Novel cancer immunotherapy agents with survival benefit: recent successes and next steps

Abstract

The US Food and Drug Administration (FDA) recently approved two novel immunotherapy agents, sipuleucel-T and ipilimumab, which showed a survival benefit for patients with metastatic prostate cancer and melanoma, respectively. The mechanisms by which these agents provideclinical benefit are not completely understood. However, knowledge of these mechanisms will be crucial for probing human immune responses and tumour biology in order to understand what distinguishes responders from non-responders. The following next steps are necessary: first, the development of immune-monitoring strategies for the identification of relevant biomarkers; second, the establishment of guidelines for the assessment of clinical end points; and third, the evaluation of combination therapy strategies to improve clinical benefit.

Figure 1. Basic mechanisms of T cell stimulation and inhibition

a | T cell activation begins with interaction of the T cell receptor (TCR) on a T cell with major histocompatibility complex (MHC) bound to antigen on an antigen-presenting cell (APC). This is known as signal 1, but appropriate activation of the T cell requires additional signals that are provided by the interaction between CD28 and B7 (signal 2). b | T cell activation is limited by cytotoxic T lymphocyte-associated protein 4 (CTLA4), which is upregulated on activated T cells, where it outcompetes CD28 for binding to B7 on an APC. Additional regulation of T cell activity is also provided by later inhibitory signals through other molecules such as programmed cell death 1 (PD1), which binds to PD1 ligand 1 (PDL1). Other regulators of T cell activation have recently been characterized and may have important roles; these regulators include T cell immunoglobulin and mucin domain-containing protein 3 (TIM3; also known as HAVCR2) and V-domain immunoglobulin suppressor of T cell activation (VISTA)^,.

Figure 2. Current therapies that induce effector T cell functions

Strategies to maintain activated tumour-specific T cells include the use of blocking monoclonal antibodies, such as anti-bodies targeting either cytotoxic T lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD1), to neutralize co-inhibitory receptors. Therefore, these antibodies that block intrinsic inhibitory immune checkpoints allow a sustained T cell response, including an increased production of cytokines, such as tumour necrosis factor-α (TNFα), interferon-γ (IFNγ) and granzyme B. APC, antigen-presenting cell; MHC, major histocompatibility complex; TCR, T cell receptor.

Figure 3. Clinical trial concepts

The standard paradigm for clinical trial design involves Phase I studies to assess the safety of an agent or therapy, Phase II studies to assess the clinical efficacy of an agent or therapy and Phase III studies to compare the agent or therapy with already established standard-of-care agents or therapies. We propose including Phase Ia and Phase IIa studies as a part of the standard paradigm for cancer immunotherapy trials, thereby allowing the evaluation of biological and immunological responses to an agent or therapy in both peripheral blood and tumour tissues.