Abstract
The Chimeric Antigen Receptor (CAR) T Cell Safety Database Project explored the use of cross-study safety data to identify risk factors associated with severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) after CAR T cell administration. Sponsors voluntarily submitted data for 1,926 subjects from 17 phases 1 and 2 studies (six acute lymphocytic leukemia [ALL], five non-Hodgkin's lymphoma [NHL], and six multiple myeloma [MM] studies). Subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. Subjects who received CAR T cells produced with gammaretrovirus vectors including CD28 sequences had higher rates of sNTX compared with subjects who received products produced with other vector designs included in the database. Use of cytokine-directed therapies and corticosteroids at lower toxicity grades were associated with lower rates of sCRS. Although this exploratory study was limited by unadjusted cross-study comparisons, it independently reproduced known risk factors for CAR T cell toxicity. Findings provide stakeholders in the CAR T cell clinical development community information on safety trends for consideration in early phase clinical trial design, as well as avenues for additional research.
Overview
- The study aimed to identify risk factors associated with severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) after CAR T cell administration using cross-study safety data. The study analyzed data from 1,926 subjects from 17 phases 1 and 2 studies (six acute lymphocytic leukemia [ALL], five non-Hodgkin's lymphoma [NHL], and six multiple myeloma [MM] studies).
- The study used unadjusted cross-study comparisons to compare outcomes observed under different experimental conditions or interventions detailed in the study. The study identified that subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. Subjects who received CAR T cells produced with gammaretrovirus vectors including CD28 sequences had higher rates of sNTX compared with subjects who received products produced with other vector designs included in the database. Use of cytokine-directed therapies and corticosteroids at lower toxicity grades were associated with lower rates of sCRS. The study independently reproduced known risk factors for CAR T cell toxicity. The primary objective of the study was to identify risk factors associated with severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) after CAR T cell administration using cross-study safety data. The study aimed to provide stakeholders in the CAR T cell clinical development community information on safety trends for consideration in early phase clinical trial design, as well as avenues for additional research.
Comparative Analysis & Findings
- The study compared outcomes observed under different experimental conditions or interventions detailed in the study. The study identified that subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. Subjects who received CAR T cells produced with gammaretrovirus vectors including CD28 sequences had higher rates of sNTX compared with subjects who received products produced with other vector designs included in the database. Use of cytokine-directed therapies and corticosteroids at lower toxicity grades were associated with lower rates of sCRS. The study independently reproduced known risk factors for CAR T cell toxicity. The key findings of the study were that subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. Subjects who received CAR T cells produced with gammaretrovirus vectors including CD28 sequences had higher rates of sNTX compared with subjects who received products produced with other vector designs included in the database. Use of cytokine-directed therapies and corticosteroids at lower toxicity grades were associated with lower rates of sCRS. These findings provide stakeholders in the CAR T cell clinical development community information on safety trends for consideration in early phase clinical trial design, as well as avenues for additional research.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The study identified that subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. This finding highlights the importance of considering patient-specific factors when designing CAR T cell clinical trials. The study also identified that subjects who received CAR T cells produced with gammaretrovirus vectors including CD28 sequences had higher rates of sNTX compared with subjects who received products produced with other vector designs included in the database. This finding suggests that the choice of vector design may impact the safety profile of CAR T cell therapy. The study also identified that use of cytokine-directed therapies and corticosteroids at lower toxicity grades were associated with lower rates of sCRS. This finding suggests that early intervention with these therapies may help mitigate the risk of sCRS. The study's limitations include unadjusted cross-study comparisons, which may have led to biased results. Future research should address these limitations by using more robust statistical methods and controlling for confounding factors. Future research should also explore the impact of other patient-specific factors, such as age and comorbidities, on the safety profile of CAR T cell therapy. Additionally, future research should investigate the long-term safety and efficacy of CAR T cell therapy in larger patient populations.