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.

Adult Stem Cells Suppress Cancerous Growth While Dormant


William Lowry and his postdoctoral fellow Andrew White at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have discovered the means by which particular adult stem cells suppress their ability to trigger skin cancer during their dormant phase. A better understanding of this mechanism could provide the foundation to better cancer-prevention strategies.

This study was published online Dec. 15 in the journal Nature Cell Biology. William Lowry, Ph.D. is an associate professor of molecular, cell and developmental biology in the UCLA College of Letters and Science.

Hair follicle stem cells are those tissue-specific adult stem cells that generate the hair follicles. Unfortunately, they also are the cell population from which cutaneous squamous cell carcinoma, a common skin cancer, begins. However, these stem cells cycle between active periods, when they grow, and dormant periods, when they do not grow.

Diagram of the hair follicle and cell lineages supplied by epidermal stem cells. A compartment of multipotent stem cells is located in the bulge, which lies in the outer root sheath (ORS) just below the sebaceous gland. Contiguous with the basal layer of the epidermis, the ORS forms the external sheath of the hair follicle. The interior or the inner root sheath (IRS) forms the channel for the hair; as the hair shaft nears the skin surface, the IRS degenerates, liberating its attachments to the hair. The hair shaft and IRS are derived from the matrix, the transiently amplifying cells of the hair follicle. The matrix surrounds the dermal papilla, a cluster of specialized mesenchymal cells in the hair bulb. The multipotent stem cells found in the bulge are thought to contribute to the lineages of the hair follicle, sebaceous gland, and the epidermis (see red dashed lines). Transiently amplifying progeny of bulge stem cells in each of these regions differentiates as shown (see green dashed lines).
Diagram of the hair follicle and cell lineages supplied by epidermal stem cells. A compartment of multipotent stem cells is located in the bulge, which lies in the outer root sheath (ORS) just below the sebaceous gland. Contiguous with the basal layer of the epidermis, the ORS forms the external sheath of the hair follicle. The interior or the inner root sheath (IRS) forms the channel for the hair; as the hair shaft nears the skin surface, the IRS degenerates, liberating its attachments to the hair. The hair shaft and IRS are derived from the matrix, the transiently amplifying cells of the hair follicle. The matrix surrounds the dermal papilla, a cluster of specialized mesenchymal cells in the hair bulb. The multipotent stem cells found in the bulge are thought to contribute to the lineages of the hair follicle, sebaceous gland, and the epidermis (see red dashed lines). Transiently amplifying progeny of bulge stem cells in each of these regions differentiates as shown (see green dashed lines).

White and Lowry used transgenic mouse models for their work, and they inserted cancer-causing genes into these mice that were only expressed in their hair follicle stem cells. During the dormant phase, the hair follicle stem cells were not able to initiate skin cancer, but once they transitioned into their active period, they began growing cancer.

Dr. White explained it this way: “We found that this tumor suppression via adult stem cell quiescence was mediated by PTEN (phosphatase and tensin homolog), a gene important in regulating the cell’s response to signaling pathways. Therefore, stem cell quiescence is a novel form of tumor suppression in hair follicle stem cells, and PTEN must be present for the suppression to work.”

Retinoids are used to treat certain types of leukemias because they drive the cancer cells to differentiate and cease dividing. Likewise, understanding cancer suppression by inducing quiescence could, potentially, better inform preventative strategies for certain patients who are at higher risk for cancers. For example, organ transplant recipients are particularly susceptible to squamous cell carcinoma, as are those patients who are taking the drug vemurafenib (Zelboraf) for melanoma (another type of skin cancer). This study also might reveal parallels between squamous cell carcinoma and other cancers in which stem cells have a quiescent phase.

A Gene that Prevents Induced Pluripotent Stem Cell Formation Linked to Cancer Severity


A Mount Sinai research team has published some remarkable observations in the journal Nature Communications. Emily Bernstein, PhD, and her team at Mount Sinai have discovered a particular protein that prevents normal cells from being reprogrammed into induced pluripotent stem cells (iPSCs). Since iPSCs resemble embryonic stem cells, these data might provide significant insights into how cells lose their plasticity during normal development, which has wide-reaching implications for how cells change during both normal and disease development.

Previously, Bernstein and others showed that during the formation of particular tumors known as melanomas in mice and human patients, the loss of a specific histone variant called macroH2A (a protein that helps package DNA) correlated rather strongly to the growth and metastasis of the tumor. In this current study, Bernstein and her team determined if macroH2A acted as a barrier to cellular reprogramming during the derivation of iPSCs (see Costanzi C, Pehrson JR (1998). “Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals”. Nature 393 (6685): 599–601).

In collaboration with researchers at the University of Pennsylvania, Bernstein evaluated mice that had been genetically engineered to lack macroH2A. When skin cells were used from macroH2A(-) mice were used to make iPSCs and compared with skin cells from macroH2A(+) mice, the cells from macroH2A(-) mice that lacked macroH2A were much more plastic and were much more easily reprogrammed into iPSCs compared to the wild-type or macroH2A(+) mice. This indicates that macroH2A may block cellular reprogramming by silencing genes required for plasticity.

Bernstein, who is an Assistant Professor of Oncological Sciences and Dermatology at the Graduate School of Biomedical Sciences at Mount Sinai, and corresponding author of the study, said: “This is the first evidence of the involvement of a histone variant protein as an epigenetic barrier to induced pluripotency (iPS) reprogramming.” She continued: “These findings help us to understand the progression of different cancers and how macroH2A might be acting as a barrier to tumor development.”

In their next group of experiments, Bernstein and her team plan to create cancer cells in a culture dish by inducing mutations in genes that are commonly abnormal in particular types of cancer cells and then couple those mutations to the removal of macroH2A to examine whether the cells are capable of forming tumors.