The past decade has been a period of tremendous progress in the area of cancer immunotherapy. The field has progressed from a point where very modest subsets of patients in just a few diseases sustained clinical benefit from cytokine therapy to one where patients with diverse diagnoses are having durable regressions from antibodies targeting critical immune checkpoints and others are showing striking responses to advanced T cell-based therapies. These steps forward were enabled by significant advances in basic science allowing for a better understanding of molecular mechanisms of immune regulation and immune cell dynamics, stressing the importance of close collaboration between basic and translational and clinical scientists. In this session, I will focus on the development of clinical reagents that foster immune response to cancer through blockade of critical immune checkpoints and stimulation of activating pathways.

Blockade of CTLA-4 was suggested to be an impactful means to augment tumor immunity based on the pioneering studies of Jim Allison, who hypothesized that impairment of this critical molecular brake would overcome tumor-induced immune suppression and allow for more robust immune response to tumors. What followed was the development of several fully human antibodies that blocked this non-redundant checkpoint immunologic checkpoint and early clinical trials demonstrating clinical activity and a unique pattern of mechanism-based adverse events in patients with melanoma, as well as other cancers. In 2011, the US FDA approved ipilimumab for the treatment of metastatic melanoma with two randomized phase 3 trials demonstrating prolongation of overall survival, the first intervention ever to demonstrate this important endpoint in this challenging clinical situation. During the clinical development program, attention was paid to the unique kinetics of response to this agent and a new set of response criteria have been proposed which incorporate the biology of immunotherapy into radiographic response-based endpoints for clinical trials. Importantly, an algorithmic approach to toxicity management was also focused upon, yielding guidelines for medical management. The clinical activity of ipilimumab in a subset of patients with melanoma called out for the study of both predictive and pharmacodynamic biomarkers for this innovative therapy. This work has led to the identification of several potentially important biomarkers including: up-regulation of the inducible co-stimulator ICOS, increase in absolute lymphocyte count, pretreatment frequency of myeloid-derived suppressor cells, presence of pre-existing anti-tumor antibody responses and inflammatory signatures in the tumor microenvironment.

Investigation of blockade of the PD-1 (programmed death-1) pathway followed very shortly after the efficacy of ipilimumab was observed. PD-1 is a marker on T cells which, while being up-regulated after activation, serves to mark T cells as being exhausted and, when engaging one of its ligands (PD-L1 or -L2), can lower the threshold for apoptosis in T cells. Not unexpectedly, a broad array of tumor cell types has evolved the ability to express PD-L1 on the cell surface, presumably as a means to evade cytotoxic T lymphocytes. An ever-expanding list of antibodies that block either PD-1 or PD-L1 has entered clinical trials with some currently in phase 3 investigation. It was not completely surprising that PD-1 blockade showed clinical efficacy in melanoma and renal cell carcinoma. However, Julie Brahmer and Suzanne Topalian at Johns Hopkins then observed that patients with non-small cell lung cancer could respond to PD-1 blockade with nivolumab, forever changing that notion that only melanoma and renal cell carcinoma were the solid tumors amenable to immune modulation. What has followed is an accelerated effort to explore PD-1 and PD-L1 blockade with a variety of agents (nivolumab, MK-3475, MEDI-4736, MPDL-3280A, MSB0010718C, pidilizumab) in many different malignancies. Although immune-related adverse events have been reported with PD-1 pathway blockade, they appear to be somewhat distinct in nature and less frequent than those accompanying CTLA-4 blockade.

Given the activity noted with both CTLA-4 and PD-1 blockade and the complementary mechanism of action as well as supportive pre-clinical data, clinical trials are now investigating combination checkpoint blockade. The most mature data has come from a combination of ipilimumab + nivolumab in patients with melanoma showed an overall response rate of 40% across dose cohorts with some over 50% of patients in some cohorts showing rapid and deep (>80% reduction) tumor regressions in the context of manageable toxicity. Phase 2 and 3 trials of this combination are ongoing in melanoma with phase 1 programs in numerous other tumor types. Similar strategies are being investigated using a combination or tremelimumab and MEDI-4736.

The above discussion focused on medicines blocking negative checkpoints and while new antagonists are entering clinical trials targeting molecules such as LAG-3, there are also numerous studies now focused on agonist antibodies for pathways which stimulate immune reactivity. CD137 (also known as 4-1BB) is a member of the TNF receptor family and is expressed on T cells, NK cells, antigen presenting cells and granulocytes. There are several antibodies in early clinical development (urelumab, PF- 05082566) that seek to both augment T cell activation as well as potentiate the antibody-dependent cellular cytotoxicity of tumor-targeting antibodies via up-regulation of Fc receptors on effector cells. OX40 is another focus for agonist antibodies, based on its role is augmenting effector T cell activation and also mediating activation induced cell death of regulatory T cells (Tregs). Early clinical trials using a murine antibody have demonstrated evidence of immune modulation and human or humanized reagents are in development. GITR (glucocorticoid induced TNF receptor like protein) is another member of the TNF receptor family that is also of interest in the generation of agonist antibodies. GITR was first considered to be a marker of Tregs, but is also expressed by activated effector cells. Pre-clinical studies have shown that GITR agonist agents can mediate tumor regression in animal models, in part based on a unique mechanism in which Tregs sustain an alteration in lineage commitment through loss of the FoxP3 protein. A phase 1 clinical trial is ongoing investigating the safety and efficacy of a GITR agonist antibody (TRX-518) in patients with advanced cancers. An agonistic antibody to CD40 is also in clinical development, based on elegant preclinical studies conducted by Bob Vonderheide.

All of the above approaches are also being considered as combinatorial partners both with other immunotherapies as well as with treatments which directly affect the cancer cell. Such approaches include combinations with radiation therapy to achieve abscopal effects and combinations with targeted pathway inhibitors to introduce durability to significant early response activity produced by driver pathway modulation. The overall goal, of course, is the durable control of disease in as many patients as possible.

Citation Format: Jedd D. Wolchok. Immune modulation for cancer therapy: Assessing antagonists and agonists. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr PL02-03. doi:10.1158/1538-7445.AM2014-PL02-03