Discussion
ascites, cancers, pleural effusion, DLTs, tumor, pleural or peritoneal disease, pleural disease, TNBC, RCC, esophagogastric carcinoma, tumors
PLEURAL EFFUSION, ASCITES, CANCERS, OVARIAN CANCER, TUMOR, PROLIFERATION, DISEASE, PLEURAL DISEASE, SOLID TUMOR, EFFUSIONS, PLEURAL EFFUSIONS, EVENTS, TUMORS, RCC
IFN-γ signaling plays an integral role in regulating immune activation and senescence in the TME, induces the expression of PD-L1 and is an essential component of an effective anti-tumor response with PD-1 pathway targeted agentsOverall, the combination was well tolerated. An increased burden of flu-like symptoms was present in most patients, slightly worse at higher doses of IFN-γ, but were generally grade 1-2 and tolerable with supportive care. We did see an unexpected number of patients develop new ascites or pleural effusions, but it is unclear whether this is attributable to IFN-γ. Prior trials of single-agent IFN-γ have not previously reported such a concern. The majority of patients who developed new fluid collections had cancers associated with ascites (i.e., ovarian cancer), or had baseline pleural or peritoneal disease that may have foreshadowed this possibility. One patient developed a pleural effusion after IFN-γ induction without baseline pleural disease that improved upon subsequent anti-cancer therapy without positive fluid cytology. Further trials that involve IFN-γ should consider incorporating planned prospective fluid analysis in patients that develop new ascites or effusions.Exploratory analyses of efficacy in this trial were modest, with one patient with metastatic TNBC and no prior immunotherapy exposure achieving a durable CR. Although two patients achieved stable disease despite progression on prior ICB, the sample size is too small to make any conclusions. One clear limitation of this trial is the heterogeneous population, with multiple diagnoses that have subsequently demonstrated poorly immunogenic tumors or modest single agent benefit from PD-1 targeted drugs, thus potentially hampering any benefit from IFN-γ. Additionally, the four dose cohorts are small, limiting efforts to assess differences in IFN-γ dose ranges, although more patients with clinical benefit were treated in the two lower dosed cohorts. Based on a combination of increased low-grade AEs and DLTs starting at 75 mcg/mNotably, in an exploratory post-hoc observation, there appeared to be a paucity of irAEs amongst patients in this study. The relative incidence of grade ≥ 3 irAE development with nivolumab is about 10-15%. With 26 treated patients, we would have predicted 3-4 events, and yet only one patient developed any manifestations attributable as an irAE, and this only after discontinuing IFN-γ. Several factors may have contributed to this, for example 46.2% patients had received prior ICB without any irAEs and thus may have been less likely to develop an irAE. Additionally, 16 of 23 patients evaluable for efficacy (69.6%) progressed within the first 100 days of therapy, and simply may not have been exposed long enough to nivolumab. It is also possible this was merely by chance. However, it is reasonable to speculate whether the IFN-γ may have altered the immune milieu in such a way to restrain irAE development. Support for this hypothesis exists with the results of the post-hoc exploratory cytokine analysis, which showed a statistically significant increase in CXCL9, CXCL10, and CXCL11. These three chemokines are known to be directly induced by IFN-γ signaling and bind to a common receptor (CXCR3). Primarily, they are responsible for regulating immune cell migration, differentiation, and activation and thus are important regulators of immune responses in the TME; however, they have also been implicated in promoting tumor proliferation and metastasesA number of notable findings were revealed in pre-planned exploratory PBMC flow cytometry studies and biopsy tissue assessments. IFN-γ induction significantly increased the frequency of intermediate monocytes (CD14Additionally, patients with the lowest frequency of circulating CD4There were several limitations to this trial that may have impacted the results. The heterogeneous population and small cohort sizes limits comparisons of efficacy and correlatives and dose comparisons. Future trials of larger cohorts in specific cancers, such as RCC, TNBC, or esophagogastric carcinoma, might allow for better assessment of efficacy and a better understanding of the impacts of IFN-γ at the TME in these tumors. The choice of subcutaneous every other day administration may not have been optimal and may have limited the impact of IFN-γ on the TME and ultimately on efficacy. Lastly, advances and standardization in PD-L1 testing that were not available when this study was designed and conducted may have affected the analytic yield.In summary, the combination of IFN-γ and nivolumab in previously treated advanced solid tumor patients was safe and based on clinical and correlative findings we recommend 50 mcg/m