ABSTRACT. This supplement will evaluate the efficacy of our highly selective immunotherapeutic platform in HIV-positive cancer patients. This novel biologics platform, termed synTac for “artificial immunological synapse for T-cell activation”, recapitulates elements of the antigen-specific and costimulatory signals experienced at the immunological synapse. Composed of covalently tethered peptide-MHC modules (c-pMHC) and costimulatory molecules linked to an Fc domain scaffold, synTac directs epitope-specific delivery of a wide range of costimulatory signals to targeted T cell populations. The sc-pMHC domain acts as an “address” to target specific T cell clones for delivery of a range of comodulatory domains (e.g., IL-2, 4-1BBL, CD28 agonists), resulting in antigen-selective modulation of disease relevant T cells in vitro and in vivo, thus eliminating the side effects of current immunotherapeutics, which elicit global immune modulation. Initial efforts will leverage the infrastructure of the Bronx site of the MACS/WIHS Combined Cohort Study (MWCCS), previously named the Women's Interagency HIV Study (WIHS) at Einstein/Montefiore. These studies will define the ability of the synTac platform to expand and activate SARS-CoV-2 specific T cells that are broadly represented across HIV-positive patients and healthy individuals as the consequence of natural infection and vaccination. Next we will examine the ability of our platform to modulate cancer specific CD8 T cells in HIV-positive cancer patients using synTacs that selectively target HPV E7-specific CD8 T cells. One such synTac is the subject of a multi-arm clinical trial for HPV-positive head and neck cancer. Importantly, HPV is implicated in a number of HIV-associated cancers (e.g., anal cancer, cervical cancer) found within the Montefiore Einstein Cancer Center catchment area in the Bronx in New York City; additional future opportunities may be provided by the MWCCS, which has collected PBMCs and has performed serial testing for HPV infection at multiple timepoints for all participants. T cell responses will be evaluated for polyfunctionality, TCR repertoire diversity and by single cell-RNAseq. The impact of synTacs delivering different costimulatory signals will be correlated with clinical parameters including viral load, gender, stage of disease, and race and ethnicity. The ability of synTacs to activate HPV E7-specific T cells will also be correlated with features of the tumor immune micro-environment, including quantification and analysis of E7- specific T cells from fresh harvested tumors, evaluation of viral and immune gene expression as well as quantification and phenotyping of tumor infiltrating T cells. Together, these studies will define the responsiveness of HIV-associated malignancies to the antigen-specific synTacs, identify the mechanistic differences between HIV-positive cancer patients, HIV-negative cancer patients and healthy individuals, and define biomarkers of response to synTa...