AUTHOR=Filipovic Aleksandra , Miller George , Bolen Joseph 

TITLE=Progress Toward Identifying Exact Proxies for Predicting Response to Immunotherapies

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 8 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.00155

DOI=10.3389/fcell.2020.00155

ISSN=2296-634X

ABSTRACT=Checkpoint inhibition (i.e., antibodies directed against pathways involved in adaptive  immune suppression, such as CTLA-4, PD-1 and PDL-1), represent a landmark accomplishment in oncology, and the most rapidly growing drug class.  Their efficacy has transformed life expectancy in multiple deadly cancer types (melanoma, lung cancer, renal/urothelial carcinoma, certain colorectal cancers, lymphomas etc.). Approved indications, however, are not universal, and the prospect of broad therapeutic efficacy across tumour histologies remains elusive. With an eye towards broadening immunotherapy applications, identification of biomarkers that predict therapeutic response and/or limit adverse events are a critical need in the field. Specificities surrounding checkpoint inhibitors in clinic, such as unexpected tumour 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 tumour 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. Multiple challenges, such as acquiring and handling biospecimens, identification and validation of new biomarkers, data sharing, and collaborating across disciplines pave the way to rapid biomarker development in immuno oncology. Multi-disciplinary efforts have already yielded some approved (PDL-1 and MSI-status) and other advanced tests (TMB, neoantigen pattern, 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.