Near future of tumor immunology: Anticipating resistance mechanisms to immunotherapies, a big challenge for clinical trials

Abstract

The success of immunotherapies brings hope for the future of cancer treatment. Even so, we are faced with a new challenge, that of understanding which patients will respond initially and, possibly, develop resistance. The examination of the immune profile, especially approaches related to the immunoscore, may foretell which tumors will have a positive initial response. Ideally, the mutation load would also be analyzed, helping to reveal tumor associated antigens that are predictive of an effective cytolytic attack. However, the response may be hindered by changes induced in the tumor and its microenvironment during treatment, perhaps stemming from the therapy itself. To monitor such alterations, we suggest that minimally invasive approaches should be explored, such as the analysis of circulating tumor DNA. When testing new drugs, the data collected from each patient would initially represent an N of 1 clinical trial that could then be deposited in large databases and mined retrospectively for trends and correlations between genetic alterations and response to therapy. We expect that the investment in personalized approaches that couple molecular analysis during clinical trials will yield critical data that, in the future, may be used to predict the outcome of novel immunotherapies.

Evidence-Based Medicine in Oncology: Commercial Versus Patient Benefit

“…The remarkable increase in knowledge in molecular biology, virology and immunology and the many new concepts of translational research call for changes in the methodology of clinical trials [48,49]. For instance, it is recommended to establish databases of results from individual patients treated with personalized or individualized medicine for early identification of effective drugs or treatment strategies in a larger patient population [50]. Basket trials allow a drug to be tested simultaneously in subgroups of different tumor types [51].…”

Current approaches to immunotherapy in noncolorectal gastrointestinal malignancies

“…Despite the clear ability of MSI-H to predict ICP inhibitor response, no perfect biomarker for selecting patients for immunotherapy has been found. Further development in this field is necessary for the accurate selection of patients for treatment with checkpoint inhibitors 69 . Additionally, combined biomarker strategies are promising; such strategies are superior to single biomarkers for predicting the response to immunotherapy 70 .…”

“…Moreover, trials evaluating the role of monoclonal antibody combinations targeting different inhibitory pathways are underway. Additionally, as immunotherapy resistance mechanisms are increasingly recognized, more effective drugs can be developed 69 . Finally, progress in molecular engineering has led to the development of chimeric antigen receptor T cells (CAR-T cells) 72 , which have demonstrated impressive results in acute lymphoblastic leukemia 73 and promising activity in early studies in GI tumors 74 - 76 .…”

Single-Cell Analysis of Circulating Tumor Cells: How Far Have We Come in the -Omics Era?

“…Consequently, the N-of-1 trial seems more suitable in the case of rare tumors, in off-label use of a treatment, or when re-cycling is permitted, as in the case of immunotherapy (Catani et al, 2017).…”

“…In this respect, the interest of researchers is strongly catalyzed in pooling data from single patients treated with molecularly driven drugs (and immunotherapies), since these could be then queried to assess preliminary efficacy in a larger patient cohort (Catani et al, 2017). Special attention should be put on collecting liquid biopsies, and perhaps biopsies of the most accessible lesions throughout the trial, to prospectively evaluate biological mechanisms of treatment-induced resistance.…”