TARGETING IMMUNE SYSTEM CHECKPOINTS
Much recent excitement in oncology has been generated by cancer immunotherapy approaches that target immune system checkpoints. When a T cell interacts with an antigen-presenting cell, the downstream T cell responses are affected by both costimulatory and coinhibitory signals. Coinhibitory signals include cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor-1 (PD-1), along with programmed death receptor ligand-1 and -2 (PD-L1 and PD-L2). Strategies targeting these inhibitory signals are potentially very powerful because cancer exploits these checkpoints to grow unchecked. Blocking these checkpoints unblocks the immune system, and current results indicate that it is producing durable responses. An important challenge with these treatments is that the unchecked immune system results in immune-related adverse events (irAEs).
By blocking the checkpoints, the cancer is less able to suppress the immune system, and then the immune system can more effectively fight the cancer. Treatments targeting these immune checkpoints are being investigated for solid tumors, melanoma, renal cell cancer, non-small cell lung cancer, hepatocellular carcinoma, prostate cancer, glioma, glioblastoma multiforme, pancreatic cancer, triple-negative breast cancer, gastric cancer, urothelial cancer, head and neck cancers, and colorectal cancer.11
The first FDA-approved treatment that blocks immune checkpoints was ipilimumab (Yervoy). Ipilimumab is a monoclonal antibody to CTLA-4 indicated for the treatment of metastatic melanoma, based on a phase III trial in which ipilimumab increased median overall survival by 3.6 months, to 10.0 months instead of the 6.4 months for patients who did not receive the agent.12 Of interest with CTLA-4 blockades, complete tumor regression for a prolonged duration occurred in most of the few patients who achieved complete tumor regression.13 However, 10% to 15% of patients treated with ipilimumab in the first phase III trial experienced severe or life-threatening toxicity. The irAEs most commonly experienced were diarrhea, enterocolitis, hepatitis, dermatitis, and endocrinopathies. These typically occurred several weeks into the course of treatment. Also, patients who experienced refractory or severe irAEs required immunosuppressants, increasing their risk for opportunistic infections.
Combining ipilimumab with GM-CSF resulted in improved overall survival in a recent phase II study with 245 patients with metastatic melanoma. The median overall survival was 17.5 months with the combination versus 12.7 months with ipilimumab alone.14 The 1-year survival rates were 68.9% with the combination and 52.9% with ipilimumab alone. These results suggest synergy between the two treatments. The combination resulted in fewer grade 3-5 adverse events in the combination arm (45% of patients) than in the ipilimumab alone arm (58% of patients).
Recent reports have described combining ipilimumab with nivolumab, an antibody against the immune checkpoint PD-1. A small phase III trial of this combination in 53 patients with advanced melanoma resulted in a 2-year survival rate of 75%.15 More than half (62%) of the patients experienced grade 3 or 4 adverse events, with the most common ones being elevated levels of lipase, aspartate aminotransferase, and alanine aminotransferase.15,16 These rates of adverse events were higher than the rates with either treatment alone. Notably, the majority of the patients had durable responses.
Monoclonal antibodies targeting PD-L1 are also in development.13 These, as with the other checkpoint inhibitors, are being tested against a variety of tumors, including non-small cell lung cancer, melanoma, colorectal cancer, renal cell carcinoma, ovarian cancer, pancreatic cancer, and breast cancer.
New approaches are being developed to measure response to checkpoint blockades because response measures that are appropriate for chemotherapeutic treatments, such as new lesions indicate progressive disease, are not appropriate for checkpoint blockades.13 Checkpoint blockades are immunomodulatory antibodies that can cause an apparent worsening of the disease before the disease ultimately stabilizes or tumors regress. Responses can take a long time to become apparent; for example, the average time to achieve a complete response to ipilimumab in one long-term study was 30 months.17 In addition, prolonged periods of stable disease can occur in patients who do not meet the criteria for an objective response. Efforts are ongoing to develop alternative response criteria, known as immune-related response criteria.18
ADOPTIVE CELLULAR THERAPY
Another area of active research is the use of adoptive T cell therapy.3 T cells are stimulated outside the body and then, once activated, reinfused into patients. T cells used for this type of therapy can include tumor infiltrating lymphocytes (TILs), which are engineered to express a cancer-specific T cell receptor, and T cells engineered to express a chimeric antigen receptor (CAR). The CAR has both the extracellular portion of an antibody and the T cell receptor signaling machinery. Notably, TILs require high-dose interleukin-2, which comes with significant toxicity. The CAR approach also has potential toxicity, but offers promise, such as for chronic lymphoid leukemia, where the engineered cells stayed at high levels in the blood and bone marrow for 6 months and remission was ongoing at 10 months.19