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Learning of a cancer diagnosis has commonly brought with it not only fears for one’s health and one’s life, but the knowledge that the path to successful treatment was by no means easy or risk free.  Most chemotherapy and radiation treatments come at a high expense to the patient’s body—harming healthy cells right along with malicious cancer cells and putting patients at risk for other cancers or even other disease or health problems.  While in the best circumstances the end result is permanent elimination of cancer, in too many instances a few cancer cells survive and lead to relapse. Immunotherapy offers the potential to allow the body to kill the remaining resistant tumor cells.

“The concept of using the body’s immune system to attack cancer has been around for many years, but attempts to show its effectiveness in treatment were hampered by a lack of sufficient understanding of the complexities of the immune system,” says Gordon D. Ginder, M.D., director of VCU Massey Cancer Center. “Recent advances in the basic understanding of how immune cells recognize cancer cells and how to overcome mechanisms that block their ability to kill cancer cells have opened a whole new chapter in immunotherapy.”

New findings regarding the immune system have brought optimism about potentially less toxic, less invasive and more successful treatments—the essence of which already exists within the patient’s own body. This line of research is called biological therapy or immunotherapy. Immunotherapy is defined by the National Cancer Institute as “treatment to boost or restore the ability of the immune system to fight cancer, infections and other diseases.” It can also be used to improve outcomes while lessening side effects of other treatments.

Researchers studying immunotherapy as it relates to cancer are exploring how the body’s immune system works to stop or slow the growth of cancer cells, destroy cancer cells and/or keep cancer cells from spreading. The better they understand how the immune system is supposed to work, the better they can improve or treat malfunctions in the system that allow cancer to grow. “Basically, immunotherapy uses the capabilities that already exist in the human body’s and makes them more effective at fighting  cancer cells,” says Ginder. “This line of research offers great potential to improve cancer treatments while decreasing unwanted side effects. As such, it fits squarely with the goal of modern cancer therapy, which is find to find new ways to eliminate cancer more effectively and simultaneously offer better quality of life.”

At VCU Massey Cancer Center, immunotherapy has gained attention and funding across several research programs, including the Developmental Therapeutics, Cancer Molecular Genetics and Cancer Cell Signaling programs.

Developing a new “vaccine” for metastatic cancers

Massey researcher Xiang-Yang Wang, Ph.D., Harrison Scholar and member of the Cancer Molecular Genetics research program, has recently published results of a pre-clinical cutting-edge study in which an engineered immune modulator called Flagrp-170 was used to achieve localized vaccination on melanoma, prostate and colon tumors. Flagrp-170 consists of two distinct proteins. One of these proteins, known as Grp170, is currently being explored for use in the development of a “cancer vaccine,” because it has been shown to help the immune system recognize cancer cells that normally have the ability to suppress the body’s natural defense system. When combined with a fragment of another protein, flagellin, the immune system is activated in a unique way that promotes apoptosis, or cell suicide, in cancer cells.

Wang conducted a study that showed a positive response in animal models of melanoma, prostate and colon cancers. The study was recently published in Cancer Research, and Wang and his team continue to gain more understanding of the molecular mechanisms responsible for Flagrp-170’s therapeutic effects.  Additional studies are underway that hope to efficiently target and deliver the molecule to tumor sites for an even stronger response.

“This immunotherapy has the potential to be used alone or in combination with conventional cancer treatments to develop and establish immune protection against cancer and its metastases,” says Wang.

Tapping into T cells to combat breast cancer

Masoud Manjili, D.V.M., Ph.D., member of the Cancer Cell Signaling program at Massey, is also at the forefront of groundbreaking research on cancer immunotherapy by targeting and manipulating specific parts of cancer cells.

Manjili and his team focused on overcoming two major barriers of cancer immunotherapy:  tumor-induced T cell suppression and T cell-induced tumor editing and relapse. The T cells are a family of immune system cells that keep people healthy by identifying and launching attacks against threats such as bacteria, viruses or cancer. Anti-tumor T cells can both stop or slow down tumor growth on the one hand, but also cause changes in the tumor cells that could lead to tumor relapse on the other hand. “The ultimate goal of immunotherapy is to overcome tumor-induced immune suppression and at the same time induce tumor rejection without facilitating tumor escape and relapse,” says Manjili.

Through lab studies led by Manjili, Massey researchers effectively reprogrammed cells of the innate and adaptive immune systems to overcome a key cancer defense mechanism and develop long-lasting memory to reject breast cancer cells, guarding against tumor relapse. In a study published in the Journal of Immunology, the researchers discovered a way to improve Adoptive Cellular Therapy (ACT), a treatment for breast cancer that taps into the immune system, by activating certain cells which enhance T cells capability to fight blood-forming cells.

These findings could lead to clinical trials that test whether using immunotherapy in a neoadjuvant (prior to surgery) or adjuvant (after surgery) setting in breast cancer patients with a high risk of relapse could prime the patient’s immune system, much like a vaccine, to prevent the likelihood of relapse.

Unlocking new treatments for blood cancers

Translating Manjili’s research into clinical application is Amir Toor, M.D., hematologist-oncologist in the Bone Marrow Transplant Program and research member of the Developmental Therapeutics program at Massey. Toor’s research concentrates on training the immune system to prevent cancer cells from evading detection and destruction. Focusing on T cells and the important role they play in warding off cancer cells, Toor and his team of investigators launched a two-pronged approach.

The first step was directed at developing safe and non-toxic treatments to perform allogeneic (donor) stem cell transplantation. The second step involved understanding the donor immune system's response to cancer in donor stem cell transplantation to develop a way to train the patient's immune system to attack the cancer cells, ultimately allowing the patient to benefit from the immunotherapeutic effect without the accompanying risk.

The clinical trials developing these ideas have focused on utilizing either the donor's or the patient's own T cells to kill cancer cells. Toor says that the process works much like locks and keys. “The small antigens on the surface of foreign cells are keys and each T cell has a receptor or a lock,” he says. “If the antigen on the threatening cell fits in the T cell receptor, then the lock is released and the T cell’s deadly arsenal is unleashed on the threat. For the recipients, the keys are proteins unique to the patient and are absent in the donor, thus becoming targets for the donor T cells.”

Another Phase II clinical trial led by Toor is showing promise in providing lasting protection against the progression of multiple myeloma following an autologous (self) stem cell transplant. Exemplifying the lock and key analogy, a combination of two drugs is trying to make cancer cells easier targets. The first drug, azacitidine, forces the cancer cells to express proteins – the keys – which the patient’s T cells – the locks – recognize as foreign. The second drug, lenalidomid, boosts the production of the T cells to recognize and attack the foreign cancer cells (see Figure above.)

In short, Toor is harnessing the immune system to improve stem cell transplant outcomes while gaining mechanistic insights into the process. The approach, which has led to a number of publications and is gaining national attention, is now being used to treat a number of cancers, including leukemia and multiple myeloma. To date, this therapy has benefitted more than 50 cancer patients treated at Massey.

Toor is also collaborating with Manjili and Gregory Buck, Ph.D., VCU Center for Genome Complexity, in an effort to catalogue the entire library of antigens that differ between stem cell donors and transplant recipients enrolled in a Phase II clinical trial. Through this project, the researchers hope to expand the selection of stem cell donors for those needing transplants.

Written by: Massey Communications Office