PROJECT SUMMARY/ABSTRACT Chimeric antigen receptor T cell therapy (CARTx) has transformed treatment for B cell malignancies. However, the effects of CARTx on humoral immunity and infection risk are incompletely understood. The high prevalence of hypogammaglobulinemia in CARTx recipients has driven frequent use of prophylactic immunoglobulin G (IgG) replacement therapy (IGRT) to prevent infections in this patient population. However, limited data exist to support this practice, and shortages, side effects, and cost necessitate careful stewardship of IGRT. Emerging data indicate that pathogen-specific antibodies often persist after CD19-CARTx, potentially contesting the need for IGRT. Well controlled studies are needed to ascertain the clinical utility of IGRT in CARTx recipients. Within this clinical context, other important and connected questions remain about how IGRT affects CAR-T cell function, in addition to the possible costs versus benefits of the effect of IGRT on healthcare resource utilization. This timely and unique proposal will be the first randomized, controlled trial of IGRT use in CARTx recipients and 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 previously unexplored outcomes such as CAR-T cell expansion, CAR- T cell persistence, CAR-T cell function, and healthcare resource utilization. For the proposed study, we have assembled an interdisciplinary group of physicians and scientists from high-volume CARTx centers who will leverage our expertise in immuno-oncology, infectious diseases, and cancer outcomes research. We propose a randomized trial of IGRT versus placebo in 150 adults with serum total IgG ≤400 mg/dL prior to CD19-CARTx. Participants will be randomized 1:1 to receive IGRT or placebo within 14 days prior to CARTx and at 28-day intervals after CARTx for 4 months. Aim 1 will compare between study arms the incidence rate of infections through 6 months after CD19-CARTx; we will also longitudinally characterize and compare total and pathogen-specific IgG levels and their association with infections. Aim 2 will explore the association of IGRT with healthcare resource utilization, cytokine release syndrome, and CARTx-associated neurotoxicity. Aim 3 will characterize the impact of IGRT on CAR-T cell expansion, persistence, and function. This will be the first randomized controlled study of IGRT after CARTx and will provide foundational data to establish evidence-based estimates of the clinical efficacy and risk-benefit of IGRT in CD19-CARTx recipients. In parallel, this study will explore other potential effects of IGRT on CAR-T cell dynamics and healthcare resource utilization. The data generated by this proposal will provide the groundwork for future studies to refine infection prevention strategies in the growing population of CARTx recipients.

PROJECT NARRATIVE People receiving chimeric antigen receptor T cell therapy (CARTx) for cancer treatment are often given immunoglobulin G (IgG) replacement therapy (IGRT) to prevent infections; however, no data support this practice in this patient population, and IGRT requires careful stewardship given national shortages, potential side effects, and high expense. To establish the risks and benefits of this frequently used infection-prevention strategy, we will conduct a randomized, placebo-controlled trial of IGRT in CARTx patients. We will compare infection rates, antibody levels, health resource utilization, and CAR-T cell kinetics and function among participants who do and do not receive IGRT to establish evidence-based data to guide the use of IGRT in the rapidly growing population of CARTx recipients.