37. Allogeneic, Off-the-Shelf, SARS-CoV-2-specific T Cells Demonstrate Reactivity Against Emerging Variant Strains

BACKGROUND: The impact of COVID-19 has been profound with >170,000,000 confirmed cases worldwide and emerging variants being a cause of global concern. Defects in T-cell function and trafficking have been described among those with severe illness, and immunodeficiency is a risk factor for persistent viral shedding and prolonged symptoms. Because of our prior clinical data demonstrating that allogeneic, off-the-shelf virus-specific T cells (VSTs) can safely and effectively treat viral infections, we investigated the feasibility of targeting COVID-19 using banked, SARS-CoV-2-specific VSTs. METHODS: We first screened PBMCs from convalescent individuals against 18 structural and non-structural/accessory (NSPs/APs) SARS-CoV-2 proteins and identified 5 [Spike (S), Membrane (M), Nucleoprotein (N), NSP4, and AP7a] as immunodominant which were then advanced to our VST production process. RESULTS: Using overlapping peptide libraries spanning these antigens as a stimulus, we achieved a mean 7.6±0.9 fold expansion (n=13) of VSTs (96±0.5%), with a mixture of cytotoxic (CD8+) and helper (CD4+) T cells that expressed activation and central/effector memory markers. These VSTs were potent, Th1-polarized and polyfunctional, producing IFNγ, TNFα, GM-CSF and Granzyme B. Moreover, the VSTs were able to kill pepmix-loaded autologous targets with no evidence of auto- or alloreactivity, attesting to their virus selectivity and safety for clinical use (Figure 1). Finally, though initially generated against the reference strain NC_045512.2 (Wuhan), these VSTs were able to recognize other clinically important variants including B1.1.7 (UK), B1.351 (South Africa) and P1 (Brazil). This demonstrates the cross-reactive potential of these polyclonal and diverse VSTs, which were developed to provide potent antiviral effects and minimize the risk of immune escape due to sequence variation. Figure 1: SARS-CoV-2 Specific T cells Have Demonstrated Selective Cytolytic Activity against SARS-CoV-2 While Leaving Non-Virus Infected Targets Intact. [Image: see text] CONCLUSION: In conclusion, it is feasible to generate polyclonal SARS-CoV-2 VSTs that provide coverage against variant strains using GMP-compliant manufacturing methodologies. We have advanced this product to the bedside for administration in a Phase I, randomized clinical trial [VSTs+ standard of care (SOC) vs SOC] in high-risk patients hospitalized with COVID-19 (NCT04401410). DISCLOSURES: Spyridoula Vasileiou, PhD, AlloVir (Consultant) Manik Kuvalekar, MSc, AlloVir (Consultant) Aster Workineh, MSc, AlloVir (Employee) Ayumi Watanabe, BSc, AlloVir (Consultant) Yovana Velazquez, BSc, AlloVir (Consultant) Helen Elisabeth Heslop, MD, AlloVir (Shareholder)Cell Medica (Grant/Research Support)Gilead Sciences (Consultant)Kiadis Pharma (Consultant)Marker Therapeutics (Consultant, Shareholder)Mesoblast (Consultant)Novartis (Consultant)PACT Pharma (Consultant)Tessa Therapeutics (Consultant, Research Grant or Support) Premal Lulla, MD, Johnson & Johnson (Shareholder) Ann Marie Leen, PhD, AlloVIr (Consultant, Shareholder)Marker Therapeutics (Consultant, Shareholder)