Development of CAR T cells designed to improve antitumor efficacy and safety

Jaspers, Janneke E.; Brentjens, Renier J.

doi:10.1016/j.pharmthera.2017.03.012

Cited by 84 publications

(65 citation statements)

References 135 publications

(146 reference statements)

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“…36 Also, phosphoproteomic analyzed differences between CD28 versus 4-1BB costimulatory CD8+ human CAR T cells has demonstrated faster changes in protein phosphorylation correlating with effector-like phenotype in CD28 constructs versus more memory-associated expression of genes in the 4-1BB product, which may contribute to greater persistence of 4-1BB CAR T. 37 Additional strategies to enhance persistence include the use of "armored" CARs expressing additional signaling molecules and/or genes promoting autonomous secretion of lymphoproliferative cytokines with the intention of enhancing persistence and effector function. 38,39 Lastly, CD19 antigen escape has been described with CD19 CAR therapy 40 and two of the subjects who progressed on our study were found to be CD19 (-) on the surface membrane at re-biopsy. CAR modified T cells recognizing multiple antigens may serve as an effective strategy to counter this mechanism of resistance.…”

Section: Discussionsupporting

confidence: 50%

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma

Sauter

Sénéchal

Rivière

et al. 2019

Blood

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High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography–positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell–induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence (P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P < .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%). Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.

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Section: Discussionsupporting

confidence: 50%

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma

Sauter

Sénéchal

Rivière

et al. 2019

Blood

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“…Finally, multiple studies in humans are currently evaluating the effect of CAR T cell therapy for the treatment of solid tumors, with modest results thus far (96). Potential strategies to increase the efficacy of CAR T in this context include combinations with immune stimulants, secondary modifications of CAR T cells, reengineering of the T cell, and specific targeting of the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies

Mochel

Ekker

Johannes

et al. 2019

AAPS J

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The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T cells for targeted cancer therapy. CAR T cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T cell therapies were approved by the US Food and Drug Administration: one for the treatment of pediatric acute lymphoblastic leukemia (ALL) and the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20-100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin's lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This commentary summarizes the current state of knowledge on CAR T cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.

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“…To solve such challenges, different NP‐based approaches have been developed to release immunostimulatory cytokines, or produce armored CAR‐T cells, a neutralized scFvs directed against checkpoint inhibitors. [ 26,98,99 ] For instance, Gu et al designed self‐degradable microneedle patch‐coupled immune checkpoint inhibitor (anti‐PD1 antibody, aPD1) delivery approaches to treat skin cancer [ 100 ] ( Figure A). The microneedle patch was conjugated with aPD1, dextran NPs as pH‐detector, and glucose oxidase (GOx) for sustained drug release.…”

Section: Nanoparticle‐based Gene Delivery Induces the Efficiency Of Cmentioning

confidence: 99%

Nanotechnology Promotes Genetic and Functional Modifications of Therapeutic T Cells Against Cancer

Abdalla

Xiao

et al. 2020

Advanced Science

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Growing experience with engineered chimeric antigen receptor (CAR)‐T cells has revealed some of the challenges associated with developing patient‐specific therapy. The promising clinical results obtained with CAR‐T therapy nevertheless demonstrate the urgency of advancements to promote and expand its uses. There is indeed a need to devise novel methods to generate potent CARs, and to confer them and track their anti‐tumor efficacy in CAR‐T therapy. A potentially effective approach to improve the efficacy of CAR‐T cell therapy would be to exploit the benefits of nanotechnology. This report highlights the current limitations of CAR‐T immunotherapy and pinpoints potential opportunities and tremendous advantages of using nanotechnology to 1) introduce CAR transgene cassettes into primary T cells, 2) stimulate T cell expansion and persistence, 3) improve T cell trafficking, 4) stimulate the intrinsic T cell activity, 5) reprogram the immunosuppressive cellular and vascular microenvironments, and 6) monitor the therapeutic efficacy of CAR‐T cell therapy. Therefore, genetic and functional modifications promoted by nanotechnology enable the generation of robust CAR‐T cell therapy and offer precision treatments against cancer.

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Development of CAR T cells designed to improve antitumor efficacy and safety

Cited by 84 publications

References 135 publications

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies

Nanotechnology Promotes Genetic and Functional Modifications of Therapeutic T Cells Against Cancer

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