ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells
University of Virginia1, Memorial Sloan Kettering Cancer Center2, Washington University in St. Louis3, Fred Hutchinson Cancer Research Center4, National Institutes of Health5, Harvard University6, Novartis7, Seattle Children's8, University of Pennsylvania9, University College London10, Center for International Blood and Marrow Transplant Research11, University of Miami12, University of Texas MD Anderson Cancer Center13
TL;DR: The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.
About: This article is published in Biology of Blood and Marrow Transplantation.The article was published on 2019-04-01 and is currently open access. It has received 1403 citations till now. The article focuses on the topics: Chimeric antigen receptor & Transplantation.
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TL;DR: Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects.
Abstract: Background Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and...
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TL;DR: The authors describe the innovative approaches to the engineering of CAR T cell products that have the potential to considerably improve the safety and effectiveness of treatment.
Abstract: T cells genetically engineered to express chimeric antigen receptors (CARs) have proven — and impressive — therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma, with promising efficacy also demonstrated in patients with multiple myeloma. Nevertheless, various barriers restrict the efficacy and/or prevent the widespread use of CAR T cell therapies in these patients as well as in those with other cancers, particularly solid tumours. Key challenges relating to CAR T cells include severe toxicities, restricted trafficking to, infiltration into and activation within tumours, suboptimal persistence in vivo, antigen escape and heterogeneity, and manufacturing issues. The evolution of CAR designs beyond the conventional structures will be necessary to address these limitations and to expand the use of CAR T cells to a wider range of malignancies. Investigators are addressing the current obstacles with a wide range of engineering strategies in order to improve the safety, efficacy and applicability of this therapeutic modality. In this Review, we discuss the innovative designs of novel CAR T cell products that are being developed to increase and expand the clinical benefits of these treatments in patients with diverse cancers. Chimeric antigen receptor (CAR) T cell therapy, the first approved therapeutic approach with a genetic engineering component, holds substantial promise in the treatment of a range of cancers but is nevertheless limited by various challenges, including toxicities, intrinsic and acquired resistance mechanisms, and manufacturing issues. In this Review, the authors describe the innovative approaches to the engineering of CAR T cell products that are providing solutions to these challenges and therefore have the potential to considerably improve the safety and effectiveness of treatment.
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TL;DR: This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.
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612 citations
TL;DR: The authors outline the key limitations of CAR T cell therapy, with a focus on mechanisms of resistance, and discuss strategies to improve the efficacy and broaden the applicability of this promising therapeutic approach.
Abstract: 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.
542 citations
TL;DR: In this article, the authors discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CART cell therapy in both B cell leukemia or lymphoma.
Abstract: Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.
509 citations
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TL;DR: Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL and was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed.
Abstract: A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti–interleukin-6 receptor antibody tocilizumab. CONCLUSIONS Chimeric antigen receptor–modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.)
4,208 citations
"ASTCT Consensus Grading for Cytokin..." refers background in this paper
...Hemophagocytic lymphohistiocytosis or macrophage activation syndrome (HLH/MAS) overlaps substantially with CRS, as illustrated by ferritin elevations seen in many CAR T cell recipients during CRS [2,12,20,22,27]....
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...In addition, rapid clinical stabilization is frequently seen with use of the IL-6 receptor antagonist tocilizumab, strongly implicating cytokines, especially IL-6 [8,20-22], in the pathophysiology of the syndrome....
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University of Texas Health Science Center at Houston1, University of South Florida2, Washington University in St. Louis3, University of Miami4, Stanford University5, Harvard University6, Yeshiva University7, Vanderbilt University8, City of Hope National Medical Center9, Mayo Clinic10, University of California, Los Angeles11, Loyola University Chicago12, University of Rochester13, Sarah Cannon Research Institute14, Rutgers University15, Cleveland Clinic16, Wayne State University17, University of Iowa18, University of Texas MD Anderson Cancer Center19, Tel Aviv University20, University of California, San Diego21
TL;DR: Patients with refractory large B‐cell lymphoma who received CAR T‐cell therapy with axi‐cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events.
Abstract: BackgroundIn a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. MethodsIn this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. ResultsAmong the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%)....
3,363 citations
"ASTCT Consensus Grading for Cytokin..." refers background in this paper
...Two CD19 CAR T cell products were recently approved in the United States and Europe [1-4], andmore indications are expected in the coming years....
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...Two CAR T products were recently approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma....
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...In addition, refractory HLH/MAS has been described only in rare cases of immune effector cellassociated CRS [2,28], whereas in the vast majority of patients, the symptoms (and characteristic elevated cytokines) suggestive of HLH/MAS resolve with CRS resolution [22]....
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...Although prospective clinical trials evaluating the timing of intervention are lacking, retrospective analyses suggest that this is not the case, at least when such therapies are implemented after CRS is well under way [2,21]....
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...Several reports suggest a role for proinflammatory cytokines and myeloid cells besides activated T cells [2,18,29,3133]....
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University of Pennsylvania1, University of Texas Southwestern Medical Center2, University of Oslo3, Boston Children's Hospital4, University of Utah5, Université de Montréal6, Goethe University Frankfurt7, University of Minnesota8, Children's Mercy Hospital9, Emory University10, Ghent University11, Kyoto University12, Stanford University13, Duke University14, Oregon Health & Science University15, University of Michigan16, Medical University of Vienna17, University of Paris18, Royal Children's Hospital19, University of Milan20, University of Toronto21, Novartis22, University of Southern California23
TL;DR: In this global study of CAR T‐cell therapy, a single infusion of tisagenlecleucel provided durable remission with long‐term persistence in pediatric and young adult patients with relapsed or refractory B‐cell ALL, with transient high‐grade toxic effects.
Abstract: Background In a single-center phase 1–2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) Methods We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months Results For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry The rates of event-f
3,237 citations
"ASTCT Consensus Grading for Cytokin..." refers background in this paper
...Two CD19 CAR T cell products were recently approved in the United States and Europe [1-4], andmore indications are expected in the coming years....
[...]
...In this new field of medicine, companies may have to face the possibility of a gap between what the FDA or European Medicines Agency (EMA) wants them to collect and what centers are actually able to provide....
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...Two CAR T products were recently approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma....
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TL;DR: The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.
Abstract: Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.
3,027 citations
"ASTCT Consensus Grading for Cytokin..." refers background in this paper
...Retrospective analysis revealed marked elevations in C-reactive protein (CRP), INF-g, TNF-a, IL-6, IL-10, IL-2, and IL-1b, among other cytokines....
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...In addition, rapid clinical stabilization is frequently seen with use of the IL-6 receptor antagonist tocilizumab, strongly implicating cytokines, especially IL-6 [8,20-22], in the pathophysiology of the syndrome....
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...In the first pediatric ALL patient treated [8,9], it became clear that supraphysiologic cytokine elevation was responsible for the vast majority of symptoms, suggesting that these toxicities were the result of CRS....
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TL;DR: 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 and non-Hodgkin lymphoma.
2,394 citations