IAP inhibitors as novel immune adjuvants for scaffold based cancer vaccines.

摘要

Inhibitors of apoptosis (IAP) antagonists are nearing approval as promising new candidates for cancer therapy, particularly for solid tumors. Previous work had uncovered the ability of the monomer version of this drug to co-stimulate T cells and enhance anti-tumor immunity when administered systemically in conjunction with B16/GVAX, a model of melanoma immunotherapy. Further published work from multiple labs revealed the ability of these drugs to influence a variety of immune subsets. Given that IAP proteins are known to regulate alternative NFkB downstream of TNFR family members (e.g. GITR, BAFF-R, LTBR), it is evident that IAP antagonism has different effects on non-immune versus immune cells. Where drug treatment in non-immune cells sensitizes these cells to apoptosis, in contrast immune cells do not undergo cell death. We have uncovered the ability of both monomer and dimer inhibitor to enhance survival in B cells cultured ex-vivo and, in the context of stimulation, further costimulate these cells. In an effort to improve the therapeutic effect in our model we investigated local delivery of IAP antagonists via bioabsorbable poly-lactide-co-glycolide (PLG) scaffolds. Interestingly, IAP monomer, but not dimer resulted in reproducible reduction in tumor growth and increased survival of mice when delivered peritumorally in the absence of additional immunotherapy. Further studies in naive mice revealed increased cellular infiltration in monomer loaded scaffolds when compared to blank scaffolds across a month time course. Upon FACS analysis of these cellular infiltrates, scaffolds loaded with drug contained a striking enrichment of B cells and follicular dendritic cells, suggesting IAP inhibitor delivered in subcutaneous site could form tertiary lymphoid structures, an intriguing possibility given that lymphotoxin signaling, essential for secondary lymphoid organ development, occurs through alternative NFkB. Additional ex vivo experiments revealed that monomer, but not dimer could enrich for lymphoid tissue inducer cells, suggesting the possibility that IAP monomer could be used as a novel immune adjuvant delivered locally where it could impact higher order immune interactions as a therapeutic agent by itself.