Titles and Affiliations
Associate Member and Attending Physician
Research Area
Expanding and enhancing immunotherapy options for patients with breast cancer.
Impact
Immune checkpoint inhibitors have changed cancer care, but most breast cancers do not respond because they lack enough immune cells that can recognize and attack the tumor. Adoptive cell transfer (ACT) can solve this by reprogramming a patient’s immune cells to recognize and destroy cancer cells. ACT approaches have already shown remarkable success in blood cancers like leukemia and lymphoma, with some patients achieving long-term remission. Dr. Klebanoff and his team have identified a potent immune cell receptor that targets the most common mutation (R175H) in TP53, the gene most often mutated in breast cancer. TP53 mutations produce abnormal protein fragments that are displayed on the cell surface, making it an ideal target for ACT. These pre-clinical experiments are paving the way for a first-of-its-kind therapy that could bring the benefits of immunotherapy to more patients with breast cancer.
Progress Thus Far
Dr. Klebanoff and his team identified and studied a set of T cell receptors, the molecules immune cells use to recognize and target specific threats, that are capable of specifically detecting cancer cells carrying the TP53 (R175H) mutation. Through careful laboratory testing, they selected one receptor that showed strong cancer-killing activity while minimizing effects on healthy tissue, supporting its potential to be developed further as a treatment.
What’s Next
The team will complete final safety studies to confirm that the engineered immune cells do not attack healthy tissue or trigger unintended immune reactions. They will also work to address two common challenges facing this kind of therapy. Engineered immune cells can lose their effectiveness over time inside a tumor, and tumors can sometimes evade immune attack altogether. The team will test whether adding a natural immune signaling molecule can help engineered immune cells stay active longer, while also activating a second type of immune cell capable of eliminating cancer cells that manage to escape the primary treatment. These steps are necessary to prepare for a clinical trial testing whether precision-engineered immune cells can safely and effectively treat breast cancer in patients.
Biography
Christopher Klebanoff, MD is a cellular immunologist and medical oncologist with over 20 years of experience in the pre-clinical and early clinical development of T cell-based immunotherapies for the treatment of cancer. Prior to joining Memorial Sloan Kettering and the Parker Institute for Cancer Immunotherapy in 2016, he was a Howard Hughes Medical Institute Research Scholar and Assistant Clinical Investigator at the National Cancer Institute in Bethesda, Maryland.
Dr. Klebanoff pioneered the paradigm that T cell subsets with the memory-like attributes of self-renewal and multipotency are a critical determinant for adoptive immunotherapy efficacy. Further, he resolved how host lymphodepletion – a standard practice for nearly all cellular immunotherapies – enhances the potency of adoptively transferred T cells through the removal of homeostatic cytokine “sinks.” The Klebanoff laboratory is currently focused on the discovery and immunologic targeting of shared neoantigens resulting from recurrently mutated driver genes using TCR gene therapy.
Clinically, Dr. Klebanoff has contributed to the successful early phase development of numerous T cell-based therapies. These include an anti-CD19 chimeric antigen receptor (CAR) that would become FDA approved (Yescarta®), tumor infiltrating lymphocyte therapy for the treatment of melanoma (Lifileucel) and other common cancers, and TCR gene therapies targeting epitopes derived from NY-ESO-1 (Letetresgene), MAGE-A3, and HPV16.
Dr. Klebanoff is an elected member of the American Society for Clinical Investigation and recipient of several prestigious awards, including the Damon Runyon Clinical Investigator Award and a National Institutes of Health MERIT Award. Multiple technologies developed in his laboratory have been licensed to biotechnology companies and he is a scientific co-founder of Affini-T Therapeutics.
