Infection prevention strategies after CAR-T cell therapy

PROJECT SUMMARY/ABSTRACT Patient-oriented research of infection prevention strategies in chimeric antigen receptor T cell therapy (CARTx) recipients will facilitate improvement in clinical outcomes and a wealth of opportunities for trainees. This award will provide protected time for Dr. Hill to mentor trainees in clinical research related to mitigating the immune-related adverse effects from CARTx, thereby reducing infectious complications. This proposal will study the use of passive and active immunotherapeutic strategies to prevent infections after CARTx, including immunoglobulin replacement therapy (IGRT) and vaccination. In Aim 1, Dr. Hill will conduct the first randomized, controlled, multicenter trial of IGRT in 150 adult CARTx recipients with serum total IgG ≤400 mg/dL at five cancer centers. These data will provide critical insights into the potential risks and benefits of IGRT in this patient population. The key objectives of this study are to evaluate whether IGRT in CARTx recipients reduces infection rates compared to placebo, and to understand the impact of IGRT on cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and healthcare resource utilization. As part of new research supported by this award, patients will be administered a validated survey to evaluate whether IGRT is associated with improvements in health-related quality of life (Aim 3), which will enable future cost-effectiveness research. In Aim 2, Dr. Hill will conduct an open-label clinical trial using an inactivated rabies vaccine in 28 CARTx recipients with relapse-free survival for ≥6 months, in addition to 10 healthy controls. Vaccination after CARTx cell therapy may provide a more durable and cost-effective approach to infection prevention than IGRT, but there are limited data to guide vaccination strategies after CARTx. The objectives of this study are to determine antibody responses, and clinical correlates of vaccine responsiveness, using a rabies virus vaccine as a neoantigen challenge. The rabies vaccine provides a unique tool to assess immune responses while patients are receiving prophylactic immunoglobulin given no or low anti-rabies immunoglobulin in these products. Dr. Hill will build on this infrastructure to study innovative vaccination strategies to improve immunogenicity in immunocompromised patients in Aim 4. He will conduct a pilot study in 20 CARTx recipients using a ‘fractional escalating dose’ delivery for the initial vaccine dose, followed by a booster ‘bolus’ dose. The objectives of this study are to determine whether the fractional escalating dose strategy improves the proportion of patients who develop protective antibody responses, which could shift the paradigm for vaccinating immunocompromised individuals. These aims address critical knowledge gaps in CARTx recipients, provide a robust infrastructure for POR training of physician scientists, and will provide the groundwork for future studies to refine infection prevention strategies in the growing population of CARTx recipients.