PD-1 antibodies are transformative in cancer therapeutics. They have shown significant anticancer activity as monotherapy across a large number of major cancer types and across lines of therapy. Precision medicine tools have enabled trial enrichment and patient segmentation. They have also provided insights to potential resistance biology and enabled informed combination selection. PD-1-based combination therapies are also showing promise broadly across tumors and lines of therapy.

Clinical combination studies including PD-1 checkpoint inhibitors exploded in the 7 years since the first PD-1 checkpoint inhibitor approvals. Expectations of combination success were high at first. Seven years on, it is important to assess these studies more realistically. The presenter recently published a cross sectional study of PD-1 pathway checkpoint inhibitor clinical trials. Encouraging and discouraging results will be reviewed to guide thinking about future combination strategies.

In a single-institution cohort, long-term outcomes were assessed after discontinuation of anti-PD-1 for advanced melanoma (n=396). Of 102 complete responders, the probability of relapse was 27% at 3 years. No association was seen between treatment duration and relapse risk. Among patients treated with anti-PD-1 who were re-treated after relapse, response was observed in 15% (of 34) patients re-treated with anti-PD-1 and 25% (of 44) patients re-treated with ipilimumab + anti-PD-1.

We will discuss the discovery of a novel tumor-intrinsic adaptive resistance pathway to anti-PD-1 immunotherapy and explore the potential implications that this pathway has on therapeutic and biomarker development in immuno-oncology.

Resistance to therapy in cancer is a major issue leading to treatment failures. Recently, there has been an increase in agents targeting intrinsic or acquired resistance. However, these approaches only target resistance mutations after they have occurred. Our proactive, anticipatory approach applies selective pressures through the immune system to prevent or reverse resistance prior to occurrence. While our initial focus is breast cancer, this approach is broadly applicable for other cancers.

Jounce’s translational platform utilizes thousands of human tumor samples and advanced bioinformatics to probe the tumor microenvironment for immuno-oncology targets that could be relevant in T cell checkpoint-resistant tumors and/or expand the number of patients benefiting from checkpoint therapy. The first therapeutic candidate to emerge from this platform is JTX-8064, a monoclonal antibody that antagonizes LILRB2 (ILT4), and promotes a pro-inflammatory, anti-tumor phenotype in macrophages and other myeloid cells. In an ex vivo human tumor histoculture system, JTX-8064 induced gene signature changes consistent with M1 skewing of macrophages and also induced IFN-g and T cell inflamed gene signatures suggesting activation of T cell immunity within the tumor microenvironment. Thus, we believe JTX-8064 antagonism of LILRB2 will directly improve the function of myeloid cells and indirectly stimulate anti-tumor T cell immunity.

Oncogenic-induced, membrane-bound NKG2D ligands stimulate NK and Cd8 T cell anti-tumor immunity. Conversely, tumor-edited soluble NKG2D ligands in the tumor microenvironment suppress anti-tumor immunity via multiple mechanisms. Here we present evidence that tumors shed soluble NKG2D ligand, the soluble MHC I chain-related molecule (sMIC), facilitates immune suppression of MDSCs. We also present evidence that targeting soluble MIC reprograms MDSC and primes the tumor immune microenvironment.

Apogenix hexavalent TNFR-SF agonists (HERA) are developed for immune-therapeutic treatment of cancer. Due to its structural layout with two trivalent CD40L-receptor-binding domains, HERA-CD40L mimics the natural ligand and enables efficient receptor agonism. Treatment increases the pro-inflammatory state of all CD40-expressing cells examined and shows single-agent antitumor activity both in vitro and in vivo. The MoA has been well defined, and the biological activity has been demonstrated to be distinct from and superior to clinical benchmark “agonistic” antibodies.

Macrophages can adopt different functional roles in response to signals from their environment, including the ability to direct pro-inflammatory and anti-inflammatory immune responses. In cancer, tumor-associated macrophages (TAMs) are key regulators of the interactions between the immune system and cancer. TAMs fuel tumor progression and negatively impact responses to therapy. Verseau has found novel targets that change macrophages into antitumor response enablers. At Verseau, we have nominated and validated more than two dozen targets that modulate human macrophage biology. The lead program targeting PSGL-1 reprograms macrophages to a pro-inflammatory state, activates T cells, and attracts other immune cells to generate a coordinated and powerful anti-tumor response.