients whose bone marrow before treatment contained a high number of certain immune cells, known as central memory cells, also had better response to MILs therapy. Patients who began treatment with signs of an overactive immune response did not respond as well.

Noonan says the research team has used these data to guide two other ongoing MILs clinical trials. Those studies, she says, are trying to extend anti-tumor response and tumor specificity by combining the MILs transplant with a Johns Hopkins-developed cancer vaccine called GVAX and the myeloma drug lenalidomide, which stimulates T cell responses.

These trials also have elucidated new ways to grow the MILs. “In most of these trials, you see that the more cells you get, the better response you get in patients. Learning how to improve cell growth may therefore improve the therapy,” says Noonan.

Kimmel Cancer Center scientists are also developing MILs treatments to address solid tumors such as lung, esophageal and gastric cancers, as well as the pediatric cancers neuroblastoma and Ewing’s sarcoma.

Two Genes Control Breast Cancer Stem Cell Proliferation and Tumor Properties

When mothers breastfeed their babies, they depend upon a unique interaction of genes and hormones to produce milk and deliver it to their hungry little tyke. Unfortunately, this same cocktail of genes and hormones can also lead to breast cancer, especially if the mother has her first pregnancy after age 30.

A medical research group at the Medical College of Georgia at Georgia Regents University has established that a gene called DNMT1 plays a central role in the maintenance of the breast (mammary gland) stem cells that enable normal rapid growth of the breasts during pregnancy. This same gene, however, can also maintain those cancer stem cells that enable breast cancer. According to their work, the DNMT1 gene is highly expressed in the most common types of breast cancer.

Also, another gene called ISL1, which encodes a protein that puts the brakes on the growth of breast stem cells, is nearly silent in the breasts during pregnancy and in breast cancer stem cells.

Dr. Muthusamy Thangaraju, a biochemist at the Medical College of Georgia, who is the corresponding author of this study, which was published in the journal Nature Communications, said, “DNMT1 directly regulates ISL1. If the DNMT1 expression is high, this ISL1 gene is low.” Thangaraju and his team first observed the connection between DNMT1 and ISL1 when they knocked out the DNMT1 gene mice and noted an increase in the expression of ISL1. These results inspired them to examine the relationship of these two genes in human breast cancer cells.

Thangaraju and his co-workers discovered that ISL1 is silent in most human breast cancers. Furthermore, they demonstrated that restoring higher levels of ISL1 to human breast cancer cells dramatically reduced cancer stem cell populations, the growth of these cells, and their ability to spread throughout the tissue; all of which are hallmarks of cancer.

Conversely, Thangaraju and his team knocked out the DNMT1 gene in a breast-cancer mouse model, the breast will not develop as well. However, according to Thangaraju, this same deletion will also prevent the formation of about 80 percent of breast tumors. In fact, DNMT1 also down-graded super-aggressive, triple-negative breast cancers, which are negative for the estrogen receptor (ER-), progesterone receptor (PR-), and HER2 (HER2-).

The findings from this work also point toward new therapeutic targets for breast cancer and new strategies to diagnose early breast cancer. For example, a blood test for ISL1 might provide a marker for the presence of early breast cancer. Additionally, the anti-seizure medication valproic acid is presently being used in combination with chemotherapy to treat breast cancer, and this drug increases the expression of ISL1. This might explain why valproic acid works for these patients, according to Thangaraju. Workers in Thangaraju’s laboratory are already screening other small molecules that might work as well or better than valproic acid.

Mammary stem cells maintain the breasts during puberty as well as pregnancy, which are both periods of dynamic breast cell growth. During pregnancy, breasts may generate 300 times more cells as they prepare for milk production. Unfortunately, these increased levels of cell growth might also include the production of tumor cells, and the mutations that lead to breast cancer increase in frequency with age. If the developing fetus dies before she comes to term, immature breast cells that were destined to become mature mammary gland cells can more easily become cancer, according to Rajneesh Pathania, a GRU graduate student who is the first author of this study.

DNMT1 is essential for maintaining a variety of stem cell types, such as hematopoietic stem cells, which produce all types of blood cells. However, the role of DNMT1 in the regulation of breast-specific stem cells that make mammary gland tissue and may enable breast cancer has not been studied to this point.

For reasons that unclear, there is an increased risk of breast cancer if the first pregnancy occurs after age 30 or if mothers lose their baby during pregnancy or have an abortion. Women who never have children also are at increased risk, but multiple term pregnancies further decrease the risk, according to data compiled and analyzed by the American Cancer Society.

Theories to explain these phenomena include the coupling of the hormone-induced maturation of breast cells that occurs during pregnancy with an increase in the potential to produce breast cancer stem cells. Most breast cancers thrive on estrogen and progesterone, which are both highly expressed during pregnancy and help fuel stem cell growth. During pregnancy, stem cells also divide extensively and as their population increases, DNMT1 levels also increase.

In five different types of human breast cancer, researchers found high levels of DNMT1 and ISL1 turned off. Even in a laboratory dish, when they reestablished normal expression levels of ISL1, human breast cancer cells and stem cell activity were much reduced, Thangaraju said.

CAR T-Cell Therapy Surpasses 90% Complete Remission Rate in Pediatric ALL

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 elicited a 91% complete remission rate in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL), according to results from a phase I trial presented at the 2015 AACR Annual Meeting.

In the treated patients, complete remissions were observed in 20 of 22 patients, as ascertained by flow cytometry.  Complete remissions were observed with all applied doses of JCAR017 and in patients who had been treated already with CD19-targeted therapies.  Severe neurotoxicity and/or severe “cytokine release syndrome” was observed in 8 patients. In total, 4 patients have relapsed—only one of which had CD19-positive disease.

“The 91% remission rate in this phase I study of JCAR017 is highly encouraging, particularly when considering these pediatric patients failed to respond to standard treatments,” Michael Jensen, MD, said in a statement. “Based on these results we are eager to advance this study, and to continue advancing the use of cell therapies to change how we treat cancer and provide patients the opportunity for better treatment options.”

Jensen serves as the director of the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute, and is also the scientific co-founder of Juno Therapeutics, which is the company that is developing JCAR017.  JCAR017 is being evaluated in an ongoing phase I/II study for pediatric and young adult patients with relapsed/refractory CD19-positive leukemia at the Seattle Children’s Hospital.

This  study intends to enroll 80 patients.  The phase I portion enrolled patients who had undergone an allogeneic hematopoietic cell transplant, but the second phase of the study is open to patients, regardless of prior transplant status (NCT02028455).

“Given the impressive clinical results with this defined cell product candidate, we are encouraged to begin testing of JCAR017 in adult patients with B cell malignancies, including non-Hodgkin lymphoma, later this year,” Hans Bishop, chief executive officer of Juno Therapeutics, said in a statement.

Juno also has three other CAR and T cell receptor therapies that are under evaluation in clinical trials.  The furthest along is JCAR015, which received a breakthrough therapy designation from the FDA as a treatment for patients with relapsed or refractory B-cell ALL in November 2014.  In one trial, JCAR015 is being used to treat precursor B cell ALL, which is the condition for which JCAR015 was awarded its orphan drug designation (NCT01840566).  In a second trial, patients with relapsed/refractory aggressive B cell non-Hodgkin lymphoma (NHL) are being treated with high dose therapy and autologous stem cell transplantation followed by infusion of JCAR015 (NCT01044069).

There are plans for future clinical trials to explore Juno’s CAR T cell therapies in combination with immune checkpoint inhibitors. Recently, Juno and MedImmune, the biologics research and development arm of AstraZeneca, announced an agreement focused on the clinical development of combination strategies.  A jointly-funded phase Ib study will explore one of Juno’s CD19-directed CAR T cell therapies in combination with the PD-L1 inhibitor MEDI4736 as a treatment for patients with NHL.  It is expected to begin later this year.

“We believe combination strategies such as this will help us better understand the full potential of our engineered T cell platform in both hematological and solid tumor settings,” Mark W. Frohlich, MD, executive vice president, Research & Development, Juno Therapeutics, said in a statement.

MEDI4736 is currently under evaluated in phase III clinical trials that are testing MEDI4736 alone and in combination with the CTLA-4 antibody tremelimumab in patients with a variety of non-small cell lung cancers and in patients with head and neck cancer who have failed prior chemotherapy.

Competition in the field of immuno-oncology has resulted in collaborations between several pharmaceutical companies, outside of the Juno deal. This is evident in the field of CAR-modified T-cell therapy, where collaborations exist between Novartis and the University of Pennsylvania (CTL019) and between Kite Pharma and the NCI (KTE-C19).

In the pediatric oncology space, results from the breakthrough therapy CTL019 were presented at the 2014 ASH Annual Meeting and demonstrated similar findings to those announced for JCAR017. In this phase I trial of 39 pediatric patients with relapsed/refractory ALL, CTL019 demonstrated a 92% complete remission rate. In total, 85% of patients who achieve a complete remission tested MRD-negative by flow cytometry.

Promising New Drug Attacks Cancer Stem Cells in Mesothelioma

The anticancer drug defactnib is currently the subject of clinical trials being conducted in multiple countries. Data from this trial in patients with a type of cancer called mesothelioma have shown that defactnib is potentially quite effective in the treatment of these cancers. Defactnib, which is being marketed by biopharmaceutical company Verastem, Inc.

Mesothelioma attacks the lining of the lung, abdomen and, in some cases, the heart. It has only one known cause; the ingestion or inhalation of asbestos fibers.

This trial is currently in its second phase, and it involves 180 patients in 13 countries. The goal of this trial is to evaluate the ability of Defactnib to kill cancer stem cells that are the main cause of the spread of the tumors and their recurrence. Even though the main focus of this trial has been on treating mesothelioma, positive results have also been achieved by using defactnib to treat other types of cancer as well.

In this trial, mesothelioma patients were treated with a combination of defactnib and pemetrexed for 12 days prior to undergoing surgery. Pemetrexed has been approved by the U.S. Food and Drug Administration to treat mesothelioma. Tumors shrunk in 70 percent of the treated mesothelioma patients. Defactnib is designed to inhibit the activity of a protein called the Focal Adhesion Kinase or FAK. FAK is very important for cancer stem cell function and without it, cancer stem cells cannot grow.

“These and other exciting developments continue to build belief that there may be an end to this horrible disease in sight,” said Russell Budd, president and managing shareholder of the mesothelioma law firm Baron and Budd. “It is extremely encouraging to see signs of progress occur on a regular basis.”

Cardio3 BioSciences Announces First Patient Enrollment in New CART Therapy Trial

The European cell therapy company Cardio3 BioSciences (C3BS) announced the enrollment of the first patient in its Phase I clinical trial to evaluate the Company’s lead CAR T-Cell therapy. This CART cell therapy is called “NKG2D CAR T-Cell” and will be tested in blood cancer patients with acute myeloid leukemia (AML) or multiple myeloma (MM). In the coming days T lymphocytes will be isolated from patients’ peripheral blood, cultured and genetically engineered to express the chimeric antigen receptor. Then these NKG2D CAR T-Cells will be infused into the patients.

NKG2D CAR T-Cells express a chimeric antigen receptor that was constructed by using the native sequence of non-engineered natural killer cell (NK cell) receptors. This receptor has the ability to target a broad range of solid tumors and blood cancers by targeting specific molecules present on cell surfaces of numerous types cancers. NKG2D CAR T-Cell is a potential new treatment option for patients with solid tumors such as breast, colorectal, lung, liver, ovarian and bladder cancer, in addition to the blood cancers targeted in this trial. The concepts that undergird this clinical trial were discovered at Dartmouth College by Professor Charles Sentman, and has been published in numerous peer-reviewed publications such as Journal of Immunology, Cancer Research and Blood.

NKG2D CAR T-Cell received an Investigational New Drug (IND) clearance, under the name CM-CS1, from the U.S. Food and Drug Administration (FDA) in July 2014 for the Phase I clinical trial in blood-borne cancers.

Dr. Christian Homsy, CEO of Cardio3 BioSciences, said: “We are extremely pleased to initiate enrollment of the first Phase I trial of our CAR T-Cell therapy program with lead product candidate NKG2D CAR T-Cell, in-line with our previously disclosed clinical development plan. As AML and MM are two underserved blood cancer subtypes, there is a clear need for new, viable treatment options. To date, NKG2D CAR T-Cell therapies have demonstrated the prevention of tumor development and increased survival in preclinical animal models, suggesting that NKG2D CAR T-Cell has the potential to be one such therapy.”

Cardio3 BioSciences expects to complete the study in mid-2016 and will provide updates as the trial advances. Because it is a Phase I trial, it will assess the safety and feasibility of NKG2D CAR T-Cell as primary endpoints, with secondary endpoints including clinical effectiveness. If the trial is successful, however, it might provide alternative therapies for patients with a variety of cancers.

Investigational “CART” Cells, A Personalized Cellular Cancer Therapy is Well Tolerated By Patients

Chimeric Antigen Receptor T cells or CART cells are genetically modified versions of a patients’ own immune cells that expressed molecules that specifically bind tumor cells and mark them for destruction.  A host of animal experiments have demonstrated the safety and effectiveness of CART cells for treating tumors, but getting a therapy to work in animals is different than getting it to work in human patients.

Thus, the recent news that patients treated with CART cells made from their own T cells are tolerating them well is very welcome news.  Equally welcome is the news that the infused CART cells successfully traveled to those tumors they were designed to attack in an early-stage trial for mesothelioma and pancreatic and ovarian cancers at the Perelman School of Medicine at the University of Pennsylvania. Data from these trials adds to an already growing body of research that shows that CAR T cell technology shows remarkable promise for fighting tumors.  These interim results will be presented at the American Association for Cancer Research (AACR) Annual Meeting 2015, April 18-22.

“The goal of this phase I trial was to study the safety and feasibility of CART-meso cells in patients with mesothelin-expressing tumors,” says Janos L. Tanyi, MD, PhD, an assistant professor of Gynecologic Oncology. “We found no major adverse events associated with the treatment, which suggests that the patients tolerated it very well. But importantly, the T cells successfully targeted the patients’ tumor sites and survived in the blood stream for up to 28 days.”

The data that Tanyi will present at this conference will consist of scans and measurements acquired from five different patients; two of whom are suffering from ovarian cancer, two who have epithelial mesothelioma, and one with pancreatic cancer.  All five patients agreed to received the new investigational CART cell therapy.  Significantly, all the patients who received this therapy had cancers that stopped responding to conventional treatments.

CAR T cells are made from each patient’s T lymphocytes that are extracted from blood by a process known as “apheresis.”  T lymphocytes are isolated from the blood cells by cell sorting and then genetically modified to secrete a special protein that identifies and attacks tumor cells.  In this case, the cells were genetically engineered to target those cancer cells that express a protein called Mesothelin on their surfaces.  The engineered protein secreted by the engineered T cells could identify and kill them the tumor cells.  Even though Mesothelin is also found on the surfaces of the pleura (membranes that surround the lungs), the peritoneum (the lining that surrounds the abdominal cavity), and the pericardium (the scar that surrounds the heart),a variety of tumors express Mesothelin at such high levels that they are much more likely to be attacked by the CAR T cells that the normal tissues.

The preliminary results suggest the T cells did not attack normal tissues, but these patients must be followed up annually for 15 years in order to more closely observe the persistence of the CART-meso cells, their potential antitumor activity, and to better characterize their safety profiles.  Because the CAR T cells to not last indefinitely in the bloodstream, their ability to attack normal tissue should, theoretically at least, be minimal.

Using Polio Virus to Kill Deadly Brain Tumors

If you spend any time with people in retirement homes, they will sometimes tell you stories about their childhood and the dreaded “summer plague” known as polio. During the summer, children would go to ponds and lakes to swim in order to cool off from the summer heat. In those bodies of water, polio viruses would lurk, waiting to infect their new host. In most cases, infected people would experience a very flu-like disease that never went any further. In other cases, the flu-like disease might be more severe. Even in these people, the virus would be shed from the body by the digestive system and contaminate sewage water.

In rare cases, the central nervous system would be affected, but the aftermath of the disease would vary substantially.  Some  might some numbness for a little while. In a fraction of cases, they might actually experience paralysis that did not go away. The extent of this paralysis could vary tremendously. In some cases, people might retain the ability to walk, but with a limp. In other cases, they might not be able to walk at all. And in more severe cases, they might lose the ability to breathe on their own and require an iron lung to breathe for them. Polio struck young and old, male and female, rich and poor alike and was no respecter of persons.

The polio vaccines made by Jonas Salk (a formalin-killed vaccine) and the live vaccine made by Albert Sabin essentially eradicated polio in many countries and saved untold of millions of lives from suffering. In fact, Albert Sabin gave away the rights to his vaccine even though those rights could have made him a millionaire. Because his live vaccine could be given in a sugar cube, it was extremely easy and inexpensive to administer to large populations.

Albert Sabin

Given this history, why would clinicians reinstate a deadly virus to fight cancer? The answer is that polio viruses is a highly lytic virus, but it can be genetically manipulated to specifically attack cancer cells.

First a bit about the molecular biology of polio virus.  Polio virus is a member of a group of RNA viruses called the “picornaviruses.”  The name of this group comes from “pico” meaning small, “RNA” to refer to the type of nucleic acid found in the virus, and the virus to indicate the type of infectious agent that it happens to be.  Viruses are nucleic acid molecules encases in a protein capsid.  When ingested from contaminated water by drinking or simply putting your hands in your mouth, the polio virus binds to a cell surface protein called CD155 found in the intestinal walls.  It enters these cells and uncoats.  The RNA genome of the polio virus is then translated by ribosomes in the cell into a large protein.  This is a key feature of picornaviruses; their viral RNA genomes can serve as messenger RNAs that are directly translated into protein right after emerging from their capsids.

This large protein has the ability to process itself.  That processing comes in the form of clipping pieces of the protein into small pieces.  These smaller pieces have specific functions.  The first pieces are creatively called P1, P2 and P3 (you have to love those biochemists and their ability to dream up creative names – yes that was a joke).  Eventually, the viral proteinases (enzymes that clip proteins) 2A and 3C further process these three precursor proteins to form the viral capsid proteins VP1-4 (formed from P1) and the viral replication proteins 2A, 2B, 2C (formed from P2), 3A, 3B, 3C, and 3D (formed from P3). As mentioned before, 2A and 3C are proteinases, 3B is a protein called VPg, and 3D is RNA-dependent RNA polymerase that replicates the viral RNA into copies that are packaged into viral capsids.

The whole infection process is insidiously effective because there is a piece of RNA at the very front of the poliovirus genome called the IRES, which stands for the internal ribosome entry site.  This sequence of 400 to 500 bases directs the viral translation initiation step in a manner independent of whether or not there is a special cap-structure on the front end of the RNA.  It allows poliovirus RNAs to be effectively recognized by the host cell and the cell’s own mRNAs to not be well-recognized because the polio 2A protease degrades elements of the cell’s own translation machinery, which prevents the cell from recognizing its own mRNAs.

As it turns out, if you swap this IRES with IRESs from other types of viruses, you can change the types of cells that polio virus will infect.  In 2000, Eckard Wimmer and his group from the State University of New York at Stony Brook showed that substituting the polio virus IRES for that of the IRES from the common cold virus (Rhinovirus) allowed poliovirus to grow in cultured brain tumor cells (see Gromeier M, et al., Proc Natl Acad Sci U S A. 2000, 97(12): 6803–6808).  Since these tumors expressed CD155, the receptor for poliovirus, they could be infected with it.  Wimmer and his team made attenuated strains of these viruses and used them in non-human primates that had brain tumors.  When injected directly into the tumor, the viruses infected only the tumor cells, and grew poorly, but the immune response against the virus and the infected cells caused the tumors to aggressively shrink.

So Gromeier and his team collaborated with neuro-oncologists to use their engineered polio viruses to treat human patients with glioblastomas.  These are very aggressive cancers that usually end up killing the patient.  in a clinical trial, of 22 people enrolled in the trial, half are doing well, and several are considered to be in remission, which is pretty much unheard of for glioblastomas.

The news show 60 Minutes even did a piece on this treatment and interviewed two patients with aggressive glioblastomas were treated by this polio virus.  Their tumors have essentially disappeared.  In fact, the first person who was ever treated with this treatment is now cancer free.

While this is a small study, it was supposed to be a Phase I study that only determined safe dosages and safety parameters.  you do not expect patients to improve much in Phase I studies because you are still tweaking the treatment.  These results are astonishing.  Also, because it uses the patient’s own immune response against the infected cells it does not depend on massive alterations of the patient’s physiology.

This is a remarkable finding.  I hope it can be developed into something mainstream that turns out to be safe and effective.

How Our Own Immune Systems Aid the Spread of Breast Cancer

Our immune systems help us fight off diseases and invasions of our bodies by foreign organisms. How surprising might it be to learn that our immune systems actually help tumors spread through our bodies?

Dr. Karin de Visser and her team at the Netherlands Cancer Institute have discovered that breast tumors cells induce certain immune cells to enable the spread of cancer cells. They published their findings online on March 30 in the journal Nature.

About one in eight women will develop breast cancer in Western countries. Of those women who die of this disease, 90 percent of them die because the cancer has spread to other parts of their body and formed metastases. Given these grim facts, cancer researchers are spending a good deal of time, treasure and energy to understand how metastasis occurs. A few years ago, several cancer biologists reported that breast cancer patients who showed high numbers of immune cells called neutrophils in their blood show an increased risk of developing metastatic breast cancers. Immune cells like neutrophils are supposed to protect our body. Why then are high neutrophil levels linked to worse outcome in women with breast cancer?

Neutrophils in a blood smear amidst red blood cells.

 

Dr. Karin de Visser, group leader at the Netherlands Cancer Institute, and her team discovered that certain types of breast tumors use a signaling molecule called Interleukin-17 to initiate a domino effect of reactions within the immune system. The tumor cells stimulate the body to produce lots of neutrophils, which typically occurs during an inflammatory reaction. However, these tumor-induced neutrophils behave differently from normal neutrophils. These tumor-induced neutrophils block the actions of other immune cells, known as T cells. T cells are the cells that can (sometimes) recognize and kill cancer cells.

De Visser and her team went on to define the role of the signaling protein called interleukin-17 (or IL-17) in this process. “We saw in our experiments that IL-17 is crucial for the increased production of neutrophils”, says De Visser. “And not only that, it turns out that this is also the molecule that changes the behavior of the neutrophils, causing them to become T cell inhibitory.”

The first author of the Nature paper, postdoctoral researcher Seth Coffelt, showed the importance of the IL-17-neutrophil pathway when he inhibited the IL-17 pathway in a mouse model that mimics human breast cancer metastasis. When these neutrophils were inhibited, the animals developed much less metastases than animals from the control group, in which the IL-17-neutrophil route was not inhibited. “What’s notable is that blocking the IL-17-neutrophil route prevented the development of metastases, but did not affect the primary tumor,” De Visser comments. “So this could be a promising strategy to prevent the tumor from spreading.”

Inhibiting neutrophils would not be a prudent clinical strategy, since drugs that inhibit neutrophils would make patients susceptible to all kinds of infections. However, Inhibition of IL-17 might be a safer strategy. Fortunately, drugs that inhibit IL-17 already exist.  Presently, anti-IL-17 drugs are being tested in clinical trials as a treatment for inflammatory diseases, like psoriasis and rheumatism. Last month, the first anti-IL-17 based therapy for psoriasis patients was approved by the U.S. Federal Drug Administration (FDA). “It would be very interesting to investigate whether these already existing drugs are beneficial for breast cancer patients. It may be possible to turn these traitors of the immune system back towards the good side and prevent their ability to promote breast cancer metastasis,” De Visser says.

City of Hope Launches Alpha Clinics – A New Stem Cell Clinic

Cancer patients usually have three different options: surgery, chemotherapy and radiation therapy. None of these options elicits a great deal of confidence. A new study at City of Hope will officially open the Alpha Clinic for Cell Therapy and Innovation. At this center, patients battling cancer and other life-threatening diseases will have another option: stem cell-based therapy.

The Alpha Clinic, which officially opened March 19, is funded by an $8 million, five-year grant from the California Institute for Regenerative Medicine. This grant will also be supplemented by matching funds from City of Hope. The Alpha clinic will combine the uniquely patient-centered care for which City of Hope is well-known with the most innovative, stem cell-based therapies being studied to date. This approach will hopefully revolutionize the treatment of not only cancer, but also AIDS and other life-threatening diseases.

“We are in a new era of cellular therapy,” said John Zaia, M.D., the Aaron D. Miller and Edith Miller Chair in Gene Therapy, chair of the Department of Virology and principal investigator for the stem cell clinic. “The California Institute for Regenerative Medicine recognizes this, and they have been leading the field. Alpha Clinics like ours aim not only to provide research to benefit patients in the future, but also to get these innovative treatments running in real-life clinics to benefit patients now.”

The christening of City of Hope’s Alpha Clinic is the culmination of a decade of planning and visionary thinking. When the state of Californian voted to found the California Institute for Regenerative Medicine, the funds now became available to start the institute. New stem cell therapies are ready for clinical trials, and City of Hope is home to one of three Alpha Clinics in the state. The other two clinics are at the University of California San Diego and a joint clinic by University of California Los Angeles and University of California Irvine.

City of Hope’s first trials will study stem cell-based therapies for leukemia, and the use of neural stem cells to deliver treatments to brain tumors. The first such study will modify a patient’s own immune cells so that they can recognize and fight cancer cells. Cancer researchers hope the modified cells will be able to attack existing cancer cells, and also be able to attack the cancer again should it recur.

Brain cancer patients will also be able to enroll in a study that uses neural stem cells, which have an innate ability to home to tumor cells, as a delivery mechanisms for cancer drugs. Genetically engineered neural stem cells can bring targeted therapies across the blood-brain barrier, and can potentially deliver drugs directly to tumor sites, which eliminates systemic toxicity.

The US Food and Drug Administration (USFDA) has already approved a new HIV trial that will be conducted at the City of Hope Alpha Clinic. This trial will use “molecular scissors” known as zinc finger nucleases to edit the blood cells of HIV patients and remove a specific gene. Without this particular gene, the cells are unable to produce a protein that HIV requires in order to invade cells and replicate. The approach has the potential to eliminate HIV from the body.

“As we move forward with our Alpha Clinic, we will also be defining a new discipline in nursing of cellular therapy,” said Shirley Johnson, R.N., senior vice president, chief nursing and patient services officer at City of Hope. “This clinic is a unique opportunity to provide patients with the most leading-edge treatments while still giving them the compassionate comprehensive care City of Hope patients expect.”

The Alpha Clinic launched officially on March 19. Future trials will include T cell immunotherapy for blood cancer, new brain cancer therapies, treatments for breast cancer metastases and ovarian cancer treatments. Zaia said the clinic also plans to work with City of Hope’s diabetes researchers to introduce treatments for diabetes, exploring both the potential of pancreatic stem cells and preventing the immune system from attacking insulin-producing cells.