Clinical deployment of antibodies for treatment of melanoma

Highlights

• Melanoma treatment has been transformed using T-cell checkpoint antibodies.

• Antibodies to CTLA-4 and PD-1 have had the largest impact on melanoma management.

• Combination T-cell checkpoint therapy holds great promise for clinical development.

• OX40 and 4-1BB are T cell costimulators with clinical potential in melanoma.

Abstract

The concept of using immunotherapy to treat melanoma has existed for decades. The rationale comes from the knowledge that many patients with melanoma have endogenous immune responses against their tumor cells and clinically meaningful tumor regression can be achieved in a minority of patients using cytokines such as interleukin-2 and adoptive cellular therapy. In the last 5 years there has been a revolution in the clinical management of melanoma in large measure based on the development of antibodies that influence T cell regulatory pathways by overcoming checkpoint inhibition and providing co-stimulation, either of which results in significantly more effective immune-mediated tumor destruction. This review will describe the pre-clinical and clinical application of antagonistic antibodies targeting the T-cell checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), and agonistic antibodies targeting the costimulatory pathways OX40 and 4-1BB. Recent progress and opportunities for future investigation of combination antibody therapy will be described.

Introduction

The humoral immune system is capable of making antibodies diverse enough to recognize over 10 billion foreign antigens with targets as diverse as microbial pathogens and tumor cells. After binding to antigen, antibody effector function is mediated by the following: complement fixation, Fc receptor binding leading to degranulation of neutrophils, engagement of other immune cells with cytotoxic function, antibody-dependent cellular cytotoxicity (ADCC) or prevention of binding of the antigen to adhesion or signaling molecules. These events in turn can promote a variety of regulatory functions that modulate the immune response including immunoglobulin class switching, cytokine release, B-cell memory and feedback regulation that influences immune enhancement or suppression. The adaptability and diversity of this system is carefully regulated, and B cells that produce antibodies that bind to self-antigen are eliminated. Autoimmune disease with significant clinical consequences can occur in patients where there is failure to eliminate or regulate self-reactive B cells. One could conjecture that allo-antibodies with the ability to promote immunologic memory or cytotoxic function in the setting of chronic infection or malignancy by engaging stimulatory T-cell receptors or inhibiting T-cell check-point proteins might confer some evolutionary benefit, but no naturally occurring antibody has been described with these properties.

Therapeutic antibodies have been used in medical care and research for decades, but in the last 15 years they have become commonplace in oncologic management. The majority of these monoclonal antibodies are antagonistic, and were engineered to block a protein antigen of interest or to induce ADCC. The value of this approach has been translated numerous times in clinical medicine. Some examples from the last 15 years in medical oncology include rituximab (used in CD20+ B-cell malignancies) (Davis et al., 2000), trastuzumab (erb-b2-overexpressing breast cancer) (Slamon et al., 2001) and cetuximab (tumors that have mutated EGFR, such as colon cancer and head and neck cancer) (Baselga et al., 2005, Cunningham et al., 2004). The mechanism of tumor elimination with these therapeutic agents is complex and likely includes antibody-dependent cellular cytotoxicity (ADCC) as well as inhibition of growth pathways salient to tumor growth (Arnould et al., 2006, Ferris et al., 2010).

Another area of therapeutic investigation has been the use of antibodies as immunomodulators. Anti-CD3, an antibody that binds the CD3 component of the T-cell receptor (TCR), administered at high doses causes immunosuppression and can be used to treat allograft rejection in patients who have received solid organ or bone marrow transplants (Bluestone et al., 1993). Anti-CD3 at low doses has immune stimulating effects and can trigger T-cell activation through the zeta chain of the TCR (Urba et al., 1992). Although anti-CD3 is not currently used as an anti-cancer agent, the observation that a T-cell-directed antibody could trigger T-cell cytotoxicity was an important conceptual insight that has lead to a proliferation of research on antibodies that influence the activation state and behavior of T cells resulting in enhanced anti-tumor immune responses. The CD3-zeta chain component has been used as a component of chimeric antigen receptors (CARs) to target tumor antigens with remarkable clinical activity in acute myelogenous leukemia and may have application in a wide variety of malignancies (Mardiros et al., 2013). Bispecific antibodies that link V_H and V_L for CD3 binding with the V_H and V_L that binds a tumor-associated antigen (e.g. CD19) have been used to redirect T cells to kill tumor cells. This approach has been studied in hematological malignancy and has recently garnered FDA approval, (Topp et al., 2014) but could also be applied to other solid tumors including melanoma.

A rapidly expanding knowledge of the receptors and pathways that regulate T cells, natural killer (NK) cells and antigen-presenting cells (APC) has identified the targets to which the current generation of melanoma therapeutic antibodies has been engineered. The T-cell pathways that have been most extensively studied to develop therapeutic antibodies in cancer are the T-cell checkpoints known as cytotoxic T lymphocyte antigen-4 (CTLA-4 designated CD152) and programmed death-1 (PD1 designated CD279). In addition, the study of the costimulatory pathways OX40 (CD134) and 4-1BB (CD137) may also yield therapeutic advances (Fig. 1). This review will describe the T-cell pathways and therapeutic antibodies that are transforming the care of patients with melanoma and other cancers, the rationale for combination antibody therapies currently undergoing clinical investigation and future questions that need to be answered to optimize antibody-based cancer therapy. Although the pathways will be presented individually, it is important to recognize that they function concurrently and that the final effect on T-cell activation is the result of the integration of the multiple coinhibitory and costimulatory signals.