Harnessing Allo-immunity to Enhance Immune Checkpoint Inhibitor Responses in Advanced NSCLC

Michael E Debakey Va Medical Center, Houston TX

Investigators

Abstract

This application seeks to conduct a phase Ib proof-of-concept clinical trial at the Houston VA Lung Precision Oncology Program (LPOP) to determine if intratumor injections with pooled human immunoglobulins (IVIG) plus an immune adjuvant are safe. Patients with stage IV non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors (ICIs) show treatment resistance. Solid tumors fail to establish in unrelated hosts because of the host’s antibodies that deposit immune complexes and activate local antigen-presenting cells (APCs) in the tumor. Further, established tumors from related donors injected with alloantibodies plus an adjuvant, poly-IC, a potent TLR-3 agonist, abrogated the original tumors and their distant metastasis in mice. In a single phase I study, patients with solid tumors refractory to ICIs tolerated multiple intratumoral (IT) and intramuscular (IM) injections with a stabilized form of poly-IC, such as poly-ICLC, (Hiltonol®; Oncovir Inc, USA). However, whether IVIG intratumor injections can cause immune complex formation and, combined with TLR-3 agonists, can enhance ICIs in patients with advanced non-small cell lung cancer (NSCLC), remains unknown. Our preliminary data indicate that IVIG (Hizentra®) binds to antigens found in human NSCLC, indicating that like the preclinical models, intratumor injection with IVIG could induce immune complexes, inducing antitumor responses. We will test our overarching hypothesis that IT injection of IVIG + poly-ICLC and IM injection of poly-ICLC to boost APCs, are safe and can activate antitumor immunity in patients with advanced NSCLC with the following Specific Aims: Specific Aim 1: To determine the safety and maximum tolerated dose of intratumor injection of an immune adjuvant plus alloantibodies in veterans with advanced NSCLC. Hypothesis: a combination of intratumor (IT) injections of IVIG + poly-ICLC, and IM injections of poly-ICLC are safe in patients with advanced- stage NSCLC. We plan to conduct a first-in-human phase Ib single-center study at the Lung Precision Oncology Program (LPOP) MEDVAMC site titled: Harnessing Allo-Immunity To Enhance Immune Checkpoint Inhibitors in Advanced NSCLC (HAITEN-ICI). The study objective will be to evaluate the safety of, and maximum tolerated dose (MTD) of IT injections of a peripherally accessible metastatic site with IVIG + poly-ICLC followed by IM poly-ICLC in veterans with stage IV NSCLC (N=16) who are eligible to receive systemic ICIs monotherapy. The primary endpoint includes assessment of an MTD dose for IT injection of IVIG + poly-ICLC, and IM injection of poly-ICLC given in combination with ICI in the same cohort. Specific Aim 2: To determine the progression- free survival in response to immune adjuvant plus alloantibodies in veterans with advanced NSCLC. Hypothesis: compared to standard of care (SOC), poly-ICLC + IVIG improve progression-free survival in patients with advanced NSCLC receiving ICI. If our proof-of-concept pilot study conducted as part of Aim 1 shows no safety concerns, and we identify MTD, we will proceed with a phase II multi-center randomized clinical trial to determine the safety and progression-free survival (PFS) in veterans with advanced NSCLC treated with intertumoral IVIG + poly-ICLC, compared to SOC. Specific Aim 3: To explore immune responses in pre-and post-intratumor treatment with IVIG + poly-ICLC in Phase Ib & II cohorts. Hypothesis: intratumor injections using IVIG + poly-ICLC activates adaptive immune responses in advanced NSCLC patients. We will examine pre-, mid-and post-treatment systemic immune activation in comparison with baseline in patients enrolled in pilot phase Ib and if safe, in phase II study. We will compare pre- and post-therapy immune responses using state-of- the-art technologies for locoregional tumors. The proposed two-stage clinical trial is a novel approach to determine if inducing tumor-specific immune responses can enhance systemic ICI treatment and improve clinical outcomes for veterans with advanced NSCLC. Therefore, a combined treatment with an immune adjuvant such as poly-ICLC, plus IVIG could provide a novel approach to overcoming the tumor-suppressive microenvironment.