Progress Toward Identifying Exact Proxies for Predicting Response to Immunotherapies

Clinical value and utility of checkpoint inhibitors, a drug class targeting adaptive immune suppression pathways (PD-1, PDL-1, and CTLA-4), is growing rapidly and maintains status of a landmark achievement in oncology. Their efficacy has transformed life expectancy in multiple deadly cancer types (melanoma, lung cancer, renal/urothelial carcinoma, certain colorectal cancers, lymphomas, etc.). Despite significant clinical development efforts, therapeutic indication of approved checkpoint inhibitors are not as wide as the oncology community and patients would like them to be, potentially bringing into question their universal efficacy across tumor histologies. With the main goal of expanding immunotherapy applications, identifying of biomarkers to accurately predict therapeutic response and treatment related side-effects are a paramount need in the field. Specificities surrounding checkpoint inhibitors in clinic, such as unexpected tumor response patterns (pseudo- and hyper-progression), late responders, as well as specific immune mediated toxicities, complicate the management of patients. They stem from the complexities and dynamics of the tumor/host immune interactions, as well as baseline tumor biology. Search for clinically effective biomarkers therefore calls for a holistic approach, rather than implementation of a single analyte. The goal is to achieve dynamic and comprehensive acquisition, analyses and interpretation of immunological and biologic information about the tumor and the immune system, and to compute these parameters into an actionable, maximally predictive value at the individual patient level. Limitation delaying swift incorporation of validated immuno-oncology biomarkers span from standardized biospecimens acquisition and processing, selection of proficient biomarker discovery and validation methods, to establishing multidisciplinary consortiums and data sharing platforms. Multi-disciplinary efforts have already yielded some approved (PDL-1 and MSI-status) and other advanced tests (TMB, neoantigen pattern, and TIL infiltration rate). Importantly, clinical trial taskforces now recognize the imperative of the biomarker-driven trial design and execution, to enable translating biomarker discoveries into the clinical setting. This will ensure we utilize the "conspiracy" between the peripheral and intra-tumoral dynamic markers in shaping responses to checkpoint blockade, for the ultimate patient benefit.