Biomarkers of therapy response and resistance in clear cell renal cell carcinoma AND Adaptive immune response to SARS-CoV-2 and COVID-19 vaccines in cancer patients

Abstract

The cornerstone of treatment for metastatic clear cell renal cell carcinoma (ccRCC) are anti-VEGF and/or immune checkpoint inhibitors (CPI). However, there are no clinically implemented predictive biomarkers in any therapeutic settings. Intratumour heterogeneity (ITH) is a pervasive phenomenon of ccRCC. Studies to date examining putative biomarkers have used single-region biopsies and therefore not accounted for ITH. Moreover, genomic and tumour immune microenvironment (TME) changes under therapy have not been examined, which could inform potential mechanisms of anti-VEGF/CPI synergy and renal dynamic correlates of therapy response and resistance. I examined the determinants of anti-PD-1 monotherapy response in multiregion tumour samples collected pre- and post-treatment within a prospective phase II clinical trial. I discovered maintenance of previously expanded T cell clones underpin nivolumab response. Within another prospective clinical study which examined effects of axitinib in patients with metastatic ccRCC, I show preliminary data from driver mutation and gene expression profiling of longitudinal, multiregion tumour samples. Separately, using a tumour-informed, phylogenetic approach to profile circulating tumour DNA, I showed clonal phylogeny of ccRCC can be recapitulated by peripheral sampling as a potential means of circumnavigating the shortcomings of tissue-based biopsies. From March 2020, the SARS-CoV-2 pandemic halted routine laboratory operations for 18 months. During this time and as an emergency response, my doctoral studies pivoted towards uncovering the immunological basis of poor outcomes to SARS-CoV-2 infection and functional immunity against SARS-CoV-2 variants of concern (VOC) and following COVID-19 vaccination in cancer patients. I report the rapid establishment of a prospective, pan-cancer study (CAPTURE) for longitudinal immune profiling of cancer patients in the context of SARS-CoV-2 and COVID-19 vaccines. CAPTURE provided a large dataset (n=784 patients enrolled to date), within which I describe a case of cytokine release syndrome following BNT162b2 vaccination in a patient under anti-PD-1 therapy; and show patients with hematological malignancies had impaired neutralising antibody responses against VOC that was disease lineage and anti-CD20 treatment-specific, in the setting of both SARS-CoV-2 infection (n=118) and COVID-19 vaccines (n=585).