Effect of therapeutic vaccine on CTLA4 and tumor debulking response in recurrent and metastatic HNSCC.

Abstract

115 Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is associated with multiple immune suppression and avoidance mechanisms . Blocking the PD-1 signal axis in second line provides a significant survival advantage compared to chemotherapy. However, checkpoint blockade efficacy is limited to the subset of patients that present with tumors highly infiltrated with effector immune cells. We investigated a novel vaccine designed to increase the infiltration of tumor-specific effector cells and counter-regulate the suppressive tumor microenvironment. Methods: Pre-treated r/m HNSCC patients with externally visible tumors were accrued. Tumor biopsy samples were processed at baseline to purify endogenous chaperones with calreticulin, hsp70, hsp90 and gr94/gp96 (CRCL) as a source of tumor neoantigen. Ex-vivo differentiated, allogeneic Th1 memory cells with CD3/CD28-coated microbeads attached (aTh1) expressing CD40L and IFN-gamma served as adjuvant. Subjects were primed with 4 weekly aTh1 ID injections to increase allo-specific Th1 memory titer. Primed subjects were provided 3 weekly ID injections of CRCL + aTh1 to increase tumor-specific Th1 memory titer followed by intravenous aTh1 in the 4th week to activate circulating memory cells through CD40-CD40L, causing their extravasation and trafficking to tumor lesions. Allo-rejection response produces a sustained Type 1 cytokine release which dys-regulates suppressor circuits. The ID/IV cycle was then repeated. Results: 10 subjects with recurrent or metastatic disease were accrued. All with prior radiochemotherapy. 50% (5/10) had clinical response with visible reduction in tumor burden. Vaccine was well tolerated. Debulking response correlated with increased CD3+ immune cell infiltration and decreased CTLA-4 expression. Conclusions: This individualized vaccine caused increased immune cell infiltration in tumors, down-regulation of CTLA4 and visible tumor debulking in a heavily pre-treated, chemotherapy-refractory population. These results provide rationale for further evaluation of this vaccine in a first-line setting with and without PD1/L1 blockade. Clinical trial information: NCT01998542.