Introduction
NSCLC, SCLC, tumor, cancers, melanoma, toxicity, cancer, head and neck (, MSI-H, CI-non-responsive, tumors
TUMOR, INFILTRATION, CANCERS, SCLC, MELANOMA, INFILTRATE, CANCER, PROSTATE, MICROSATELLITE INSTABILITY, NSCLC, INFILTRATING, TUMORS, COLD
Checkpoint inhibitors (CIs) such as anti-PD-1, anti-PD-L1 and anti-CTLA-4 have demonstrated activity in multiple immunogenic tumor types, including melanoma, NSCLC, SCLC, bladder, renal, and head and neck (One strategy that has been tried to increase the cytotoxic activity of CD8 T cells and to overcome the immunosuppressiveness of the tumor microenvironment is the administration of immunotherapy in combination: checkpoint inhibitors with non-overlapping mechanisms of action such as an anti-PD-1 and an anti-CTLA-4 have been evaluated in several tumor types (It has been proposed that the difference between CI-responsive or “hot” tumors i.e., melanoma and NSCLC and CI-non-responsive or “cold” tumors i.e., pancreas, prostate, ovarian and microsatellite stable (MSS)-colorectal is the density of T cell infiltration; the denser the immune infiltrate (i.e., the hotter the tumor) the greater the likelihood of benefit from checkpoint blockade. Conversely, the less dense the infiltrate (i.e., the colder or the more “immune excluded”) the tumor the less responsive to checkpoint blockade. The positive effect of tumor infiltrating lymphocytes (TILs) has been reported in several cancers (Inefficient trafficking of T cells to the tumor is a function of several factors including an aberrant vasculature with irregular blood flow (RRx-001 is a minimally toxic NLRP3 inhibitor (Given the favorable toxicity profile of RRx-001 and since both CD-47 and PD-L1 serve as innate and adaptive checkpoints, respectively, it was hypothesized that the combination of RRx-001 and nivolumab would be well-tolerated and potentially active in tumor types that were traditionally non-CI-responsive due to the broadness of induced innate and adaptive immune stimulation against target tumors.Different dosing schedules exist for the treatment with RRx-001, ranging from pretreatment as a single agent once or twice weekly for up to 1 month or to co-administration with a combination partner every week or every other week until progression. Schedules, which involve pretreatment may be less active in combination with immunotherapy since RRx-001 administration has been associated with the generation of the immunosuppressive and pro-fibrotic cytokine, TGF-β (The top dose of RRx-001 chosen was 16 mg since activity has been observed at approximately this dose in the Phase 1 study (No biopsies were performed, and no biomarkers were analyzed or assessed before or during this study. In another study (ClinicalTrials.gov Identifier: NCT02489903), an association was observed between tumor associated macrophage (TAM) density and response to RRx-001. However, as no biopsies were performed in PRIMETIME due to investigator and patient reluctance, this correlation could not be confirmed (Commonly used biomarkers to predict response to checkpoint inhibitors include tumoral PD-L1 expression and presence of high tumor mutation burden (TMB), deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H); however, the PD-L1, TMB, and dMMR/MSI-H status of these patients was and is unknown. On-treatment “liquid biopsy”, that is circulating tumor DNA (ctDNA) analysis may provide early evidence of response and progression both to RRx-001 and checkpoint inhibitors, but this was not performed.One potential biomarker of efficacy, which it is possible to assess, is that of pseudoprogression wherein tumors, having initially enlarged due to immune cell infiltration, subsequently regress or stabilize as these immune cells eliminate cancer cells (