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 c...