Since checkpoint blockade relies on activation of the patient’s own immune system against tumors, its effects are not immediately evident, presenting a challenge in evaluating clinical responses to such therapy. Guidelines for evaluating clinical responses were based on the immediate effects of chemotherapeutic drugs or radiation, whereas checkpoint blockade requires more time for reversing immune inhibition and expanding tumor-specific T cells that then exert their effects within the tumor. Once such issues were considered, it became possible to design clinical trials that could document the effects of checkpoint blockade used in combination with traditional anticancer therapies.
Checkpoint blockade based on the anti-CTLA-4 antibody ipilimumab has now been shown to be effective in treating metastatic melanoma and recently received FDA approval for this indication. Patients with metastatic melanoma who were treated with ipilimumab showed an increase in the number and activity of T cells recognizing NY-ESO-1, a cancer-testis antigen expressed by melanoma. Overall only about 15% of patients exhibited a response to ipilimumab, but the treatment appeared to induce long-term remission in responding patients. One side-effect of ipilimumab in these patients seemed to be an increased risk of autoimmune phenomena, in agreement with the role of CTLA-4 in maintaining tolerance of self-reactive T cells.
Another checkpoint involves the inhibitory receptor PD-1 and its ligands PD-L1 and PD-L2. PD-L1 is expressed on a wide variety of human tumors; in renal cell carcinoma, PD-L1 expression is associated with a poor prognosis. In mice, transfection of the gene encoding PD-L1 into tumor cells increased their growth in vivo and reduced their susceptibility to lysis by cytotoxic T cells. These effects were reversed by an antibody against PD-L1. In humans, the anti-PD-1 antibody pembrolizumab has been shown to be effective in previously treated melanoma patients, giving a nearly 30% response rate. It is FDA-approved for use following treatment with ipilimumab, or in patients with a BRAF mutation after treatment with ipilimumab and a B-raf inhibitor. Another anti-PD-1 antibody, nivolumab, is also approved for treatment of metastatic melanoma and is being considered for use in treatment of Hodgkin’s lymphoma. Ongoing clinical trials are evaluating checkpoint blockade using antibodies to PD-L1 and PD-L2.
Summary.
Some tumors elicit specific immune responses that suppress or modify their growth. Tumors evade or suppress these responses in several ways, passing through various stages of a process known as immunological editing. Understanding how the immune system promotes and prevents cancer growth has led to new therapies now deployed in the clinic. The possibility of eradicating cervical cancer, for example, has been brought closer by the development of an effective vaccine against specific strains of cancer-causing human papilloma virus. Monoclonal antibodies have also been successfully developed for tumor immunotherapy in several cases, such as an anti-CD20 antibody used to treat B-cell lymphoma. Attempts are also being made to develop vaccines incorporating peptides designed to generate effective cytotoxic and helper T-cell responses. CAR T cells engineered to recognize CD19 expressed on B cells can be an effective treatment for acute lymphocytic leukemia. Checkpoint blockade strategies for CTLA-4 and PD-1 have been approved for treating melanoma, and related strategies are being developed for other biologic targets to stimulate antitumor immune responses or block inhibitory mechanisms that suppress such responses. One vaccine using dendritic cells that present tumor antigens has been approved for treating prostate cancer. A current trend in cancer therapy has been to incorporate immunotherapy with other traditional anticancer treatments to take advantage of the specificity and power of the immune system.
Fighting infectious diseases with vaccination.