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.

CAR Immune Cells to Treat Childhood Cancers


In clinical trials, cancer treatments that use genetically modified versions of a patient’s own cells to specifically target the disease have remarkable results. The next step for these companies that spent enormous amounts of time, capital, and intellectual energy inventing and designing these treatments is to get them into hospitals despite their enormous price tags.

Novartic CAR T-Cell therapy

In two separate clinical trials, one sponsored by the Swiss company Novalis AG and another by the Seattle-based biotech company Juno Therapeutics Inc., close to 90% of all patients saw their leukemia completely disappear after being given experimental “CAR” or “chimeric antigen receptor” T-cell therapies.

Both trials examined small numbers of patients (22 children in the Novartis trial and 16 adults in the Juno trial). These patients had acute lymphoblastic leukemia, which is the most common childhood cancer. All of them had also not responded to the available standard treatments. Consequently, both companies are now conducting larger trials.

“CAR T cells are probably one of the most exciting concepts and fields to come out in cancer in a very, very long time,” says Dr. Daniel DeAngelo, a Boston-based hematologist and associate professor of medicine at Harvard Medical School, who wasn’t involved in either study.

Usman Azam, head of cell and gene therapies at Novartis, calls the therapies “critically important” for Novartis. “I think that a cure for cancers such as leukemia and lymphoma through a CAR technology is plausible,” said Dr. Azam in an interview with The Wall Street Journal. “Our job is to get this into patients as soon as we feasibly can.”

Novatis created a new research unit headed by Dr. Azam. Novartis’ rationale is to accelerate the advent of CAR T-Cell Therapy to medical markets. The U.S. Food and Drug Administration (US FDA) granted Novartis’ leading CAR therapy “breakthrough” designation in July of 2014. Presently Novartis wants to file it with regulators in 2016.

CAR therapies use the patient’s own immune system to fight the cancer, but with a genetic-engineering twist. “Immunotherapies,” culture immune cells from the patient and manipulate them in culture to sensitize them to the cancer. CAR therapies extract T-cells, which are disease-fighting white blood cells, from a patient’s blood. These T-cells are then genetically engineered and grown in a laboratory for around 10 days and reintroduced into the patient.

The T-cells are usually infected with a hamstrung virus that can introduce genes into cells but cannot productively infect them. These recombinant viruses endows the T-cells with genes that encode chimeric antigen receptors, or CARs. CARS bind specifically to proteins on the surface of malignant cancer cells. Once attached to the cancer cells, the T-cells can kill them very effectively.

Both Novartis and Juno are tapping academic scientists to develop their treatments. For example, Novartis has teamed with the University of Pennsylvania and Juno has formed a formal relationships with scientists at Memorial Sloan-Kettering Cancer Center in New York, Seattle Children’s Hospital and the Fred Hutchinson Cancer Research Center, which is also in Seattle.

Even though Novartis and Juno will probably be the first to bring their immunotherapies to the market, other companies are also in the hunt to bring similar therapies to medical markets. Pfizer Inc., Kite Pharma Inc., and Celgene Corp., which is working in collaboration with Bluebird Bio Inc. all are developing competing strategies.

“Competition will keep all of the companies involved on their toes,” said Hans Bishop, Juno’s chief executive.

Unfortunately, CAR therapies still have a few unanswered questions surrounding them. For example: “How long do they last?” Given the small numbers of patients who have been treated with these treatments to date, it is very hard to tell with the available data. Another confounding factor is that those patients in the previous clinical trials whose cancer went into remission after the CAR therapies then became eligible for stem-cell transplants, which can also prolong survival.

Secondly, a potentially dangerous side effect called “cytokine-release syndrome,” shows the therapy is working, but can cause a sharp drop in blood pressure and a surge in the heart rate. The deaths of two patients in a Juno-backed Sloan-Kettering trial in March caused a temporary halt in the study because of worries over these particular adverse reactions.  “Patients need to be healthy enough to combat that side effect,” says Mr. Bishop, who thinks it is now manageable. Patients are once again being recruited for this trial, and patients with a risk of heart failure are excluded, and the modified cell dose for patients with very advanced leukemia also has been lowered.

But largest hurdle of all will probably be the cost of these therapies. Since they are a genetically engineered product, CAR T-cells are very complex to manufacture; each batch is composed of unique, personalized T-cells that were made from a patient’s own blood cells. The inability to mass-produce CAR T-cells will definitely increase the price companies charge for them.

“What we’re talking about here is a single, very expensive therapy that’s used once for a specific patient and is not generalizable,” says Dr. Malcolm Brenner, director of the Center for Cell and Gene Therapy at the Texas Children’s Hospital in Houston, who, in MArch, signed an agreement to commercialize his own CAR research with Celgene.

Novartis and Juno both insist that it is too early to speculate on the price of the treatment, but Dr. Usman agrees the challenge is getting the manufacturing process to “a viable level where it’s both affordable and attractive.”

Citigroup believes CAR therapies could cost in excess of $500,000 per patient, which it notes is roughly in line with the cost of a stem cell transplant, even though most analysts think it is too early to estimate potential revenue or price.

“This technology needs to be widely developed and accessible to patients,” says Dr. DeAngelo. “If the cost is going to be a hindrance, it’s going to be a really sad day.”

Scalability and cost are one reason Pfizer is taking a different approach to this field. “We would like to take it to the next level, where CAR therapies become a more standardized, highly controlled treatment,” said Mikael Dolsten, Pfizer’s head of global research and development.

Working with French biotech Cellectis SA, Pfizer wants to develop a generic CAR therapy for use in any patient. While this will certainly lower the cost of the treatment, since it is the result of a mass-produced, off-the-shelf-product, this work is still at the preclinical stages and may not work in humans.

Global head of health-care research at Société Générale, Stephen McGarry, thinks that the revolutionary treatments being developed by Novartis and Juno could justify “astronomical” prices, he believes health-care payers and patients will probably protest such high prices. “When you look at the initial data with the Novartis therapy, you’re getting cures in some kids—what do you charge for that?” he asks.

Rejuvenating the Blood of Older People With New Stem Cells


Like it or not, the blood of young people and older people is different. Can the blood of an older person be rejuvenated and made young again?

In an article published recently by the scientific journal Blood, a research group at Lund University in Sweden details a series of experiments in which they rejuvenated the blood of mice by reversing, or re-programming, the blood cell-making stem cells.

Stem cell populations throughout the body form and replace cells in the body and help repair organs. Stem cells have the capability to divide an unlimited number of times, and when they divide, one cell remains a stem cell and the other matures into another cell type needed by the body.

Martin Wahlestedt, a doctoral student in stem cell biology at the Faculty of Medicine at Lund University, and principal author of the article explained, “Our ageing process is a consequence of changes in our stem cells over time.” Wahlestedt continued, “Some of the changes are irreversible, for example damage to the stem cells’ DNA, and some could be gradual changes, known as epigenetic changes, that are not necessarily irreversible, even if they are maintained through multiple cell divisions. When the stem cells are re-programmed, as we have done, the epigenetic changes are cancelled.”

Shinya Yamanaka was awarded the Nobel Prize in Medicine last year for this very discovery.

Blood composition changes as we age. For example, blood from a young person contains a certain mix of B- and T-lymphocytes and myeloid cells, but in older people, according to Wahlestedt, “In older people, the number of B- and T-lymphocytes falls, while the number of myeloid cells increases.” Therefore, when an elderly person is affected by leukemia, the cancer usually originates in the myeloid cells, since the elderly have more myeloid cells. Being able to refurbish the blood, as Martin and his colleagues have done in their mouse studies, therefore, presents interesting possibilities for future treatment.

“There is a lot of focus on how stem cells could be used in different treatments, but all that they are routinely used for in clinical work today is bone marrow transplants for diseases where the blood and immune systems have to be regenerated”, said Martin Wahlestedt, continuing:  “A critical factor that gives an indication of whether the procedure is going to work or not is the age of the bone marrow donor. By reversing the development of the stem cells in the bone marrow, it may be possible to avoid negative age-related changes.”

Even if the composition of the blood in old and young mice is remarkably like that in young and elderly people, Martin Wahlestedt stressed that at this stage; the technology is only at the basic research stage and is far from a functioning treatment. The research group is pleased with the results, because they indicate that it may not primarily be damage to DNA that causes blood to age, but rather the reversible epigenetic changes.

Keeping Stem Cells Stem Cells


Chengcheng Zhang is an assistant professor in the UT Southwestern Medical Center departments of physiology and developmental biology in Dallas, Texas. His lab has identified a receptor on the surface of cancer stem cells that, when activated, prevents them from differentiating.

Zhang explains his work this way: “Cancer cells grow rapidly in part because they fail to differentiate into mature cells. Drugs that induce differentiation can be used to treat cancers.” In his however has identified a new target for cancer: “Our research has identified a protein receptor on cancer cells that induces differentiation, and knowing the identity of this protein should facilitate the development of new drugs to treat cancers.”

The receptor to which Zhang is referring is a member of a family of proteins known as the “leukocyte immunoglobulin-like receptors.” These LIRs, as they are called, have bits located outside the cell and help regulate cells of the immune system. The LIR that Zhang’s lab found is called the subfamily B member 2 or LILRB2. LILRB2 is found on the surface of immune cells where it binds to molecules on the surface of cells that process antigens (foreign substances in the body) and prevents the initiation of an immune response. LILRB2 also has a newly-described role in stem cell biology.

Zhang again: “The receptor we identified turned out to be a protein called a classical immune inhibitory receptor, which is known to maintain stemness of normal adult stem cells and to be important in the development of leukemia.”

What does Zhang mean by “stemness?” He is referring to the potential of a bone marrow stem cell that makes blood cells to develop into different kinds of cells and replenish red blood cells lost to wear and tear or injury. Once stem cells differentiate into adult cells, they cannot return to their original stem cell state. The body seems to only have a finite number of stem cells and, therefore, depleting them is unwise.

Before Zhang’s study, there was no indication that LILRB2 could bind to anything but surface proteins on antigen-presenting cells, but Zhang and his team has discovered a new function for LILRB2. LILRB2 can bind to members of a poorly understood group of proteins known as angiopoietic-like proteins that support stem cell growth. By binding angiopoietic-like proteins, LILRB2 sends a signal to the interior of the stem cell to not differentiate. This inhibition keeps cancer stem cells from differentiating. By not differentiating, the stem cells divide furiously and never differentiate and make progeny cells that also divide many times and do not differentiate. This is the main mechanism that drives the progression of leukemia.

Zhang said that this inhibition does not cause cancer stem cells to make new stem cells but does not preserve their potential to do so. Also, making inhibitors that prevent the interaction between angiopoietin-like proteins and LILRB2 can force cancer stem cells to differentiate. Thus these new findings may give us a target for fighting leukemia.