The Role of Anti-PD-L1 Immunotherapy in Cancer

Published Online: Wednesday, January 29, 2014
Antibody and PD-L1 interactionImmunotherapy 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 castrationresistant 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 PD-1/PD-L1 pathways will be reviewed in this supplement, including a comprehensive review of selected ongoing clinical trials to evaluate the potential of targeting immunotherapy in cancer drug development. Emerging clinical data discussed in this supplement suggest that targeting immunotherapy in cancer will become an integral part of the clinical management strategy for solid tumors.

Introduction

Cancer is traditionally treated with either 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 of harnessing the immune system to fight cancer.2 The immune system protects the body from foreign invading agents by recognizing “non-self” proteins (antigens) displayed on their surface that distinguish them from normal, healthy tissue. This subsequently initiates a protective response that neutralizes these organisms.3 William Coley was the first to draw 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 Since then, a dyna mic and complex relationship between the immune system and cancer has been uncovered, and the concept of immunotherapy was born.

Cancer cells are normal cells that have acquired numerous hallmark abilities that allow them to become malignant; 4 thus, they are essentially “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 mounted. 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 refers to a diverse range of therapeutic approaches that aim to harness the immune system to re-establish 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 two 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. Thus far, mAbs have been the biggest success story for immunotherapy; the top three best-selling anticancer drugs in 2012 were mAbs.10 Among them is rituximab (Rituxan, Genentech), which binds to the CD20 protein that is highly expressed on the surface of B cell malignancies such as non-Hodgkin’s lymphoma (NHL). Rituximab is approved by the FDA for the treatment of NHL and chronic lymphocytic leukemia (CLL) in combination with chemotherapy.11 Another important mAb is trastuzumab (Herceptin; Genentech), which revolutionized the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer by targeting the expression of HER2.12

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