Comment on Management Practices of CAR T-cell-Related Inflammatory Toxicities: A Survey of Pediatric CAR T-cell Providers.

Management Practices of CAR T-cell-Related Inflammatory Toxicities: A Survey of Pediatric CAR T-cell Providers.

Decreased Chimeric Antigen Receptor T-Cell Efficacy with Severe or Prolonged Post-Infusion Cytopenias

CAR-T cell therapy is associated with life-threatening inflammatory toxicities, partly due to the activation and secretion of inflammatory cytokines by bystander myeloid cells (BMCs). However, due to limited clinical data, it is unclear whether CAR-NK cells cause similar toxicities. We characterized the soluble factors (SFs) released by activated human CAR-T and CAR-NK cells and assessed their role in BMC activation (BMCA). We found that SFs from both activated, peripheral blood-derived CAR-T (PB-CAR-T) and CAR-NK (PB-CAR-NK) cells induced BMCA; however, PB-CAR-NK cells caused significantly lower BMCA compared to PB-CAR-T cells. Interestingly, SFs from cord-blood-derived (CB) NK cells caused little to no BMCA, consistent with previous clinical studies showing minimal inflammatory toxicity with CB-CAR-NK cells. Comparative analysis of SFs released by PB-NK and PB-CAR-NK cells following CAR-dependent and CAR-independent activation revealed several candidate factors with the potential to cause BMCA. Antibody-mediated neutralization studies identified a combination of four factors that contribute to PB-CAR-NK cell-mediated BMCA. siRNA-mediated knockdown studies confirmed that inactivating these four factors in PB-CAR-NK cells significantly reduces BMCA. Importantly, neutralization or knockdown of these four factors did not affect CAR-NK cell potency. These data suggest that specific SFs released by PB-CAR-NK cells activate BMCs and have the potential to contribute to inflammatory toxicities. Furthermore, inactivation of these four factors in PB-CAR-NK cells could reduce inflammatory toxicities and improve safety of PB-CAR-NK cell therapy without compromising potency.

Engineered T cell therapies such as chimeric antigen receptor (CAR) expressing T cells (CAR-T cells) have great potential to treat many human diseases; however, inflammatory toxicities associated with these therapies present safety risks and can greatly limit its widespread use. This article briefly reviews our current understanding of mechanisms for inflammatory toxicities during CAR T-cell therapy, current strategies for management and mitigation of these risks and highlights key areas of knowledge gap for future research.

Understanding and treating the inflammatory adverse events of cancer immunotherapy

Cytokine release syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies

Risk Factors and Outcomes for Hematotoxicity Following Tisagenlecleucel for Pediatric B-Acute Lymphoblastic Leukemia

INSPIRED Symposium Part 3: Prevention and Management of Pediatric Chimeric Antigen Receptor T Cell-Associated Emergent Toxicities

CD22 TCR-Engineered T Cells Exert Anti-Leukemia Cytotoxicity without Causing Inflammatory Responses

Racial and Ethnic Differences in Clinical Outcomes Among Multiple Myeloma Patients Treated with CAR T Therapy

Chimeric Antigen Receptor T Cell Therapies Clinical Trials in Pediatric Oncology: A Retrospective Analysis from Clinicaltrials.Gov

Chimeric antigen receptor (CAR) T cells effectively treat B cell malignancies. However, CAR-T cells cause inflammatory toxicities such as cytokine release syndrome (CRS), which is in contrast to T cell receptor (TCR)-engineered T cells against various antigens that historically have rarely been associated with CRS. To study whether and how differences in receptor types affect the propensity for eliciting inflammatory responses in a model system wherein TCR and CAR target equalized sources of clinically relevant antigen, we discovered a CD22-specific TCR and compared it to CD22 CAR. Both CD22 TCR-T and CD22 CAR-T cells eradicated leukemia in xenografts, but only CD22 CAR-T cells induced dose-dependent systemic inflammation. Compared to TCR-T cells, CAR-T cells disproportionately upregulated inflammatory pathways without concordant augmentation in pathways involved in direct cytotoxicity upon antigen engagement. These differences in antileukemia responses comparing TCR-T and CAR-T cells highlight the potential opportunity to improve therapeutic safety by using TCRs.

Global Distribution of Clinical Trials on Chimeric Antigen Receptor T-Cells in the Pediatric Population: The Economic Impact on Clinical Trials Development

B - 20 Neuropsychological Functioning of Pediatric CAR T-Cell Therapy Patients.

GFAP and NfL increase during neurotoxicity from high baseline levels in pediatric CD19-CAR T-cell patients