The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have ...revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma - the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.
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The clinical use of chimeric antigen receptor (CAR) T-cell therapy is growing rapidly because of the expanding indications for standard-of-care treatment and the development of new ...investigational products. The establishment of consensus diagnostic criteria for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), alongside the steady use of both tocilizumab and corticosteroids for treatment, have been essential in facilitating the widespread use. Preemptive interventions to prevent more severe toxicities have improved safety, facilitating CAR T-cell therapy in medically frail populations and in those at high risk of severe CRS/ICANS. Nonetheless, the development of persistent or progressive CRS and ICANS remains problematic because it impairs patient outcomes and is challenging to treat. In this case-based discussion, we highlight a series of cases of CRS and/or ICANS refractory to front-line interventions. We discuss our approach to managing refractory toxicities that persist or progress beyond initial tocilizumab or corticosteroid administration, delineate risk factors for severe toxicities, highlight the emerging use of anakinra, and review mitigation strategies and supportive care measures to improve outcomes in patients who develop these refractory toxicities.
With 6 chimeric antigen receptor (CAR) T-cell products approved by the US Food and Drug Administration and many more showing promise in clinical trials, the need for hematologists to be aware of challenging complications and know how to manage them in routine practice is paramount. Introduced by Associate Editor Helen E. Heslop, this How I Treat series highlights several key complications, reviews current understanding of their etiologies, and provides guidance on therapies through discussion of illustrative cases.
In this issue of
Blood
,
Pan et al
highlight their approach toward dual-antigen chimeric antigen receptor (CAR) T-cell targeting in an effort to reduce the risk of immune escape in pediatric B-cell ...acute lymphoblastic leukemia (B-ALL). They demonstrate the feasibility of sequentially administering CD19 CAR T cells followed by CD22 CAR T cells alongside the safety, toxicity, and efficacy of such a model.
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Their observation suggests that sequential CAR T-cell targeting strategies may be safe and effective and provides proof-of-concept of a potential strategy that may allow for dual-antigen CAR T-cell targeting.
Summary Background Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, ...but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. Methods This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1–30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 106 CAR-transduced T cells per kg (dose 1), 3 × 106 CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov , number NCT01593696. Findings Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 106 CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0–36·3). The most common non-haematological grade 3 adverse events were fever (nine 43% of 21 patients), hypokalaemia (nine 43% of 21 patients), fever and neutropenia (eight 38% of 21 patients), and cytokine release syndrome (three 14%) of 21 patients). Interpretation CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. Funding National Institutes of Health Intramural funds and St Baldrick's Foundation.
By increasing disease‐free survival and offering the potential for long‐term cure, chimeric antigen receptor (CAR) T‐cell therapy has dramatically expanded therapeutic options among those with ...high‐risk B‐cell malignancies. As CAR T‐cell utilization evolves however, novel challenges are generated. These include determining how to optimally integrate CAR T cells into standard of care and overcoming mechanisms of resistance to CAR T‐cell therapy, such as evolutionary stress induced on cancer cells leading to immunophenotypic changes that allow leukemia to evade this targeted therapy. Compounding these challenges are the limited ability to determine differences between various CAR T‐cell constructs, understanding the generalizability of trial outcomes from multiple sites utilizing unique CAR manufacturing strategies, and comparing distinct criteria for toxicity grading while defining optimal management. Additionally, as understanding of CAR behavior in humans has developed, strategies have appropriately evolved to proactively mitigate toxicities. These challenges offer complimentary insights and guide next steps to enhance the efficacy of this novel therapeutic modality. With a focus on B‐cell malignancies as the paradigm for effective CAR T‐cell therapy, this review describes advances in the field as well as current challenges and future directions.
The tremendous successes of CD19-directed CAR T cells in children and young adults with B-cell acute lymphoblastic leukemia (B-ALL) has led to the more widespread use of this important treatment ...modality. With an ability to induce remission and potentially lead to long-term survival in patients with multiply relapsed/chemotherapy refractory disease, more children are now receiving this therapy with the hope of inducing a long-term durable remission (with or without consolidative hematopoietic cell transplantation). While overcoming the acute toxicities was critical to its broad implementation, the emerging utilization requires close evaluation of subacute and delayed toxicities alongside a consideration of late effects and issues related to survivorship following CAR T cells. In this underexplored area of toxicity monitoring, this article reviews the current state of the art in relationship to delayed toxicities while highlighting areas of future research in the study of late effects in children and young adults receiving CAR T cells.
Immune targeting of B-cell malignancies using chimeric antigen receptors (CARs) is a promising new approach, but critical factors impacting CAR efficacy remain unclear. To test the suitability of ...targeting CD22 on precursor B-cell acute lymphoblastic leukemia (BCP-ALL), lymphoblasts from 111 patients with BCP-ALL were assayed for CD22 expression and all were found to be CD22-positive, with median CD22 expression levels of 3500 sites/cell. Three distinct binding domains targeting CD22 were fused to various TCR signaling domains ± an IgG heavy chain constant domain (CH2CH3) to create a series of vector constructs suitable to delineate optimal CAR configuration. CARs derived from the m971 anti-CD22 mAb, which targets a proximal CD22 epitope demonstrated superior antileukemic activity compared with those incorporating other binding domains, and addition of a 4-1BB signaling domain to CD28.CD3ζ constructs diminished potency, whereas increasing affinity of the anti-CD22 binding motif, and extending the CD22 binding domain away from the membrane via CH2CH3 had no effect. We conclude that second-generation m971 mAb-derived anti-CD22 CARs are promising novel therapeutics that should be tested in BCP-ALL.
•We have created a new highly active chimeric antigen receptor (CAR) specific for CD22.•The design of new CARs may benefit more from target antigen epitope selection than from optimizing affinity.
To discuss the curative potential for chimeric antigen receptor T-cell (CAR-T) therapy, with or without consolidative hematopoietic stem cell transplantation (HCT) in the treatment of children and ...young adults with B lineage acute lymphoblastic leukemia (B-ALL).
CAR-T targeting CD19 can induce durable remissions and prolong life in patients with relapsed/refractory B-ALL. Whether HCT is needed to consolidate remission and cure relapse/refractory B-ALL following a CD19 CAR-T induced remission remains controversial. Preliminary evidence suggests that consolidative HCT following CAR-T in HCT-naïve children improves leukemia-free survival. However, avoiding HCT-related late effects is a desirable goal, so identification of patients at high risk of relapse is needed to appropriately direct those patients to HCT when necessary, while avoiding HCT in others. High disease burden prior to CAR-T infusion, loss of B-cell aplasia and detection of measurable residual disease by flow cytometry or next-generation sequencing following CAR-T therapy associate with a higher relapse risk and may identify patients requiring consolidative HCT for relapse prevention.
There is a pressing need to determine when CD19 CAR-T alone is likely to be curative and when a consolidative HCT will be required. We discuss the current state of knowledge and future directions.
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