Frontiers in Cancer Immunotherapy 2020

Cell therapy currently plays an important role in the treatment of patients with various cancers. Responses to cell therapeutics are regulated by multiple factors including the patient's immune system status, genetic profile, stage at diagnosis, age, and underlying disease. Outside of T cell engineering using chimeric antigen receptors (CARs) and artificial T-cell receptors, T-cell therapies can be mediated by ex vivo expansion of antigen-specific T cells targeting viral and/or nonviral tumor-associated antigens. However, tumor immune evasion mechanisms such as immune suppressive cytokines, antigen loss, and upregulation of inhibitory checkpoint signals all can affect T cell activity in vivo. Strategies including infusion of checkpoint inhibitors, the adoptive transfer of T cells that express receptors that render the T cell resistant to the immune suppressive environment and target multiple tumor antigens in a single product will be discussed. These approaches are contributing to enhanced clinical responses and overall survival for some cancer populations. This session will therefore present an overview of T-cell therapeutics for cancer including receptor engineering and beyond to overcome tumor immune evasion.

With the recent availability of novel immunologic agents, priority has shifted to understanding the mechanisms of and predicting responses to each treatment. While the search for immunogenic tumor antigens has been the subject of decades-long studies, multiple lines of evidence have convincingly demonstrated tumor neoantigens as an important class of immunogenic tumor antigens. Neoantigens arise from amino acid changes encoded by somatic mutations in the tumor cell and have the potential to bind to and be presented by personal HLA molecules. We can now systematically identify mutations leading to amino acid changes that can be potentially recognized immunologically through the implementation of neoantigen discovery pipelines. In recent studies, we have demonstrated that neoantigens can be safely and feasibly targeted to generate customized cancer vaccines. We have been undertaking pilot clinical trials to develop personal cancer vaccines in melanoma and glioblastoma that utilize synthetic long peptides as delivery approach for this therapy. Recent results and new directions will be discussed.

Immune checkpoint therapies have revolutionized clinical oncology by improving survival in several malignancies; however, they have had limited efficacy in prostate cancer. This has been attributed to the immunosuppressive prostate tumor microenvironment (TME), characterized by paucity of T cells, high frequency of immunosuppressive myeloid cells, and elevated levels of immunosuppressive cytokines. Nevertheless, a subset of patients with metastatic prostate cancer respond to ipilimumab (anti-CTLA-4).

We recently found that patients who experienced a prolonged progression-free survival (PFS) and overall survival (OS) to ipilimumab were more likely to have within their pretreatment prostate tumors a high intratumoral CD8 density and/or express a high IFN-gamma-response gene signature, which were associated with Th1 antitumor responses. To better understand mechanisms of resistance to ipilimumab, we evaluated pre- and post-treatment tissues. Although ipilimumab increased infiltration of effector T cells within the prostate tumor microenvironment, this was countered by upregulation of the inhibitory immune checkpoints, PD-L1 and VISTA. Combining nivolumab (anti-PD-1) plus ipilimumab induced striking clinical responses in a subset of men with metastatic prostate cancer, suggesting that adaptive resistance to ipilimumab monotherapy could be overcome by concurrently targeting more than one immune checkpoint. More recently, we found that high levels of TGF-beta within the metastatic prostate bone tumor microenvironment conferred primary resistance to immune checkpoint therapies. In a preclinical model, simultaneously targeting TGF-beta and CTLA-4 promoted Th1 responses associated with improved overall survival. Taken together, our data supports the rational development of combination therapies to overcome the immunosuppressive prostate tumor microenvironment.

Computational deconvolution, neoantigen prediction and other immune-based characterizations of cancers have been developed and refined over the past few years. These approaches are now being applied to the study of longitudinal cancer samples as a means of evaluating the changes that occur over time and in response to therapy, therapeutic resistance, and progression. Our studies aim to apply immune characterization to pediatric CNS cancers in an effort to contextualize the tumor microenvironment, existing and evolving neoantigens, and other immune-related changes that occur in the course of progression from primary to recurrent cancers. My lecture will feature a description of the approaches we are using and their application to specific case studies, in an effort to turn patient-based observations into testable  hypotheses that advance our understanding of the interaction of CNS cancers and the host immune system, and further permit us to evaluate response to novel therapeutic interventions.

High parameter single cell analysis has driven deep understanding of immune processes. Using a next-generation single-cell “mass cytometry” platform we quantify surface and cytokine or drug responsive indices of kinase target with 45 or more parameter analyses (e.g. 45 antibodies, viability, nucleic acid content, and relative cell size). Similarly, we have developed two advanced technologies termed MIBI and CODEX that enable deep phenotyping of solid tissue in both fresh frozen and FFPE formats (50 –100 markers). Collectively, the systems allows for subcellular analysis from the 70nm resolution scale to whole tissue in 3D.I will present evidence of deep internal order in immune functionality demonstrating that differentiation and immune activities have evolved with a definable “shape”. Further, specific cellular neighborhoods of immune cells are now definable with unique abilities to affect cellular phenotypes—and these neighborhoods alter in various cancer disease states. In addition to cancer, these shapes and neighborhoods are altered during immune action and “imprinted” during, and after, pathogen attack, traumatic injury, or auto-immune disease. Hierarchies of functionally defined trans-cellular modules are observed that can be used for mechanistic and clinical insights in cancer and immune therapies.