Background: Response to anti-PD1 blockade has been associated with the presence of “partially exhausted” PD-1+ CD8 tumor-infiltrating lymphocytes (TILs) and ‘adaptive immune resistance’, characterized by INF gamma-driven upregulation of PD-L1. Poorly immunogenic tumors are associated with a low probability of response to this class of agents. Conversion of ‘cold’ poorly immunogenic tumors into ‘hot’ inflamed tumors, therefore, represents a major therapeutic goal.
Hypothesis: Electroporation-mediated IL-12 gene therapy (IT-pIL12-EP) will enhance immunogenicity in the low TIL/PD-1 refractory B16 model, leading to the generation of a systemic anti-tumor immune response and increased TILs.
Methods: To assess the ability of IT-pIL12-EP to generate a systemic anti-tumor effect, we developed a two-tumor model (B16.F10 or B16-OVA), where one only one tumor receives IT-pIL12-EP treatment. Histologic, transcriptional (NanostringTM) and flow cytometric analysis was performed on spleen and both treated and untreated tumors.
Results: IT-pIL12-EP led to tumor necrosis, leukocyte infiltration, up-regulation of pro-inflammatory genes and regression of most treated lesions. In the B16-OVA model, a significant enrichment of tumor antigen-specific (SIINFEKL-tetramer+) KLRGhiCD127low CD8 T cells was observed. The generation of these CD8T cells correlated with growth inhibition of the contralateral, untreated tumor. Transcriptional and flow cytometric analyses of the untreated tumor showed the presence of TAA-specific CD8 populations, and an increased INF gamma signature (i.e. Ifng, Cd274, STAT1, Cxcl10).
Conclusions: IT-pIL12-EP enhances the immunogenicity in the poorly immunogenic, low TIL B16.F10 syngeneic mouse model, leading to the generation and dissemination of a TAA-specific KLRGhiCD127low CD8T cell population. The emergence of this population correlates with the induction of a INF-gene signature consistent with the induction of ‘adaptive immune resistance’ in the distant, untreated tumors. Based on these data, we predict that IT-pIL-12-EP will increase the response rates of anti-PD1 blockade in immunologically ‘cold’ tumors.
Credits: None available.
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