CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR.

Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared with EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).

Weathering the storm when the end of the road is near: A qualitative analysis of supportive care needs during CAR T-cell therapy in pediatrics.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy provides promising outcomes in relapsed/refractory B acute lymphoblastic leukemia (ALL), yet still carries high toxicity rates and relatively poor long-term survival. Efficacy has yet to be demonstrated in other diagnoses while toxicity and risk profiles remain formidable. To date, treatment-related symptom burden is gleaned from clinical trial toxicity reports; the patient perspective remains understudied. METHODS: English- or Spanish-speaking patients (ages 8-25 years) undergoing CAR T-cell therapy for any malignancy and their primary caregivers were recruited from Seattle Children's Hospital (SCH), St. Jude Children's Research Hospital (SJCRH), and the Pediatric Oncology Branch of the National Cancer Institute (NCI). Both patient and caregiver completed semi-structured dyadic interviews 3 months post treatment. We used directed content analysis for codebook development and thematic network analysis for inductive qualitative analysis. RESULTS: Twenty families completed interviews (13 patients, 15 parents). Patients were a median age 16.5 years, predominantly female (65%), White (75%), and diagnosed with ALL (75%). Global themes included "A clear decision," "Coping with symptoms," and "Unforeseen psychosocial challenges." When families were asked to describe the "most challenging part of treatment," most described "the unknown." Most reported "the symptoms really weren't that bad," even among patients hospitalized for severe toxicity events. Fatigue, pain, and nausea were the most prevalent symptoms. Importantly, only one family would have chosen a different therapy, if given another opportunity. CONCLUSIONS: Although physical symptoms were largely tolerable, recognizing supportive care opportunities remains imperative, particularly psychosocial concerns.

A comprehensive analysis of adverse events in the first 30 days of phase 1 pediatric CAR T-cell trials.

The tremendous success of chimeric antigen receptor (CAR) T cells in children and young adults (CAYAs) with relapsed/refractory B-cell acute lymphoblastic leukemia is tempered by toxicities such as cytokine release syndrome (CRS). Despite expansive information about CRS, profiling of specific end-organ toxicities secondary to CAR T-cell therapy in CAYAs is limited. This retrospective, single-center study sought to characterize end-organ specific adverse events (AEs) experienced by CAYAs during the first 30 days after CAR T-cell infusion. AEs graded using Common Terminology Criteria for Adverse Events were retrospectively analyzed for 134 patients enrolled in 1 of 3 phase 1 CAR T-cell trials (NCT01593696, NCT02315612, and NCT03448393), targeting CD19 and/or CD22. A total of 133 patients (99.3%) experienced at least 1 grade ≥3 (≥Gr3) AE across 17 organ systems, of which 75 (4.4%) were considered dose- or treatment-limiting toxicities. Excluding cytopenias, 109 patients (81.3%) experienced a median of 3 ≥Gr3 noncytopenia (NC) AEs. The incidence of ≥Gr3 NC AEs was associated with the development and severity of CRS as well as preinfusion disease burden (≥ 25% marrow blasts). Although those with complete remission trended toward experiencing more ≥Gr3 NC AEs than nonresponders (median, 4 vs 3), nonresponders experiencing CRS (n = 17; 37.8%) had the highest degree of NC AEs across all patients (median, 7 vs 4 in responders experiencing CRS). Greater understanding of these toxicities and the ability to predict which patients may experience more toxicities is critical as the array of CAR T-cell therapies expand. This retrospective study was registered at www.clinicaltrials.gov as NCT03827343.

Fertility and CAR T-cells: Current practice and future directions.

Chimeric antigen receptor (CAR) T-cells serve to overcome chemotherapeutic resistance and have been proven to be highly effective in B-cell hematologic malignancies. Although initial use has been in patients with multiply relapsed/refractory disease, as CAR T-cells are used earlier in the treatment paradigm, it will be important to explore implications of this novel therapy on cancer late-effects. We sought to assess the current framework for considerations of fertility surrounding CAR T-cell use and identify opportunities for education and future research. To assess current practice patterns regarding post-CAR T-cell fertility, peri-CAR T-cell fertility guidance, utilization of fertility preservation surrounding CAR T-cell administration and identify future areas of research, a cross-sectional survey assessing practice patterns regarding fertility counseling and outcomes surrounding CAR T-cell therapy was distributed electronically to approximately 300 Center for International Blood and Marrow Transplant Research medical centers treating patients with CAR T-cell therapy in the United States and internationally between October 12 and November 2, 2021. One medical provider was asked to complete the study survey on behalf of their institution. We received 96 survey responses, of which 66 centers utilized CAR T-cells and provided at least partial responses that were used for the primary analysis. Centers were varied in demographics, experience in administering CAR T-cells, and aspects of patients receiving CAR T-cells. Eighteen centers exclusively treated pediatric patients, and patients at these centers were more likely to be treated for B-cell acute lymphoblastic leukemia. Seven pregnancies and 5 live births after CAR T-cells were reported from 6 centers (1 pediatric-only). Most centers had no established guidelines in place regarding fertility preservation in the peri-CAR T-cell period or regarding recommendations for avoiding pregnancy/fathering a child after receiving CAR T-cells. Areas for future research were elicited from responding centers and categorized into 3 broad themes, including: standardized peri-CAR T-cell fertility guidelines; long-term fertility outcomes after CAR T-cell therapy; impact of CAR T-cells on a developing fetus; and determining the relevance of studying fertility in patients who receive CAR T-cells. We identified a high degree of variability in peri-CAR T-cell guidance on avoidance of pregnancy/fathering a child, as well as a wide-range of practices surrounding referral for fertility preservation, the latter of which may be likely due to the fact that patients receiving CAR T-cells in the present era are likely multiply relapsed/refractory. In summary, this is the first report of several live-births following CAR T-cells, which highlights the important need for further research in CAR T-cell therapy and fertility, with a host of novel research questions identified.

Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion.

Chimeric antigen receptor (CAR) T cells have emerged as a potent therapeutic approach for patients with certain haematological cancers, with multiple CAR T cell products currently approved by the FDA for those with relapsed and/or refractory B cell malignancies. However, in order to derive the desired level of effectiveness, patients need to successfully receive the CAR T cell infusion in a timely fashion. This process entails apheresis of the patient's T cells, followed by CAR T cell manufacture. While awaiting infusion at an authorized treatment centre, patients may receive interim disease-directed therapy. Most patients will also receive a course of pre-CAR T cell lymphodepletion, which has emerged as an important factor in enabling durable responses. The time between apheresis and CAR T cell infusion is often not a simple journey, with each milestone being a critical step that can have important downstream consequences for the ability to receive the infusion and the strength of clinical responses. In this Review, we provide a summary of the many considerations for preparing patients with B cell non-Hodgkin lymphoma or acute lymphoblastic leukaemia for CAR T cell therapy, and outline current limitations and areas for future research.

How Should We Determine the Value of CAR T-Cell Therapy?

In 2017, the US Food and Drug Administration approved the first chimeric antigen receptor (CAR) T-cell therapies for patients with relapsed or refractory B-cell leukemia and selected B-cell lymphomas. This novel form of cellular immunotherapy creates a "living drug" that effectively reprograms a patient's T cells to target specific antigens on the surface of a tumor. The therapy has high response rates in patients with refractory disease, although a single infusion of CAR T cells costs hundreds of thousands of dollars. A value analysis is required to determine whether and how to offer patients these expensive, customized drugs.