Immunotherapy has become an increasingly appealing therapeutic strategy for patients with cancer, with many late-stage clinical trials demonstrating overall survival (OS) advantages in melanoma and castration-resistant prostate cancer. More recently, non-small cell lung cancer (NSCLC) has become a focus for the next generation of immune-based therapeutic strategies.
Immunotherapy, in particular the use of monoclonal antibodies that block inhibitory immune checkpoint molecules and therefore enhance the immune response to tumors, has shown clinical promise in advanced solid tumors. The clinical rationale for targeting the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) pathways will be reviewed in this supplement, including an update on the results of select clinical trials that evaluate the potential of targeted immunotherapy as presented at the 2015 American Association of Cancer Research (AACR) Annual Meeting. Emerging clinical data suggest that targeted immunotherapy in cancer will become an integral part of the clinical management strategy for solid tumors.Introduction
Cancer is traditionally treated with conventional therapy (ie, chemotherapy or radiation therapy) or targeted drugs that directly kill tumor cells. While the number of patients who survive cancer has seen significant increases, the “war” rages on.1
More than a century ago, a series of primitive experiments hinted at the potential for harnessing the immune system to fight cancer.2
The immune system protects the body from foreign invading agents by recognizing “nonself” proteins (antigens) displayed on their surface that distinguish them from normal, healthy tissue (“self”). This subsequently initiates a protective response that neutralizes these organisms.3
William Coley was the first to suspect a link between the immune system and cancer. He observed spontaneous remission in cancer patients following infection with a mixture of killed infectious agents, dubbed Coley’s toxins.2
In the years that followed, a dynamic and complex relationship between the immune system and cancer was uncovered, giving birth to the concept of immunotherapy.
Cancer cells are normal cells that have acquired numerous hallmark abilities that allow them to become malignant 4
; thus, they are essentially identified as “self”—part of the host. In spite of this, they often display unusual or inappropriate proteins on their cell surface that allow the immune system to identify them as “non-self,” and an antitumor immune response is often initiated. However, cancer cells have evolved a number of mechanisms to enable evasion of this immune response and render it ineffective. Typically, by the time a cancer becomes detectable, the balance of power between the immune system and the cancer has shifted in favor of the growing tumor, and a state of immune tolerance has been established. Immunotherapy comprises a diverse range of therapeutic approaches intended to harness the immune system to reestablish a targeted antitumor immune response. The goal of cancer immunotherapy is to enable the patient’s immune system to specifically recognize and kill cancer cells.5-9
There are 2 distinct types of immunotherapy: passive immunotherapy uses components of the immune system to direct targeted cytotoxic activity against cancer cells, without necessarily initiating an immune response in the patient, while active immunotherapy actively triggers an endogenous immune response. Passive strategies include the use of the monoclonal antibodies (mAbs) produced by B cells in response to a specific antigen.6 The development of hybridoma technology in the 1970s and the identification of tumor-specific antigens permitted the pharmaceutical development of mAbs that could specifically target tumor cells for destruction by the immune system.
To actively drive an antitumor immune response, therapeutic cancer vaccines have been developed. Unlike the prophylactic vaccines that are used preventively to treat infectious diseases, therapeutic vaccines are designed to treat established cancer by stimulating an immune response against a specific tumor-associated antigen. In 2010, sipuleucel- T (Provenge; Dendreon Corporation) was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic, castration-resistant prostate cancer based on results of the IMPACT (Immunotherapy Prostate Adenocarcinoma Treatment) trial in which it improved OS by 4.1 months and reduced the risk of death by 22% versus placebo.10,11
The advantage of active immunotherapies is that they have the potential to provide long-lasting anticancer activity by engaging both the innate and adaptive arms of the immune response. While mAbs are typically considered passive immunotherapies, there is increasing evidence that they also induce an adaptive immune response via a “vaccination-like” effect.12