Summary Chimeric antigen receptor T‐cell (CAR T‐cell) therapy is associated with significant toxicities secondary to immune activation, including a rare but increasingly recognised severe toxicity resembling haemophagocytic lymphohistiocytosis (carHLH). We report the development of carHLH in 14·8% of paediatric patients and young adults treated with CD19‐specific CAR T‐cell therapy with carHLH, occurring most commonly in those with high disease burden. The diagnosis and treatment of carHLH required a high index of suspicion and included multidrug immunomodulation with variable response to therapies. Compared to patients without carHLH, patients with carHLH had both reduced response to CAR T‐cell therapy (P‐value = 0·018) and overall survival (P‐value = < 0·0001).

Adoptive cellular immunotherapy using immune cells expressing chimeric antigen receptors (CARs) has shown promise, particularly for the treatment of hematological malignancies. To date, the majority of clinically evaluated CAR cell products have been derived from autologous immune cells. While this strategy can be effective it also imposes several constraints regarding logistics. This includes i) availability of center to perform leukapheresis, ii) necessity for shipment to and from processing centers, and iii) time requirements for product manufacture and clinical release testing. In addition, previous cytotoxic therapies can negatively impact the effector function of autologous immune cells, which may then affect efficacy and/or durability of resultant CAR products. The use of allogeneic CAR cell products generated using cells from healthy donors has the potential to overcome many of these limitations, including through generation of “off the shelf” products. However, allogeneic CAR cell products come with their own challenges, including potential to induce graft-versus-host-disease, as well as risk of immune-mediated rejection by the host. Here we will review promises and challenges of allogeneic CAR immunotherapies, including those being investigated in preclinical models and/or early phase clinical studies.

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Adolescent and young adult (AYA) oncology patients experience many physical and psychological symptoms at the end of life (EOL); however, data on these experiences for AYA patients that have undergone hematopoietic cell transplantation (HCT) remains sparse. We sought to investigate the characteristics of AYA patients aged 15 − 25 who received allogeneic HCT and subsequently died while inpatient at our institution between the years 2008 − 2014. A standardized data extraction tool was used to collect information about patient demographics, treatment, and symptoms. We found that during this time frame, 34 AYA patients had received HCT and died while inpatient at our institution, 23 (68%) of which were due to treatment-related complications. Compared to non-HCT AYA oncology patients (n = 35), patients who received HCT (n=34) were more likely to have died in the intensive care unit (71% vs. 23%, P < .0001) and to have received mechanical ventilation (68% vs. 17%, P < .0001) or hemodialysis (53% vs. 0%, P < .0001) in the last 30 days of life. These findings demonstrate that AYA patients who receive allogeneic HCT receive intensive EOL treatment, suggesting that these patients may benefit from early integration of expert interdisciplinary services to prospectively assess and manage distressing symptoms.

Highlights d CD19-CAR T cells undergo extensive DNA methylation reprogramming during therapy d DNA methylation status of the CAR T cell product can predict in vivo expansion d CD8 + CD19-CAR T cells acquire exhaustion-associated DNA methylation programs d Antigen-positive tumor relapse does not elicit CAR T cell expansion