Novel Immune Checkpoint Identified as Promising Target for Blockade Strategies

John Hunter, PhD

A new immune checkpoint called PVRIG has emerged as a ripe target for anticancer therapy in solid tumors and an antibody that blocks its ability to suppress an antitumor response is in development, according to original research presented in a late-breaking abstract at the at the Society for Immunotherapy of Cancer (SITC) 31st Annual Meeting & Associated Programs.¹

Researchers have demonstrated in preclinical experiments that inhibiting PVRIG results in enhanced activation of tumor-infiltrating lymphocytes (TILs), primary CD4-positive T cells, and tumor-derived CD8+ T cells.

In humanized mouse models, there was a reduction in tumor growth and increased survival when anti-PVRIG antibodies were used in combination with PD-L1 pathway blockade. Tumor growth also was reduced in PVRIG knockout mice.

The goal of the research is to find a way to boost the efficacy of checkpoint blockade immunotherapy strategies, said John Hunter, PhD, site head and vice president of antibody research at Compugen USA, Inc., who presented the findings on behalf of the company.

“Despite the outstanding advancements that were made in the last 6 years, we’re still in the position where the majority of patients do not derive long-term benefit from these treatments, and this constitutes a very large unmet medical need,” said Hunter.

The company plans to file an investigational new drug application with the FDA in 2017 for COM701, its lead antibody that targets PVRIG, said Hunter. The compound binds to PVRIG with high affinity (KD <1nM) and blocks the receptor from binding to its ligand, PVRL2.

Compugen identified PVRIG as a novel immune system target through the use of computational biology tools. The company, based in Israel with a US headquarters in South San Francisco, works with researchers at Johns Hopkins University, Bar-Ilan University, and Tel Aviv University.

Hunter said PVRIG&rsquo;s functional gene structure matched that of known checkpoint receptors such as PD-1 and CTLA-4. Additionally, the tumor expression characteristics of PVRIG were similar to those of T-cell receptor checkpoints.

PVRIG is an immunoglobulin (Ig) domain protein that can be expressed on the surface of tumor cells or on myeloid cells in the tumor microenvironment, Hunter said in an interview. Although researchers are still developing an understanding of the functioning of PVRIG, Hunter said it exerts negative regulatory effects on T-cell activation.

&ldquo;Likely, in a normal cell setting, it plays a role in keeping the immune response in check, similar to the other co-inhibitory checkpoints,&rdquo; said Hunter. &ldquo;There&rsquo;s differences among the known checkpoints in terms of where they operate and the exact mechanism of action. But in a broader sense, we do think that [PVRIG] serves in the normal immune system to make sure that the immune system does not become hyperstimulated.&rdquo;

In human cancer, increased expression of PVRIG would inhibit an antitumor response. Specifically, investigators found that expression of PVRIG was highest in CD8+ effector memory RA T cells, Hunter said. its expression also was found to be upregulated in human and mouse tumors.

In further characterizing the activity of PVRIG, researchers focused on its binding partner, PVRL2, by designing COM701 to target the interaction of the receptor and its ligand.

&ldquo;The antibody binds to a site on PVRIG that is required for the interaction with PVRL2, and, because it binds at a higher affinity than PVRL2, it blocks that binding site so that you can&rsquo;t get that interaction,&rdquo; explained Hunter. &ldquo;We think that that interaction is required for activating PVRIG and inducing the inhibition of T-cell response.&rdquo;

Moreover, this interaction is important because PVRL2 is known to be a binding counterpart to DNAM-1, a key element in the TIGIT immune checkpoint axis, Hunter said. Compugen found that combined blockade of PVRIG and TIGIT also enhanced TIL activation.

The company&rsquo;s experiments are in keeping with a current trend toward exploring combination checkpoint blockade approaches, Hunter noted. &ldquo;Obviously the existing immune checkpoints aren&rsquo;t effective in all patients and we think one of the underlying reasons is that there may be other checkpoints that have to be inhibited as well to reactivate the immune response,&rdquo; he said.

Hunter said Compugen&rsquo;s findings about PVRIG&rsquo;s mechanisms of action complement conclusions reached by University of Colorado researchers earlier this year.²Zhu et al described PVRIG (also called CD112R) as a poliovirus receptor (PVR)—like protein that is a member of the B7/CD28 family.

DNAM-1 (also known as CD226) competes with PVRIG to bind to PVRL2 (also called CD112).²Disrupting the ability of PVRIG to interact with its ligand enhances T-cell response, Zhu and colleagues said.

Meanwhile, TIGIT is becoming an increasing focus of immuno-oncology research. In another poster presented at the SITC 31st Annual Meeting & Associated Programs, researchers from Genentech described efforts to inhibit expression of TIGIT in conjunction with PDL1 inhibition in mouse models as a means of enhancing CD8+ T-cell function.³The strategy resulted in significant tumor clearance, and Genentech has moved into phase I testing of an anti-TIGIT molecule.

MTIG7192A is a fully human monoclonal antibody that binds to TIGIT and prevents its interaction with PVR. The trial, which opened in June, will evaluate the safety and efficacy of MTIG7192A as a monotherapy and in combination with the PD-L1 inhibitor atezolizumab (Tecentriq) in a 2-step study that aims to enroll 300 patients with locally advanced or metastatic tumors.⁴

References

1. Levy O, Chan C, Cojocaru G, et al. Computational identification, functional characterization, and antibody blockade of a new immune checkpoint in the TIGIT family of interacting molecules. Presented at: 2016 SITC Annual Meeting; November 9-13, 2016; National Harbor, MD. Abstract O3.
2. Zhu Y, Paniccia A, Schulick AC, et al. Identification of CD112R as a novel checkpoint for human T cells. J Exp Med. 2016;213(2):167-176. doi: 10.1084/jem.20150785.
3. Grogan J, Manieri N, Chiang E, et al. The immunoreceptor TIGIT regulates anti-tumor immunity. Presented at: 2016 SITC Annual Meeting; November 9-13, 2016; National Harbor, MD. Abstract 214.
4. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02794571. Accessed November 11, 2016.