Novel Biologics to Treat Lung Cancer and COVID-19 Comorbidity

Novel Biologics to Treat Lung Cancer and COVID-19 Comorbidity: Analyses of patients with COVID-19 treated at the Montefiore Medical Center (University Hospital of the Albert Einstein College of Medicine) indicate a high mortality (28%) in cancer patients, in general, and a 55% mortality in patients with lung cancer, especially those that received lung radiation 1-12 months prior to COVID-19 diagnosis. We propose to study the role that CD8 T cell depletion plays as a determinant of this adverse outcome, as CD8 T cells have been shown to provide substantial protection from lethal severe acute respiratory syndrome due to coronavirus infection. We are exploiting a novel biologics platform to provide mechanistic insight into the impact of radiation therapy on the number and quality of protective lung-resident COVID-19 T specific cells. This platform, termed synTac (artificial immunological Synapse for T-cell Activation), selectively modulates specific disease-relevant T cell clones for targeted treatment of malignancies, autoimmune disease and infectious diseases. In this unique design, single chain peptide-MHC (sc-pMHC) constructs are covalently linked to a variety of costimulatory, coinhibitory and cytokine molecules. The sc-pMHC domain acts as an "address" to target specific T cell clones for delivery of a range of comodulatory domains (MODS), resulting in clonal-selective T cell modulation, thus eliminating the side effects of current immunotherapeutics, which elicit global immune modulation (i.e., stimulation or inhibition of all T cells). This technology is the foundation of Cue Biopharma (Almo, founder), a publically traded immunotherapy company focused on development and application of this platform. A synTac containing the HPV-derived E7 peptide and IL-2 cytokine elicits selective T cell expansion and tumor growth inhibition of an E7-driven tumor in pre-clinical models. The human analog of this synTac (CUE-101) is in a Phase 1 clinical trial for head/neck squamous cell carcinoma - HNSCC (NCT03978689) demonstrating favorable tolerability and drug exposure. Preclinical studies demonstrated antitumor efficacy as monotherapy and with anti-PD1 treatment. Based upon these findings, Merck, collaborating with Cue Biopharma, is launching a Phase I first-line study of CUE-101 in combination with Keytruda for HPV+ advanced HNSCC. We have adapted this platform to generate viral-targeted synTacs, possessing antigenic peptides for HIV and CMV, to deliver costimulatory signals through CD28 or 4-1BB receptors. These reagents support substantial in vivo expansion of HIV- and CMV-specific T cells (in the NGS murine system), and this platform is being expanded to utilize COVID-19 derived peptides for selective in vivo expansion of protective CD8 T cells for COVID-19 treatment and cancer/radiation comorbidities.