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

Chimeric antigen receptor (CAR) T cell (CAR-T) therapy has emerged as a revolutionary cancer treatment modality, particularly in children and young adults with B cell malignancies. Through clinical trials and real-world experience, much has been learned about the unique toxicity profile of CAR-T therapy. The past decade brought advances in identifying risk factors for severe inflammatory toxicities, investigating preventive measures to mitigate these toxicities, and exploring novel strategies to manage refractory and newly described toxicities, infectious risks, and delayed effects, such as cytopenias. Although much progress has been made, areas needing further improvements remain. Limited guidance exists regarding initial administration of tocilizumab with or without steroids and the management of inflammatory toxicities refractory to these treatments. There has not been widespread adoption of preventive strategies to mitigate inflammation in patients at high risk of severe toxicities, particularly children. Additionally, the majority of research related to CAR-T toxicity prevention and management has focused on adult populations, with only a few pediatric-specific studies published to date. Given that children and young adults undergoing CAR-T therapy represent a unique population with different underlying disease processes, physiology, and tolerance of toxicities than adults, it is important that studies be conducted to evaluate acute, delayed, and long-term toxicities following CAR-T therapy in this younger age group. In this pediatric-focused review, we summarize key findings on CAR-T therapy-related toxicities over the past decade, highlight emergent CAR-T toxicities, and identify areas of greatest need for ongoing research.

Chimeric antigen receptor T cells for mature B-cell lymphoma and Burkitt lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy has changed the landscape of immunotherapy for B-cell malignancies, including mature B-cell lymphomas. Although two CD19 CAR T-cell products have been commercially approved to treat relapsed/refractory B-cell lymphomas, outcomes in these patients remain inferior to those of patients with B-cell leukemia, regardless of therapy. Recent clinical studies and preclinical reports suggest that certain characteristics, such as the suppressive lymphoma tumor microenvironment and inferior endogenous T-cell fitness, may contribute to discrepant responses in these patients. In addition, these studies revealed that limited CAR T-cell persistence and tumor antigen escape, which also impact B-cell acute lymphoblastic leukemia, may play a more prominent role in lymphoma. Multiple promising strategies to overcome these barriers have advanced to clinical trials. In this review, we assess CAR T-cell therapies for pediatric relapsed/refractory mature B-cell lymphomas, potential obstacles diminishing antitumor activity and limiting CAR T-cell persistence, and current strategies to overcome these obstacles.

Replacing CAR-T cell resistance with persistence by changing a single residue.

Sustained persistence of chimeric antigen receptor T (CAR-T) cells is a key characteristic associated with long-term remission in patients with hematologic malignancies. Attempts to uncover mechanisms that enhance persistence and thus functionality will have a substantial impact in broadening application of CAR-T cell therapy, especially for solid tumors. In this issue of the JCI, Guedan et al. describe a promising strategy to limit T cell exhaustion and improve persistence by changing a single amino acid in the costimulatory domain of CD28. The authors demonstrated that this single amino acid substitution in CD28-based mesothelin CAR-T cells results in improved persistence and functionality in a xenograft model of pancreatic cancer. Furthermore, reciprocal alteration of the same residue in inducible costimulator-containing (ICOS-containing) CAR-T cells resulted in limited antitumor activity and persistence. These findings suggest that simple alterations in the costimulatory domain may enhance CAR-T cell persistence, warranting future evaluation in other CD28-costimulatory CARs in an effort to improve durable antitumor effects.

Medication use in the neonatal intensive care unit.

OBJECTIVE: The aim of the article is to provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time. STUDY DESIGN: We performed a retrospective review (2005-2010) of a large prospectively collected administrative database. RESULT: Medications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56-681 exposures per 1,000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram. CONCLUSION: Medication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are Food and Drug Administration -approved in infants.