Anti-PD1 blockade results in durable responses across a wide range of solid tumor types, including squamous cell carcinoma of the head and neck (HNSCC). The presence of PD1+ ‘partially exhausted’ CD8 T cells adjacent to PDL1+ cells within the tumor correlates with response to anti-PD1 blockade. This phenotype, often referred to as ‘adaptive immune resistance’, is thought to reflect compensatory upregulation of PDL1 due to IFNg produced by CD8 T cells upon antigen binding. In contrast to high TIL tumors, which have a high probability of response to PD1 inhibition, the major pattern of PD1 nonresponsive tumors is a lack of these ‘exhausted’ TILs. A high prevalence of poorly immunogenic tumors represents a significant unmet medical need in immuno-oncology, in general, including in HNSCC. To convert PD1 nonresponders into responders, effective approaches are needed to enhance tumor immunogenicity and generate tumor-associated antigen (TAA)-specific TILs. IL-12 is a potent proinflammatory cytokine critical in driving anti-tumor Th1 immune responses.
We hypothesize that intratumoral electroporation of plasmid DNA-encoded IL-12 (IT-pIL12-EP) can lead to immunogenic cell death and release of TAAs, including neo-antigens, in the appropriate proinflammatory context to achieve an effective “in situ vaccination”. We developed a contralateral syngeneic mouse model, wherein tumor cells are implanted in the subcutis on the left and right flanks, allowing analysis of both treated and untreated tumors.
Initial studies utilized the low TIL, PD1 refractory B16.F10 syngeneic mouse tumor model, stably transfected with the experimental neo-antigen ovalbumin (B16-OVA). In this model, IT-pIL12-EP leads to necrosis, a pleomorphic inflammatory infiltrate, generation of a proinflammatory gene signature, and complete regression of treated tumors (>95%). Growth of untreated distant tumors is significantly inhibited and correlates with expansion of specific anti-OVA (SIINFEKL+) CD8 T cells in the spleen and in TILs. IT-pIL12-EP is now being tested in the E6/E7 (HPV-16) expressing TC1 mouse model.
Two Phase 2 trials with IT-pIL12-EP in Merkel cell carcinoma and melanoma have been completed. IT-pIL12-EP leads to sustained increases in intralesional IL-12 levels (tissue ELISA), increased TILs (IHC and NanostringTM-based gene expression analysis), abscopal effects, and objective clinical responses. To date, IT-pIL12-EP is safe and well-tolerated. Based on these data, a multicenter Phase 2 study of IT-pIL12-EP in treatment refractory metastatic and unresectable HNSCC was initiated. Interim clinical data and immunological correlates will be discussed.