Background: Despite the availability of effective vaccines, post-allogeneic hematopoietic stem cell transplant (HSCT) patients are at risk for severe and/or prolonged disease due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early after HSCT (i.e. prior to vaccine eligibility and prior to reconstitution of adaptive immunity). Effective preventive as well as treatment strategies are therefore needed. We have developed an ex vivo expanded donor-derived SARS-CoV-2-specific T cell (CST) product (IND 27588) for the prevention of SARS-CoV-2 infection early post-allogeneic HSCT. Herein we report preliminary results from our phase I dose escalation trial (NCT05141058) evaluating the safety, feasibility, and preliminary efficacy of donor-derived CST prophylaxis administered early (<4 months) post-allogeneic HSCT.

Objectives: The primary objectives of this study were to: (i) evaluate the safety of CST therapy, defined through incidence of dose-limiting toxicities (DLT) (Grade ≥3 infusion-related adverse events, Grade ≥3 acute graft versus host disease [GVHD], and/or any cytokine release syndrome [CRS])or multisystem inflammatory syndrome [MIS] within 45 days post-CST infusion and (ii) measure preliminary efficacy of donor-derived CST prophylaxis be evaluating immunologic correlates of antiviral immune reconstitution using results from adults (Arm A) treated at Dose Level 1 (DL1) on NCT05141058.

Methods: Donor-derived CSTs were generated in a Good Manufacturing Process (GMP) facility using a rapid ex vivo expansion protocol that has been previously described. Eligible adult (≥18 to 80 years) participants were enrolled to receive a single CST infusion of 1E7 cells/m2 ≥28 days and <4 months post allogeneic HSCT and were monitored for DLTs over a 45-day safety monitoring period. Serial SARS-CoV-2 antigen screening and blood collection for immune correlative assays were performed for 1 year post infusion. Antiviral T cell responses were assessed using IFN-γ ELISpot and flow cytometry with intracellular staining (ICS) to measure cytokine production in response to viral antigen.

Results: Ten recipient/donor pairs were enrolled and had a donor-derived product successfully manufactured. Six potential recipients did not meet eligibility criteria within the specified time for infusion (2 withdrew, 1 tested positive for SARS-CoV-2, and 3 had complications post-transplant). Four patients received a CST infusion with no occurrence of DLTs. One recipient experienced acute gastrointestinal GVHD 19 days post CST infusion, coinciding with a decrease in immune suppressive medications and considered unlikely related to the CST product. All four recipients have completed 1 year follow up and none have tested positive for SARS-CoV-2. Manufactured products maintained specificity against both Wuhan-Hu1 and circulating SARS-CoV-2 variants on IFN-γ ELISpot when compared to actin negative control (Wuhan-Hu1 40.8 [SD=35.1], BQ1.1 12.6 [SD=11.6], XBB1.5 13.3 [SD=13.1], JN.1 21.3 [SD=5.3] v actin 2.4 [SD=3.4] spots per 1E5 cells, p <0.05). On Day 270 post CST infusion PBMCs were available for 3 out of 4 patients with an average of 1.45% [SD=1.31%] of CD3+ cells secreting IFN-γ and TNF-α in response to SARS-CoV-2 spike antigen compared to 0.14% [SD=0.08%] of cells exposed to actin negative control (p <0.05).

Conclusions: Infusion of donor-derived CSTs as a prevention strategy early post allogeneic HSCT was safe in adults at DL1. CSTs generated against the Wuhan-Hu1 strain of SARS-CoV-2 maintain specificity against circulating viral variants. Polyfunctional SARS-CoV-2-specific T cell responses are present in CST recipients and can be tracked post infusion.

Future Directions: Recruitment to NCT05141058 is ongoing and recently extended to pediatric HSCT recipients. Further deep phenotyping and clonotype tracking by TCR sequencing may help advance antiviral T cell therapies post allogeneic HSCT.

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2025
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