SU2C Dream Teams
SU2C-CRI Dream Team: Immune Checkpoint Blockade and Adoptive Cell Transfer in Cancer Therapy
Dream Team Leaders
James P. Allison, Ph.D.
Chairman, Dept. of Immunology; Director of Immunotherapy Platform and Co-Director of David H. Koch Center for Applied Research of Genitourinary Cancers at the Univ. of Texas MD Anderson Cancer Center
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Antoni Ribas, M.D., Ph.D.
Professor, Medicine, Surgery and Molecular and Medical Pharmacology; Director, Tumor Immunology Program Area, Jonsson Comprehensive Cancer Center
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Drew M. Pardoll, M.D., Ph.D.
Director, Division of Immunology; Professor, Departments of Oncology, Medicine, Pathology and Molecular Biology and Genetics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
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Cassian Yee, M.D.
Member, Clinical Research Division at Fred Hutchinson Cancer Research Center; Professor of Medicine at the University of Washington School of Medicine
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“The patient’s own immune system can be harnessed to treat some cancers. The SU2C-CRI Dream Team grant will help develop this mode of treatment to more broadly benefit patients.” – Antoni Ribas, M.D., Ph.D
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, scientists use a type of white blood cell called a T lymphocyte from the patient to kill the cancer cells. These T lymphocytes have receptors (TCR) on their surface that activate the T lymphocytes and allow them to recognize and specifically target cancer cells. However, under normal biological conditions, only limited numbers of T lymphocytes are activated. Additionally, this anticancer process can be blocked by specific inhibitory molecules called checkpoints, some of which are expressed by the cancer cells themselves. Checkpoints act like the parking brake of a car, stopping the process that T lymphocytes use to kill cancer cells.
The Dream Team will focus on two approaches to overcome these obstacles. First, they will investigate checkpoint blockade where they hope to “disable the brakes.” The Dream Team will investigate the use of antibodies to remove the checkpoints, once again allowing T lymphocytes to kill the cancer cells.
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, where a large army of cancer-specific T lymphocytes is generated from a cancer patient’s samples and given back to the patient. One approach 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 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.
Watch a short video in which the SU2C-CRI Immunology Dream Team leaders Allison and Ribas talk more about the science behind their project: