Spreading the success of cancer immunotherapy beyond those patients currently enjoying powerful, long-term responses to treatment requires greater understanding of the immune response to tumors, two leaders in the field note in a review in Science.
“Identifying in advance who will benefit from treatment and developing combination therapies to improve and expand on current results will require us to decipher the dynamics of human immune response to tumors and their surrounding microenvironment,” said co-author Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology at The University of Texas MD Anderson Cancer Center.
Immune checkpoint blockade, the unleashing of immune response against cancer by blocking molecules on T cells that shut down those attacking cells, produces durable results and long-term survival in a substantial fraction of patients with some cancers. For example, 22 percent of advanced melanoma patients treated with ipilimumab (Yervoy®), the first checkpoint inhibitor, live for four years or longer. Right now there’s no way to identify those most likely to benefit.
Ipilimumab and a second group of drugs that thwart a different brake on the immune system both set off a complicated cascade of events, said co-author Jim Allison, Ph.D., chair of Immunology at MD Anderson, who pioneered checkpoint blockade as a cancer therapy.
“We know the constantly evolving nature of immune responses makes it highly unlikely that a single biomarker could predict a patient’s response to one of these drugs,” Allison said. The goal should be to develop biomarker panels to help cultivate combination therapies and then examine tumor tissues for changes in those biomarkers to increase treatment impact.
Allison is executive director and Sharma scientific director of the immunotherapy platform for MD Anderson’s Moon Shots Program. The program is designed to accelerate the conversion of scientific discoveries into clinical advances that significantly reduce cancer deaths. The platform has conducted immune monitoring analysis of tumor tissues in more than 50 MD Anderson clinical trials in the past two-plus years.
Barriers to T cell activation and attack
Targeted cancer therapies, designed to hit specific mutations on a cancer cell, come with ready-made predictive biomarkers. Patients whose tumors have the mutation receive the targeted therapy. In contrast, immune checkpoint blockade doesn’t directly target tumors. It treats the immune system, freeing it to find and kill cells bearing recognized tumor antigens.
Immune response, the authors note, particularly regulation of T cells, consists of opposing pathways both to stimulate immune response and to inhibit it. Ipilimumab blocks a molecule on T cells called CTLA-4, which is turned on by the same binding molecules, or ligands, that stimulate a T cell response. CTLA-4′s job is to block runaway immune response.
Research was funded by the Stand Up to Cancer Immunotherapy Dream Team grant, Prostate Cancer Foundation Challenge Grant in Immunology, the National Cancer Institute of the National Institutes of Health (CA1633793-01) and the Cancer Prevention and Research Institute of Texas (CPRIT).
Sharma and Allison are founders and advisors for Jounce Therapeutics. Sharma is a consultant to Bristol-Myers Squibb, Amgen and GlaxoSmithKline. Allison is an inventor of immunotherapy intellectual property owned by the University of California, Berkeley, and licensed to Bristol-Myers Squibb and has received royalties. These relationships are managed in accordance with MD Anderson’s conflict-of-interest policies.