TO PUT THAT INTO CONTEXT
Elizabeth M. Jaffee, MD
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, MarylandWhat Are the Key Factors Driving Successes in Immunotherapy? Immune-responsive cancers naturally attract T cells, and these cancers have higher burdens of genetic mutations that produce neoantigens recognized by T cells. These T cells infiltrate the tumor but are inhibited from functioning because immune checkpoint signals are turned on by suppressive mechanisms. Immune checkpoint inhibitors allow full function of these T cells. Unfortunately, most gastrointestinal (GI) cancers have lower mutation burdens and few T cells, and are less likely to respond to these agents. But there are ways to convert GI cancers into immune-responsive cancers.How Do We Turn GI Cancers Into Immunogenic Cancers? Therapeutic vaccines are the most efficient way to induce T cells, although local radiation and chemotherapy also expose proteins that can be recognized by the immune system. We don’t yet know which antigens are the best tumor rejection antigens for most GI cancers, nor do we know how to best deliver radiation and chemotherapy (type, dosing, and schedule) for this purpose. We do know that vaccines can induce T-cell infiltration, prolonging tumor recurrence in pancreatic cancer patients with mesothelin-expressing tumors.[1-3] Such vaccines work together with immune-modulating agents like anti-cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) to cause regressions. Clinical trials are underway in GI cancers to determine which immune checkpoint inhibitors are most effective in combination with T-cell–inducing therapies. Agents inhibiting multiple immune- and non–immune-suppressive cells, including myeloid-derived cells, T cells, and stromal cells (vascular, neuronal, smooth muscle, and fibroblasts), are under development in GI cancers to determine the best combinations. In the future, we will use biopsies to determine the patient-specific immune checkpoint inhibitors required to successfully treat each patient. Multiple immune checkpoints will be needed to facilitate T-cell function induced by vaccines, chemotherapy, or radiation therapy, or adoptively transferred as genetically engineered T cells.Financial Disclosure: Dr. Jaffee receives research funding from Aduro Biotech, Bristol-Myers Squibb, and Roche.References1. Le DT, Wang-Gillam A, Picozzi V, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33:1325-33.2. Lutz ER, Wu AA, Bigelow E, et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res. 2014;2:616-31.3. Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013;36:382-9.