Systemic Infusion of dsRNA (Rintatolimod) plus IFNa Selectively Enhances Intratumoral CTL Influx in Cancer Patients 2701

Abstract Description Entry of cytotoxic T cells (CTLs) into tumor microenvironments (TME) is critical for the clinical efficacy of immune checkpoint inhibitors (ICI), adoptive T cell therapies (ACT) and other immunotherapies. Our preclinical studies show that a chemokine-modulatory regimen (CKM) combining TLR3-ligands and IFNa synergistically induce transient production of CTL attracting chemokines and suppresses Treg-attractants. CKM also selectively targets (NFkB-high) cancer lesions, but not healthy tissues, suggesting a feasibility of its systemic application to abolish heterogeneity of TMEs, promote uniform CTL infiltration and responsiveness to immunotherapies. Our pilot trial NCT03403634 tested the safety and immunologic efficacy of IV infusion of IFNa2b (20MU/m2 over 30 mins) and selective TLR3-ligand (rintatolimod/Ampligen; 200 mg over 2.5h), 6 infusions over 2 weeks, in patients with metastatic triple-negative breast cancer (TNBC). It showed very good tolerability, average 10.3-fold increase in intratumoral CTL markers and preliminary signals of clinical activity (1 objective response, 50% survival of > 4 years), when followed by pembrolizumab. Analogous CTL increases were also seen on study NCT04081389 (neoadjuvant CKM/chemotherapy in TNBC) and NCT03403634 (liver-metastatic colon cancer). Ongoing studies NCT04093323 (PD1-resistant solid tumors), NCT02432378 (advanced ovarian cancer), test the clinical efficacy of concomitant application of CKM with PD1 blockade and/or DC vaccines. Funding Sources Supported by NIH/NCI grants P01CA234212, P30A016056, P50CA159981, K08CA279766, NIH/NCATS grants UL1TR001412, KL2TR001413, R03TR004607, DOD grant W81XWH-19-1-0674, Jacobs Family Foundation, Rustum Foundation, Roswell Park Alliance Foundation and Roswell Park Institutional Funds. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)