The Evolution and Future of CAR T Cells for B‐Cell Acute Lymphoblastic Leukemia

Annesley, Colleen; Summers, Corinne; Ceppi, Francesco; Gardner, Rebecca

doi:10.1002/cpt.950

Cited by 33 publications

(24 citation statements)

References 64 publications

(154 reference statements)

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“…The application of CAR-T has been implicated in acute leukemia and non-Hodgkin's lymphoma, and it has made prominent progress in B-ALL during the past several years. Clinical studies in the United States and Europe illustrate that the CR rate to CAR-T therapy is around 90% in R/R B-ALL patients, which is similar to that in de novo B-ALL patients [8][9][10][11][12][13][14] . The survival profiles of R/R B-ALL patients have also been improved by CAR-T therapy, but with inevitable adverse events (such as cytokine release syndrome (CRS), B cell aplasia, neurotoxicity, and tumor lysis syndrome) 15,16 .…”

Section: Introductionmentioning

confidence: 76%

“…The CD4 + T cells are then stimulated and recognize antigen-presenting MHC on APC along with co-stimulatory proteins, including CD28 and 4-1BB. Subsequently, cytotoxic T cells are activated and release perforin as well as granzyme B that induce apoptosis of malignant cells 11,22 . However in B-ALL, which is characterized by cancerous progression that takes place in B cell lineage of immature lymphoid cells, leukemic B cells reduce the expression of MHC and upregulate immunosuppression cells to escape from the adaptive immune system 3 .…”

Section: Discussionmentioning

confidence: 99%

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Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients

Liu

et al. 2020

Cell Death Dis

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This study aimed to evaluate treatment response, survival, safety profiles, and predictive factors to chimeric antigen receptor T cell (CAR-T) therapy in Chinese patients with relapsed or refractory B cell acute lymphoblast leukemia (R/R BALL). 39R/R BALL patients who underwent CART therapy were included. Baseline data were collected from patients' electronic medical records. Patients' peripheral bloods, bone marrow aspirates, and biopsies were obtained for routine examination, and treatment response and survival profiles as well as adverse events were evaluated. The rates of complete remission (CR), CR with minimal residual disease (MRD) negative/positive, and bridging to hematopoietic stem-cell transplantation (HSCT) were 92.3%, 76.9%, 15.4%, and 43.6%, respectively. The median event-free survival (EFS) was 11.6 months (95% confidence interval (CI): 4.0-19.2 months) and median overall survival (OS) was 14.0 months (95% CI: 10.9-17.1 months). Bridging to HSCT independently predicted better EFS and OS, while high bone marrow blasts level independently predicted worse EFS. The incidence of cytokine release syndrome (CRS) was 97.4%, and refractory disease as well as decreased white blood cell independently predicted higher risk of severe CRS. Other common adverse events included hematologic toxicities (grade I: 5.1%, grade II: 7.7%, grade III: 17.9%, grade IV: 69.2%), neurotoxicity (28.2%), infection (38.5%), and admission for intensive care unit (10.3%). In conclusion, CART therapy presents with promising treatment response, survival and safety profiles, and higher disease burden predicts worse survival as well as increased risk of severe CRS in Chinese R/R BALL patients.

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Section: Introductionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients

Liu

et al. 2020

Cell Death Dis

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“…Current treatment options for relapsed/refractory (R/R) pediatric B cell acute lymphoblastic leukemia (B-ALL) have limited curative potential and substantial short-term and long-term toxicities. Immunotherapies, such as the bispecific T cell engager blinatumomab (1), the antibody drug conjugate inotuzumab ozogamicin (2), and chimeric antigen receptor (CAR) T cells targeting CD19 and/or CD22 (3) and exhibited substantial therapeutic activity in this patient population (4,5). Specifically, clinical trials using CD19 CAR T cells to treat advanced B cell malignancies report impressive therapeutic responses, with complete response rates ranging from 70%-94% (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

CD19 CAR T cell product and disease attributes predict leukemia remission durability

Finney¹,

Brakke²,

Rawlings‐Rhea³

et al. 2019

Journal of Clinical Investigation

260

249

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BACKGROUND. Chimeric antigen receptor (CAR) T cells can induce remission in highly refractory leukemia and lymphoma subjects, yet the parameters for achieving sustained relapse-free survival are not fully delineated. METHODS. We analyzed 43 pediatric and young adult subjects participating in a phase I trial of defined composition CD19 CAR T cells (ClinicalTrials.gov, NCT02028455). CAR T cell phenotype, function, and expansion, as well as starting material T cell repertoire, were analyzed in relationship to therapeutic outcome (defined as achieving complete remission within 63 days) and duration of leukemia-free survival and B cell aplasia. RESULTS. These analyses reveal that initial therapeutic failures (n = 5) were associated with attenuated CAR T cell expansion and/or rapid attrition of functional CAR effector cells following adoptive transfer. The CAR T products were similar in phenotype and function when compared with products resulting in sustained remissions. However, the initial apheresed peripheral blood T cells could be distinguished by an increased frequency of LAG-3 + /TNF-α lo CD8 T cells and, following adoptive transfer, the rapid expression of exhaustion markers. For the 38 subjects who achieved an initial sustained minimal residual disease-negative remission, 15 are still in remission, 10 of whom underwent allogenic hematopoietic stem cell transplantation (alloHSCT) following CAR T treatment. Subsequent remission durability correlated with therapeutic products having increased frequencies of TNF-α-secreting CAR CD8 + T cells, but was dependent on a sufficiently high CD19 + antigen load at time of infusion to trigger CAR T cell proliferation. CONCLUSION. These parameters have the potential to prospectively identify patients at risk for therapeutic failure and support the development of approaches to boost CAR T cell activation and proliferation in patients with low levels of CD19 antigen. TRIAL REGISTRATION. ClinicalTrials.gov, NCT02028455.

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“…IV therapeutics such as blinatumomab and other CD19-directed immunotherapies [ 34 , 35 ] can trigger the rapid release of inflammatory mediators and cellular cytokines into the blood. Organ toxicity affecting cardiovascular, respiratory, neurologic, and renal function may result.…”

Section: Safety Profile Of Blinatumomabmentioning

confidence: 99%

“…One proposed mechanism for neurotoxicity is the release of neurotoxic cytokines and chemokines by blinatumomab-activated T cells en route to the central nervous system, causing inflammation at the neuroendothelium [ 36 ]. Neurotoxicity is also seen with the administration of other CD19 immunotherapies [ 34 , 35 ]. For example, axicabtagene ciloleucel and tisagenlecleucel are two CD19 chimeric antigen receptor T-cell agents that have boxed warnings for neurologic toxicities (e.g., encephalopathy, delirium, or seizures) in their FDA-approved labels [ 37 , 38 ].…”

Section: Safety Profile Of Blinatumomabmentioning

confidence: 99%

Benefit–Risk Assessment of Blinatumomab in the Treatment of Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

et al. 2018

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Blinatumomab is the first-and-only Food and Drug Administration (FDA)-approved cluster of differentiation (CD) 19-directed CD3 bispecific T-cell engager (BiTE ® ) immunotherapy. It is currently FDA approved for the treatment of adults and children with Philadelphia chromosome-positive (Ph+) and Philadelphia chromosome-negative (Ph−) relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) and B-cell precursor ALL with minimal residual disease. Similarly, initial marketing authorization for blinatumomab in the European Union was granted for the treatment of adults with Ph− R/R B-cell precursor ALL. The benefits of treating R/R B-cell precursor ALL patients with blinatumomab include increased overall survival, more favorable hematologic remission and molecular response rates, and a lower incidence rate of selected adverse events when compared with standard-of-care chemotherapy. The key risks associated with blinatumomab treatment include cytokine release syndrome, neurotoxicity, and medication errors. Here, we review the benefits and risks of blinatumomab treatment and describe how these risks can be mitigated.

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The Evolution and Future of CAR T Cells for B‐Cell Acute Lymphoblastic Leukemia

Cited by 33 publications

References 64 publications

Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients

Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients

CD19 CAR T cell product and disease attributes predict leukemia remission durability

Benefit–Risk Assessment of Blinatumomab in the Treatment of Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

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