The Evolving Role of Immune Checkpoint Inhibitors in Cancer Treatment

Abstract

Traditional treatment modalities for advanced cancer (radiotherapy, chemotherapy, or targeted agents) act directly on tumors to inhibit or destroy them. Along with surgery, these modalities are predominantly palliative, with toxicity and only modest improvements in survival in patients with advanced solid tumors. Accordingly, long-term survival rates for most patients with advanced cancer remain low, thus there is a need for cancer treatments with favorable benefit and toxicity profiles that can potentially result in long-term survival. The immune system plays a critical role in the recognition and eradication of tumor cells ("immune surveillance"), and immunotherapies based on this concept have been used for decades with some success against a few tumor types; however, most immunotherapies were limited by a lack of either substantial efficacy or specificity, resulting in toxicity. We now have a greater understanding of the complex interactions between the immune system and tumors and have identified key molecules that govern these interactions. This information has revitalized the interest in immunotherapy as an evolving treatment modality using immunotherapeutics designed to overcome the mechanisms exploited by tumors to evade immune destruction. Immunotherapies have potentially complementary mechanisms of action that may allow them to be combined with other immunotherapeutics, chemotherapy, targeted therapy, or other traditional therapies. This review discusses the concepts and data behind immunotherapies, with a focus on the checkpoint inhibitors and their responses, toxicities, and potential for long-term survival, and explores promising single-agent and combination therapies in development.

Implications for practice: Immunotherapy is an evolving treatment approach based on the role of the immune system in eradicating cancer. An example of an immunotherapeutic is ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. Ipilimumab is approved for advanced melanoma and induced long-term survival in a proportion of patients. The programmed death-1 (PD-1) checkpoint inhibitors are promising immunotherapies with demonstrated sustained antitumor responses in several tumors. Because they harness the patient's own immune system, immunotherapies have the potential to be a powerful weapon against cancer.

Keywords: CTLA-4; Checkpoint inhibitors; Combination; Immunotherapy; PD-1; Survival.

Figure 1.

T cells are an important component of the antitumor immune response. Abbreviation: APC, antigen-presenting cell.

Figure 2.

Mechanisms exploited by tumors to evade and suppress the immune system [, –16]. Abbreviations: APC, antigen-presenting cell; DC, dendritic cell; IDO, indoleamine 2,3-dioxygenase; iNOS, inducible nitric oxide synthase; MDSC, myeloid-derived suppressor cell; NK, natural killer.

Figure 3.

Checkpoint and activating receptors on T cells are targets for immunotherapy. From [17] with permission from Macmillan Publishers Ltd.

Figure 4.

The immune status of the tumor microenvironment may have implications for the selection and success of immunotherapy. From [23] with permission from Elsevier. Abbreviation: IDO, indoleamine 2,3-dioxygenase.

Figure 5.

Long-term survival in melanoma patients treated with ipilimumab: results of a pooled analysis. From [74] with permission from the American Society of Clinical Oncology. Abbreviations: CI, confidence interval; OS, overall survival.

Figure 6.

Response duration with nivolumab in a phase I trial: responses may occur early or late, and may continue after discontinuation. From [47] with permission from Dr. F.S. Hodi, Dana-Farber Cancer Institute, Boston, MA.