Immune Checkpoint Blockade in Cancer: Inhibiting CTLA-4 and PD-1/PD-L1 With Monoclonal Antibodies

Patrick A. Ott, MD, PhD
Published: Friday, Feb 21, 2014

Abstract

Inhibitory receptors such as anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) expressed on tumor-specific T cells lead to compromised activation and suppressed effector functions such as proliferation, cytokine secretion, and tumor cell lysis. Modulating these receptors using monoclonal antibodies, an approach termed “immune checkpoint blockade,” has gained momentum as a new approach in cancer immunotherapy. This treatment concept was first introduced in patients with advanced melanoma: in this patient population, the anti-CTLA-4 antibody ipilimumab was the first drug ever to show improved overall survival in phase III trials. Antibodies directed against PD-1 and its ligand, PD-L1, have shown much promise in the treatment of melanoma, renal cell cancer, non-small cell lung cancer, and other tumors, as evident by encouraging rates and durability of tumor responses. Because of the successes with immune checkpoint inhibitors in cancer immunotherapy, many new agents and strategies, including combination approaches, are being developed at a fast pace.


Figure. T-Cell Interaction With Dendritic Cells and Tumor Cells: The Immune Checkpoints CTLA-4 and PD-1/PD-L1

T-Cell Interaction With Dendritic Cells and Tumor Cells:
The Immune Checkpoints CTLA-4 and PD-1/PD-L1

Introduction

Tumor mutations give rise to tumor-specific neoantigens that can be recognized by the immune system, leading to elimination of cancer cells. To defend themselves from immune attack, tumors can employ a host of mechanisms such as local immune suppression in the tumor microenvironment, induction of T cell tolerance, and immune editing.1-3 Many previous cancer immunotherapies have likely been limited by these suppressive mechanisms. A novel therapeutic strategy that tackles a critical immune-modulating mechanism has recently risen to the forefront of cancer immunotherapy: the blockade of the inhibitory receptors cytotoxic T-lymphocyte–associated antigen 4 (anti-CTLA-4) and programmed death-1 (PD-1) and its ligand, PD-L1, an approach termed immune-checkpoint blockade. This treatment is designed to improve activation and effector function of tumor-specific T cells.

Evidence that immune-checkpoint blockade is an effective cancer therapy was first documented in patients with advanced melanoma. In this patient population, the anti-CTLA-4–specific monoclonal antibody ipilimumab led to overall survival (OS) benefit in phase III trials, resulting in FDA approval for this agent in 2010.4,5 Recently reported data from large phase I studies have indicated that targeting the inhibitory receptors PD-1 and PD-L1 may be even more powerful. The observation that PD-1 and PD-L1 inhibition seem to induce tumor regression in patients with non-small cell lung cancer (NSCLC) and other tumor types (in addition to melanoma and renal cell cancer [RCC]) has attracted particular attention by the oncology community since these cancers have traditionally not been considered susceptible to any form of immunotherapy.6-8 The documented tumor activity of immune checkpoint blockade has validated this therapeutic approach and has brought the field of cancer immunotherapy to the forefront of novel cancer therapeutics.

Ipilimumab

CTLA-4 is an inhibitory receptor expressed on T cells. It has much higher binding affinity to the co-stimulatory receptor B7 than the co-stimulatory receptor CD28, and therefore tips the balance from the T cell activating interaction between CD28 and B7 to inhibitory signaling between CTLA-4 and B-7, leading to suppression of T cell activation.9 The biological role of CTLA-4 is the modulation of T cell responses, predominantly during initial activation in the lymph node and the prevention of autoimmunity, which is impressively illustrated by the development of lethal massive lymphoproliferation in CTLA-4 knock-out mice.10,11 Ipilimumab and tremelimumab are fully-human monoclonal antibodies targeting CTLA-4.


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