Cancer immunologists have long hypothesized that specific interventions could stimulate and “re-educate” patients’ own immune systems to attack their cancer. In one approach of immunology-based cancer treatment, what kills cancer cells is a type of white blood cell called the T lymphocyte. These T lymphocytes have receptors (TCRs) on their surface that activate the T lymphocytes and allow them to recognize and specifically target cancer cells. Expanding these T lymphocytes outside the body, engineering them to be more potent and reinfusing these souped up anti-cancer lymphocytes into patients – a process termed adoptive cell therapy or ACT - is like adding more soldiers to the immune army. However, lymphocytes also have inhibitory receptors, termed checkpoints, that put the brakes on immune responses. Cancers exploit these checkpoints to resist immune attack by the anti-tumor lymphocytes.
The Dream Team will focus on two approaches to overcome these obstacles. First, they will investigate checkpoint blockade, where the checkpoints are inhibited with specific antibodies, disabling the brakes and allowing the immune system to get the upper hand. To do this, they will analyze tumor samples to determine checkpoint expression in tumors before and after checkpoint blockade or adoptive cell transfer (ACT), possible synergistic treatment combinations, and biomarkers that may be able to predict response or resistance to therapy. In addition, based on previous research, the Dream Team will investigate whether a combination treatment of a specific checkpoint blockade (anti-CTLA-4) and inhibition of tumor blood vessel formation will improve patient outcomes. Furthermore, they will test the hypothesis that multiple T lymphocyte targets are expressed by tumor cells.
Second, the team will pursue multiple ACT approaches. One method is to start from a few T lymphocytes with the desired ability to recognize and kill cancer, grow them in the laboratory, and then give them to the patient. Another way is to use gene transfer techniques to take the TCR from one T lymphocyte that is cancer-specific and insert it into many other T lymphocytes that then become cancer-specific. The team will also use artificial receptors based on antibodies, termed chimeric antigen receptors (CAR) to redirect the killing ability of T cells and restrict it to cancer cells.
The Dream Team will jointly address key factors currently limiting the efficacy and wide applicability of tumor immunotherapy. The clinical impact of this project lies with the potential synergy of combining checkpoint blockade and ACT to treat a range of tumor types to improve the lives of patients with cancer.
Glenn Dranoff, MD, Dana-Farber Cancer Institute, Boston, Mass.
Philip D. Greenberg, M.D., Fred Hutchinson Cancer Research Center, Seattle, Wash.
James R. Heath, PhD, California Institute of Technology (CalTech)
Michel Sadelain, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York, N.Y.
Ton Schumacher, PhD, Netherlands Cancer Institute, Amsterdam, The Netherlands
Jedd D. Wolchok, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York, N.Y.