Quadriparesis and paraparesis following chimeric antigen receptor T-cell (CART) therapy in children and adolescents.

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common but potentially severe adverse event associated with chimeric antigen receptor T-cell (CART) therapy characterized by the development of acute neurologic symptoms following CART infusion. ICANS encompasses a wide clinical spectrum typified by mild to severe encephalopathy, seizures and/or cerebral edema. As more patients have been treated with CART new ICANS phenomenology has emerged. We present the clinical course of five children who developed acute onset of quadriparesis or paraparesis associated with abnormal brain and/or spine neuroimaging after infusion of CD19 or CD22-directed CART, adverse events not previously reported in children. Orthogonal data from autopsy studies, cerebrospinal fluid (CSF) flow cytometry and CSF proteomics/cytokine profiling demonstrated chronic white matter destruction, but a notable lack of inflammatory pathologic changes and cell populations. Instead, children with quadriparesis or paraparesis post-CART therapy had lower levels of pro-inflammatory cytokines such as interferon gamma (IFN), CCL17, CCL23, and CXCL10 than those who did not develop quadriparesis or paraparesis. Taken together, these findings imply a non-inflammatory source of this newly described ICANS phenomenon in children. The pathophysiology of some neurologic symptoms following CART may therefore have a more complex etiology than exclusive T-cell activation and excessive cytokine production.

Mapping child and adolescent self-reported symptom data to clinician-reported adverse event grading to improve pediatric oncology care and research.

BACKGROUND: Clinicians are the standard source for adverse event (AE) reporting in oncology trials, despite the subjective nature of symptomatic AEs. The authors designed a pediatric patient-reported outcome (PRO) instrument for symptomatic AEs to support the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) (the Pediatric PRO-CTCAE). The current study developed a standardized algorithm that maps all possible Pediatric PRO-CTCAE response patterns to recommended CTCAE grades to improve the accuracy of AE reporting in pediatric oncology trials. METHODS: Two rounds of surveys were administered to experienced cancer clinicians across 9 pediatric hospitals. In round 1, pediatric oncologists assigned CTCAE grades to all 101 possible Pediatric PRO-CTCAE response patterns. The authors evaluated clinician agreement of CTCAE grades across response patterns and categorized each response pattern as having high or low agreement. In round 2, a survey was sent to a larger clinician group to examine clinician agreement among a select set of Pediatric PRO-CTCAE response patterns, and the authors examined how clinical context influenced grade assignment. RESULTS: A total of 10 pediatric oncologists participated in round 1. Of the 101 possible patterns, 89 (88%) had high agreement. The Light weighted kappa was averaged across the 10 oncologists (Light kappa = 0.73; 95% CI, 0.66-0.81). A total of 139 clinicians participated in round 2. High clinician agreement remained for the majority of generic response patterns and the clinical context did not typically change grades but rather improved agreement. CONCLUSIONS: The current study provides a framework for integrating child self-reported symptom data directly into mandated AE reporting in oncology trials. Translating Pediatric PRO-CTCAE responses into clinically meaningful metrics will guide future cancer care and toxicity grading.

Relationship Between State-Level Google Online Search Volume and Cancer Incidence in the United States: Retrospective Study.

BACKGROUND: In the United States, cancer is common, with high morbidity and mortality; cancer incidence varies between states. Online searches reflect public awareness, which could be driven by the underlying regional cancer epidemiology. OBJECTIVE: The objective of our study was to characterize the relationship between cancer incidence and online Google search volumes in the United States for 6 common cancers. A secondary objective was to evaluate the association of search activity with cancer-related public events and celebrity news coverage. METHODS: We performed a population-based, retrospective study of state-level cancer incidence from 2004 through 2013 reported by the Centers for Disease Control and Prevention for breast, prostate, colon, lung, and uterine cancers and leukemia compared to Google Trends (GT) relative search volume (RSV), a metric designed by Google to allow interest in search topics to be compared between regions. Participants included persons in the United States who searched for cancer terms on Google. The primary measures were the correlation between annual state-level cancer incidence and RSV as determined by Spearman correlation and linear regression with RSV and year as independent variables and cancer incidence as the dependent variable. Temporal associations between search activity and events raising public awareness such as cancer awareness months and cancer-related celebrity news were described. RESULTS: At the state level, RSV was significantly correlated to incidence for breast (r=.18, P=.001), prostate (r=-.27, P<.001), lung (r=.33, P<.001), and uterine cancers (r=.39, P<.001) and leukemia (r=.13, P=.003) but not colon cancer (r=-.02, P=.66). After adjusting for time, state-level RSV was positively correlated to cancer incidence for all cancers: breast (P<.001, 95% CI 0.06 to 0.19), prostate (P=.38, 95% CI -0.08 to 0.22), lung (P<.001, 95% CI 0.33 to 0.46), colon (P<.001, 95% CI 0.11 to 0.17), and uterine cancers (P<.001, 95% CI 0.07 to 0.12) and leukemia (P<.001, 95% CI 0.01 to 0.03). Temporal associations in GT were noted with breast cancer awareness month but not with other cancer awareness months and celebrity events. CONCLUSIONS: Cancer incidence is correlated with online search volume at the state level. Search patterns were temporally associated with cancer awareness months and celebrity announcements. Online searches reflect public awareness. Advancing understanding of online search patterns could augment traditional epidemiologic surveillance, provide opportunities for targeted patient engagement, and allow public information campaigns to be evaluated in ways previously unable to be measured.

Chimeric Antigen Receptor T Cell Manufacturing on an Automated Cell Processor.

Chimeric antigen receptor (CAR)-T cells represent a promising immunotherapeutic approach for the treatment of various malignant and non-malignant diseases. CAR-T cells are genetically modified T cells that express a chimeric protein that recognizes and binds to a cell surface target, resulting in the killing of the target cell. Traditional CAR-T cell manufacturing methods are labor-intensive, expensive, and may carry the risk of contamination. The CliniMACS Prodigy, an automated cell processor, allows for manufacturing cell therapy products at a clinical scale in a closed system, minimizing the risk of contamination. Processing occurs semi-automatically under the control of a computer and thus minimizes human involvement in the process, which saves time and reduces variability and errors. This manuscript and video describes the T cell transduction (TCT) process for manufacturing CAR-T cells using this processor. The TCT process involves CD4+/CD8+ T cell enrichment, activation, transduction with a viral vector, expansion, and harvest. Using the Activity Matrix, a functionality that allows ordering and timing of these steps, the TCT process can be customized extensively. We provide a walk-through of CAR-T cell manufacturing in compliance with current Good Manufacturing Practice (cGMP) and discuss required release testing and preclinical experiments that will support an Investigational New Drug (IND) application. We demonstrate the feasibility and discuss the advantages and disadvantages of using a semi-automatic process for clinical CAR-T cell manufacturing. Finally, we describe an ongoing investigator-initiated clinical trial that targets pediatric B-cell malignancies [NCT05480449] as an example of how this manufacturing process can be applied in a clinical setting.

Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies.

Chimeric antigen receptor T-cell (CAR-T) therapy is an exciting development in the field of cancer immunology and has received a lot of interest in recent years. Many time-to-event (TTE) endpoints related to relapse, disease progression, and remission are analyzed in CAR-T studies to assess treatment efficacy. Definitions of these TTE endpoints are not always consistent, even for the same outcomes (e.g., progression-free survival), which often stems from analysis choices regarding which events to consider as part of the composite endpoint, censoring or competing risk in the analysis. Subsequent therapies such as hematopoietic stem cell transplantation are common but are not treated the same in different studies. Standard survival analysis methods are commonly applied to TTE analyses but often without full consideration of the assumptions inherent in the chosen analysis. We highlight two important issues of TTE analysis that arise in CAR-T studies, as well as in other settings in oncology: the handling of competing risks and assessing the association between a time-varying (post-infusion) exposure and the TTE outcome. We review existing analytical methods, including the cumulative incidence function and regression models for analysis of competing risks, and landmark and time-varying covariate analysis for analysis of post-infusion exposures. We clarify the scientific questions that the different analytical approaches address and illustrate how the application of an inappropriate method could lead to different results using data from multiple published CAR-T studies. Codes for implementing these methods in standard statistical software are provided.

Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial.

PURPOSE: To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy. METHODS: Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial. RESULTS: The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (P < .001), but persistence was not different (P = .73). Event-free and overall survival were worse in the HTBC (P = .004, P < .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (P = .18). CONCLUSION: Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.

Humanized CD19-Targeted Chimeric Antigen Receptor (CAR) T Cells in CAR-Naive and CAR-Exposed Children and Young Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia.

PURPOSE: CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed. METHODS: We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19. RESULTS: Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts. CONCLUSION: HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy.