PD-L1 was always a controversial biomarker, in part because assays were not harmonized, and in part because many oncologists prefer “all-comers” rather than biomarker-selected drug indications. PD-L1 nevertheless is important biologically and, consequently, its importance as a selective biomarker continues to expand across more indications and across more drugs. This program will provide an overview of PD-L1 companion diagnostics and associated drug indications in 2021.

We have extensive clinical data on the effectiveness of PD-1 blockade in cancer. However, we lack a mechanistic understanding of PD-1 blockade despite many recent findings. While “exhausted’ T cells in the tumor microenvironment are known to be reactivated with PD-1 blockade, we also know that systemic priming and activation of T cells may provide the source of anti-tumor reactivity. In this presentation, all the current data is summarized on this topic.

Head and neck squamous cell carcinoma (HNSCC) upregulates TIGIT, PD-1 and LAG-3 to inhibit T cell activation. Vectra® Polaris™ multiplex immunofluorescence panels and Indica Halo® algorithms reveal TIGIT-expressing T cells within HNSCC, including exhausted T cells (TIGIT+PD1+LAG3+CD3+(CD4+/CD8+), T helper cells (CD3+CD4+), T cytotoxic cells (CD3+CD8+) and T regulatory cells (CD3+CD4+FoxP3).

The critical immunosuppressive role of the tumor microenvironment (TME) in cancer immunotherapy is now recognized in the research and clinical community. However, our understanding of the relationship between the TME components and the immune system is limited. We will explore AIM Biotech’s easy-to-use and versatile organ-on-a-chip platform to better understand immune-oncology biomarkers with relationship to the tumor microenvironment. Six examples will be presented and discussed. 

PD-L1 IHC has demonstrated predictive value for IO monotherapy, but predictive role of this assay for combination therapies is more diffuse. PD-L1 assay is still used in most clinical lung cancer practices for guidance of IO. Tumor mutation burden (TMB) is an emerging predictive biomarker in tissue and plasma. The TMB assays need standardization. New and better predictive biomarker(s) for immunotherapy are needed.

Cancer samples are predictive biomarkers that have long been used to select a patient’s therapy. Predictive biomarkers such as the expression of proteins or DNA mutations are used to select patients for targeted therapies. It is unlikely a single biomarker will suffice selecting patients for therapy. These concepts will be discussed in the setting of colorectal cancer.

Biospecimen sourcing is becoming a challenge for many scientists who need to respect timelines for R&D plans as well as regulatory and ethical constraints. Are the scientists working with the samples aware of all the imperatives to obtain them; quality, respect of laws, ethics and regulations?

As PD-1 checkpoint inhibitor containing regimens become standard of care in first line therapy, oncologists and cancer biologists are shifting focus to address the care of patients after PD-1 treatment failure. Data addressing the biology of PD-1 treatment failure remain uncertain. Several prospective trials have shown increased efficacy of a variety of agents after PD-1 failure. A cross-sectional survey of available data from the post-PD-1 treatment clinical literature will be reviewed.

Data presented will include the pharmacologic profile of axicabtagene ciloleucel, a first in class anti-CD19 CAR T cell therapy approved for the treatment of  aggressive NHL. In addition, top-line results and the pharmacologic profile of KTE-X19 in the setting of r/r MCL will be presented. Biological factors that influence CAR therapy including product fitness, tumor immune microenvironment and tumor biology in relation to clinical outcomes will be described.

JTX-8064 is a LILRB2/ILT4 antagonist mAb that may relieve myeloid cell immuno-suppression by shifting macrophages to an M1-like state and activating T cells. Using histoculture, pharmacodynamic (PD) responses to JTX-8064 can be measured preclinically in a human ex vivo tumor system. Ex vivo evaluation of human tumors identified hypotheses for both predictive and pharmacodynamic markers that can be evaluated in the clinical development of JTX-8064.

Biomarkers have become a cornerstone in the study of immuno-oncology. Biomarkers contribute to the elucidation of response and resistance to immunotherapies and co-administered agents and are used as selection criteria to enrich for response. Immunohistochemical markers such as PD-L1 in addition to next-generation molecular markers including MSI, TMB and gene expression signatures continue to deliver insights into novel I-O therapies and the dynamics within the tumor and its microenvironment.

Developing the next generation of sophisticated immune oncology therapies will require new tools to identify and characterize cascades of changes within the larger tumor context. Spatial technologies are rapidly advancing and the balance between efficiency and depth of discovery will be addressed. Examples of how multiplexed immunofluorescence has been integrated into a larger immune oncology drug discovery program will be presented.

The cancer genome plays a fundamental role in the ability of the immune system to recognize a cancer as foreign. Here we will review the latest updates in understanding how TMB, HLA, mutations in the DNA damage response, neoantigen prediction algorithms, amongst others can help identify which tumors are the most immunogenic and likely to benefit from immunotherapy based treatment approaches.

Through innovations in single cell sequencing and spatial transcriptomics, solutions from 10x Genomics help researchers dissect the immune and tumor microenvironment, track the anti-tumor immune response, and uncover immune cell types and states governing response and resistance to immunotherapies. Join 10x Genomics to learn how researchers are using our single cell assays and spatial tools to gain a multidimensional view of cancer immunity.

Recent changes in the understanding of melanoma immunotherapy response and resistance have resulted in the identification of new tumor and blood-based biomarkers for prediction and/or monitoring melanoma patients prior to and during treatment with immunotherapy. Integration of multiple data sets will be critical for utilization of this data for clinical care.

Blocking either the PD-1 receptor or its ligand PD-L1 has improved overall survival in patients across tumor types. While some tumors fail to respond due to a lack of immune cells infiltrating the tumor, others fail despite immune cells in the tumor. By targeting other B7 pathways such as VISTA and HHLA2, we may be able to improve outcomes for patients with these "hot" tumors.

Exosomes, a subset of small extracellular vesicles (EVs), are emerging as key components of liquid tumor biopsy in cancer and as biomarkers of immune competence. Plasma-derived exosomes can be separated by immune capture into tumor cell-derived and T cell-derived fractions. Each fraction carries information about the tumor or immune competence of the cancer patient, respectively. Simultaneous real-time molecular profiling of the tumor and of the host immune status by plasma-derived exosomes suggest that sEVs are highly promising biomarkers in immune oncology.

In recent years metastatic melanoma patients have had improved survival on treatment with checkpoint inhibitor immunotherapies (CII).  Efficient real-time monitoring of patients' disease progression is needed to improve management. Cell-free nucleic acids detection is a sensitive blood biomarker assay. A robust next-generation sequencing targeted assay was developed to assess plasma cell-free microRNA (cfRNA) to assess patients' disease status during CII. cfmiR signature can be used to monitor CII responders and nonresponders.   

Our lab is interested in finding blood-based biomarkers that could be predictive of immunotherapy success, for different tumor types and different immunotherapy settings. We use CyTOF mass cytometry, with in vitro polyclonal stimulation, to read out a broad range of cell type frequencies and functions. In two trials involving CTLA-4-based immunotherapy of advanced melanoma, we found CD8+ T cells with a central memory (CM) phenotype, or that are capable of producing IL-2, to be increased in responders compared to non-responders. Because CM T cells are capable of greater proliferation and functional differentiation than more effector-like T cells, their abundance may be one indicator of the ability to mount an effective anti-tumor T cell response. However, in anti-PD-1 treated melanoma patients, we did not find a significant correlation of CM CD8+ T cell frequencies and response. Instead, we found activated NK cells to be increased in responders vs. non-responders, suggesting a possible unexpected mechanism of action of PD-1 through NK cells. We anticipate that, while CM CD8+ T cells may be important for anti-tumor T cell immunity generally, and for CTLA-4 based therapy in particular, there will be other blood-based predictive biomarkers unique to certain immunotherapy agents.