ihood 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.