COVID-19 Vaccination Strategies Should Consider Infection Risks for CAR T-Cell Therapy Recipients

Although CAR T-cell therapies have demonstrated unprecedented activity in patients with heavily pretreated relapsed/refractory hematologic malignancies, they are marked by a significant risk of infections and may limit the efficacy of COVID-19 vaccines. As such, data are needed to inform how to optimize COVID-19 vaccination and booster strategies among CAR T-cell therapy recipients, according to findings from a review published in Transplantation and Cellular Therapy.¹

“Although CAR T[-cell] therapy prolongs the survival of patients with relapsed/refractory diseases, the associated on-target, off-tumor toxicities, particularly infections, limit the effective utilization of this curative therapy,” wrote lead study author Juliet Meir, MD, a PL2 categorical resident at Westchester Medical Center of the Westchester Medical Center Health Network, and coauthors in the study publication.

To date, several CD19- and BCMA-directed CAR T-cell therapies have been FDA approved across multiple relapsed/refractory hematologic malignancies, including acute lymphoblastic leukemia, diffuse large B-cell lymphoma and other lymphomas with similar histopathological features, mantle cell lymphoma, and multiple myeloma.

With all products, CAR T-cell therapy is associated with unique short- and long-term toxicities and infection risks in patients with hematologic malignancies who were heavily pretreated with anti-cancer agents and, often, allogeneic hematopoietic stem cell transplant (allo-HSCT).

Acute toxicities, such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome, confer an early risk of infection following CAR T-cell therapy infusion. CAR T-cell therapy recipients are further predisposed to severe infections from long-term toxicities, including prolonged B-cell aplasia, hypogammaglobulinemia, and cytopenias. Moreover, these long-term adverse effects hinder the chance for remission associated with CAR T-cell therapy.

Ultimately, the risk of infections with CAR T-cell therapy is largely variable and depends on several patient-, disease-, and CAR T-cell therapy–related factors. Some of these factors include age at the time of CAR T-cell therapy, race/ethnicity, body mass index, Karnofsky performance status, disease status, cytogenetics, prior lymphodepletion chemotherapy regimens, the interval between cell collection and infusion, bridging therapy, minimal residual disease status at CAR T-cell therapy infusion, disease burden, CAR T-cell dose, signaling and costimulatory domains, target antigen, and duration of lymphopenia and hypogammaglobulinemia.

Notably, data suggest that CD19-directed CAR T-cell therapies induce more bacterial infections, whereas BCMA-directed therapies induce more viral infections because of differential expression patterns on the B-cell surface.

It is known that patients with cancer, particularly those with hematologic malignancies, are at an increased risk of developing severe and potentially fatal COVID-19 infections. Patients who have received CAR T-cell therapy or undergone allo-HSCT are at a heightened risk of morbidity and mortality from COVID-19 infections.

Additionally, data suggest that COVID-19 vaccine responses could be substantially decreased in patients who receive CAR T-cell therapy vs those who undergo allo-HSCT. Early data suggest that adequate humoral and cellular responses to COVID-19 vaccines may not be obtained in patients with hematologic malignancies.

Currently, the FDA is advising against checking vaccine responses; however, in select CAR T-cell therapy recipients, routine serological assessment could gauge vaccine responses and inform the need for additional vaccine doses.

Additionally, because of the potential diminishing effect corticosteroid use has on immune responses, the timing and intensity of steroids for prevention and treatment of CAR T-cell therapy–related toxicities should be weighed in the context of available COVID-19 vaccine platforms.

Regardless, patients who receive CAR T-cell therapy should continue implementing precautionary measures even if an immune response is confirmed. When possible, telemedicine should be utilized to minimize the risk of exposure to COVID-19 in immunosuppressed CAR T-cell therapy recipients. Telemedicine should be considered for long-term follow-up in the hospital and community settings.

Additionally, all health care professionals and caregivers should be vaccinated to minimize the risk of spreading COVID-19 to CAR T-cell recipients. Transplantation and cellular therapy centers should continue to implement strict mitigation strategies as well.

Ultimately, significant research is needed to determine how CAR T-cell therapy recipients are responding to COVID-19 vaccinations, particularly as booster vaccine dosing and heterologous prime-boosting strategies become more actualized.

“Given the immunosuppressed milieu as a driver for mutational SARS-CoV-2 variants, antiviral agents and long-acting monoclonal antibodies or small molecules, potentially resistant to current SARS-CoV-2 mutations, merit evaluation in prospective studies to halt the development of mutations and spread to close contacts,” Meir and coauthors wrote.

“Immunity to SARS-CoV-2 is conferred by intricate crosstalk of both antibody and T-cell responses. Insight into both responses is needed for an optimal understanding of protection in this vulnerable patient group,” Meir and coauthors concluded.

Reference

1. Meir J, Abid MA, Abid MB. State of the CAR-T: risk of infections with CAR-T therapy and determinants of SARS-CoV-2 vaccine responses. Transplant Cell Ther. Published online September 26, 2021. Accessed October 26, 2021. doi:10.1016/j.jtct.2021.09.016