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Chimeric Antigen Receptor (CAR) T cell therapy targeting CD19 has introduced a paradigmatic shift in our treatment approach for advanced B cell malignancies. A major advance has been in the field of pediatric B-ALL where complete responses have been achieved across clinical trials with rates of 65-90% in the relapsed/refractory setting. These striking early response rates led to FDA approval of Tisagenlecleucel, CD19-specific CAR T cells, in August 2017. With broadened access and available longitudinal follow up, it is imperative to study the true durability of CAR-mediated responses and establish long-term relapse free and survival outcomes following CAR therapy. Phase I and II clinical trials have reported event-free survival rates of 50% at 1 year following CD19-CAR infusion in children and young adults with B-ALL. Here, we review some of the major challenges accounting for the discrepancy between early response rates and long term outcomes. In specific, relapse with CD19 or CD19 disease has emerged as a major challenge following CD19-CAR T cell therapy. Related, is the issue of CAR persistence which has been shown to correlate with long-term outcomes. We highlight select efforts to optimize clinical strategies and CAR design to promote enhanced persistence. To date, we do not have robust predictors of response durability and relapse following CAR therapy. The ability to identify patients at risk of relapse in an manner may introduce an interventional window to consolidate CAR-mediated remissions and enhance response durability. This review highlights the need to bridge the gap between the remarkable early complete responses achieved with CD19-CAR T cell therapy and the long-term survival outcomes.

Adoptive cellular therapy using chimeric antigen receptors (CARs) has revolutionized our treatment of relapsed B cell malignancies and is currently being integrated into standard therapy. The impact of selecting specific T cell subsets for CAR transduction remains under investigation. Previous studies demonstrated that effector T cells derived from naive, rather than central memory T cells mediate more potent antitumor effects. Here, we investigate a method to skew CAR transduction toward naive T cells without physical cell sorting. Viral-mediated CAR transduction requires ex vivo T cell activation, traditionally achieved using antibody-mediated strategies. CD81 is a T cell costimulatory molecule that when combined with CD3 and CD28 enhances naive T cell activation. We interrogate the effect of CD81 costimulation on resultant CAR transduction. We identify that upon CD81-mediated activation, naive T cells lose their identifying surface phenotype and switch to a memory phenotype. By prelabeling naive T cells and tracking them through T cell activation and CAR transduction, we document that CD81 costimulation enhanced naive T cell activation and resultantly generated a CAR T cell product enriched with naive-derived CAR T cells.

Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study. In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment. From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25–84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3–8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome. This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach. National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22 + malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3–4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

Standard testing for disease evaluation in B-cell acute lymphoblastic leukemia (B-ALL) includes examination of the bone marrow and cerebrospinal fluid. Radiographic or functional imaging are indicated when clinical signs of non-CNS extramedullary disease are present but are not standard in the relapsed/refractory setting. We describe two cases of patients with relapsed/refractory B-ALL with prior exposure to blinatumomab and/or inotuzumab ozogamicin presenting for CAR-T cell treatment. Both patients were thought to only have minimal residual disease (MRD) at the pre-CAR disease assessment, with MRD of 6,648 (0.66%) and 100 (0.01%) cells per million cells, respectively, as measured by next-generation sequencing (NGS) in their bone marrows. Both patients for distinct reasons unrelated to non-CNS extra-medullary (EM) symptoms had PET-MRIs prior to lymphodepletion and CAR T cell infusion. In both cases patients were found to have significant bulky subclinical EM disease that required changes in clinical management. In the newly-emergent era of antigen-targeted immunotherapy, it is foundational that incidence and relapse patterns following targeted therapy are well-understood. Herein we contribute to a growing body of literature addressing this fundamental clinical gap and highlight a future role for formal prospective imaging studies to better establish response, toxicity and relapse patterns following CAR-T cell therapy in EM B-ALL.

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated efficacy in children and young adult patients with acute lymphoblastic leukemia (ALL). The purpose of our study was to investigate thymus size changes after CAR T-cell therapy, explore the associated clinical conditions, and assess survival differences of patients who underwent CAR T-cell therapy, we conducted a single-center retrospective study of children and young adult patients who underwent CAR T-cell therapy for ALL between April 2015 and October 2023.We measured the volume of the thymus on pre- and post-CAR T-cell chest CT scans of 20 patients (median [IQR] age, 18[11] years; 11 females). We divided patients into two groups, those who did (group 1) or did not (group 2) demonstrate increase in thymus size after therapy. Clinical and survival data were collected. We used the Wilcoxon signed-rank test or Fisher’s exact test for group comparisons and analyzed event-free survival data. Seven of 20 patients (35%, group 1) showed increase in thymus volume (pre- vs. post-CAR T-cell thymus volume; 5.01 [2.18] cm³ vs. 20.87 [19.86] cm³, p = 0.01), while 13 patients (65%, group 2) showed no increase in thymus volume (pre- vs. post-CAR T-cell thymus volume; 3.01 [13.42] cm³ vs. 2.09 [8.34] cm³, p = 0.01). Patients in group 1 were younger (12 [8] years vs. 19[10] years, p = 0.028) and showed a higher rate of event-free survival compared to those in group 2 (p = 0.003). In children and young adults with ALL, increased thymus size after CAR T-cell therapy was associated with younger age and improved clinical outcomes.

Purpose of ReviewLymphodepleting chemotherapy (LD) has emerged as a key determinant of chimeric antigen receptor T cell (CAR) efficacy across pediatric/adult B cell malignancies. Clinical trials demonstrate the superiority of fludarabine/cyclophosphamide (Flu/Cy) regimens, resulting in the adoption of Flu/Cy as the pre-CAR LD standard. In the context of a global fludarabine shortage, consideration of alternative regimens is timely, yet limited clinical data exists, specifically in the pediatric B-ALL CAR setting.Recent FindingsBendamustine has been used as an effective LD prior to CD19-CAR in adult lymphoma. Although use in the pediatric CAR setting is limited, tolerability has been established in pediatric Hodgkin’s lymphoma. Clofarabine is a purine nucleoside analog with mechanistic overlap with fludarabine; however, toxicity is high in the upfront leukemia setting, and thus use as an LD pre-CAR should be pursued with caution.SummaryWe review the experience using bendamustine and clofarabine to serve as a resource when considering LD regimens as an alternative to fludarabine for pediatric B-ALL.

Relapse following CD19‐targeting chimeric antigen receptor T‐cell therapy (CD19‐CAR) remains a major barrier to long‐term cure in relapsed/refractory B‐cell acute lymphoblastic leukemia, with nearly 50% of patients relapsing within 6 months. Early B‐cell recovery (BCR), as detected by the re‐emergence of CD19‐positive cells, has been strongly associated with relapse risk and serves as a surrogate marker for loss of CAR T‐cell persistence. However, clinical use of BCR is hindered by variability in monitoring practices, including inconsistent definitions, timing, and measurement across institutions. To address this gap, we convened an international working group of pediatric cellular therapy experts to establish a consensus definition for BCR. Our collaborative effort outlines standardized criteria for BCR assessment aimed at improving comparability across studies and guiding post‐CAR T‐cell surveillance strategies.