Discussion
cancer, tumor, melanoma, HNSCC
TUMOR, MELANOMA, CANCER, DISEASE, SECONDARY
Immune checkpoint inhibitors have transformed the practice of clinical oncology; yet, there remains a need for improvement in clinical outcomes by rational development of novel therapeutic approaches to overcome the multifaceted mechanisms of tumor evasion. The nonclinical evidence we present provides support for ICOS stimulation as a promising therapeutic strategy in the context of cancer.Because of priming of T cells through contact with cognate antigens and activation is necessary for induction of ICOS expression (Feladilimab was primarily identified on the basis of the mechanism to potentiate primary T-cell activation. In addition to demonstrating primary T-cell activation via induction of cytokines and phenotypic markers of activation, we demonstrated antibody-mediated forward signaling via AKT phosphorylation. Typically, experiments with primary T cells require cross-linking by either secondary antibody or cell-mediated FcrγIIB-Fc coengagement. However, as shown here, detectable antibody-mediated activation may be observed without strong cross-linking (e.g., in solution vs. plate-bound antibody) as reported previously (Intuitively, more effective antitumor immunity could potentially be achieved through combination of ICOS activation with other agents known to elicit T-cell activation via distinct mechanisms or pathways. The observed, robust induction of IFNγ by feladilimab in Other monoclonal ICOS antibodies such as alomfilimab (KY1044) and vopratelimab (JTX-2011) have demonstrated agonistic activity on human primary T cells, with requirement for FcR cross-linking, induction of proinflammatory cytokines such as IFNγ, and activation of forward signaling pathways; they have also shown antitumor efficacy as monotherapies in mouse models, with improved efficacy when administered in combination with anti-PD-1 antibodies (Our data represent the foundation for evaluating a humanized IgG4 ICOS agonist mAb, feladilimab, in clinical trials. In case studies from INDUCE-1 (NCT02723955), evidence of ICOS receptor engagement and immune activation with feladilimab treatment was observed in different tumor types as evidenced by the changes in the TME of patients with melanoma and HNSCC who experienced some clinical benefit and the overall reductions in tumor burden. While these example cases represent the translatability of functional changes with ICOS stimulation in patients who had clinical benefit, these findings may not characterize the cumulative data from all patients treated with feladilimab. Although the presented data from INDUCE-1 study are preliminary, these data support the randomized investigation of feladilimab in combination with pembrolizumab; however, it should be acknowledged that the INDUCE-3 and INDUCE-4 studies investigating the same combination in participants with recurrent or metastatic HNSCC were halted. Analysis is underway, and this will be the subject of a future article (Collectively, while these data provide support for ICOS stimulation and PD-1 blockade as a therapeutic strategy for cancer, they also underscore the need to continuously refine our understanding of the dynamic TME and the translational efforts that accompany drug development to identify disease indications and patients who could benefit from these novel therapies, and the need for randomized survival data to characterize their clinical benefit potential.