Allogeneic, off-the-shelf, SARS-CoV-2-specific T cells (ALVR109) for the treatment of COVID-19 in high-risk patients

Abstract

Defects in T cell immunity to SARS-CoV-2 have been linked to an increased risk of severe COVID-19 disease (even after vaccination), persistent viral shedding and the emergence of more virulent viral variants. To address this T cell deficit, we sought to prepare and cryopreserve banks of virus-specific T cells (VSTs), which would be available as a partially HLAmatched off-the-shelf product for immediate therapeutic use. By interrogating the peripheral blood of healthy convalescent donors, we identified immunodominant and protective T cell target antigens, and generated and characterized polyclonal VST lines with activity against multiple clinically important SARS-CoV-2 variants (including ‘delta’ and ‘omicron’). The feasibility of making and safely utilizing such VSTs clinically was assessed by administering partially HLAmatched, third-party, cryopreserved SARS-CoV-2-specific T cells (ALVR109) in combination with other antiviral agents to 4 individuals who were hospitalized with COVID-19. In conclusion, this study establishes the feasibility of preparing and delivering off-the-shelf SARS-CoV-2-directed VSTs to patients with COVID-19 and supports the clinical use of VSTs outside of the profoundly immune compromised setting (ClinicalTrials.gov number, NCT04401410).

Respiratory virus infections after allogeneic stem cell transplantation: Current understanding, knowledge gaps, and recent advances

“…The potential to ex-vivo expand T cells against a respiratory virus has already been demonstrated by our group and others in the context of SARS-COV-2. [221][222][223] A novel approach has recently been developed to expand polyclonal multi-respiratory T cells against selected viral antigens based on their T cell immunogenicity and sequence conservation: hMPV (F, N, M2-1, and M), hPIV-3 (M, HN, N and F), RSV (N and F), and IFV (NP1 and MP1). 224 This multivirus allogeneic T cell product named ALVR106 is undergoing testing in a phase 1-2 trial currently enrolling patients (NCT04933968).…”

Expanded specific T cells to hypomutated regions of the SARS-CoV-2 using mRNA electroporated antigen-presenting cells

“…Efforts have started to address the gaps in the care of immunosuppressed patients and thus, SARS-CoV-2 peptide-based T cell therapies are being developed against structural SARS-CoV2 proteins. 36 , 37 , 38 Remarkably, we were able to mount T cell responses in about three-quarters of HDs, who were not previously exposed to COVID-19 or vaccinated against SARS-CoV2 immediately suggesting cross-reactivity with other types of coronaviruses. However, de novo priming and expansion of specific T cells cannot be excluded as a larger antigen repertoire may be presented by APCs loaded with full length mRNAs potentially due to a more physiologic antigen processing.…”

T cell immune profiling of respiratory syncytial virus for the development of a targeted immunotherapy

“…Our group has previously demonstrated the feasibility, safety and clinical efficacy of administering allogeneic ex vivo expanded multi-virus-specific T cells (multi-VSTs) as a banked, partially HLA-matched off-the-shelf investigational product designed for the treatment of EBV, CMV, BKV, HHV6, AdV and SARS-CoV-2 infections/disease in immunocompromised individuals. 9,10 This precedent of clinical success using adoptively transferred T cells, along with the accumulating evidence for the importance of functional T cell immunity in mediating virus control in respiratory viral infections, 11,12 provide the rationale for extending the therapeutic scope of VST therapy to RSV infections in vulnerable populations. Thus, with the current work we identified immunodominant antigens for RSV-ST generation that should F I G U R E 1 T cell immune profiling of RSV and detailed characterization of ex vivo expanded RSV-STs.…”