How Can We Engineer CAR T Cells to Overcome Resistance?

Glover, Maya; Avraamides, Stephanie; Maher, John

doi:10.2147/btt.s252568

Cited by 14 publications

(11 citation statements)

References 245 publications

(427 reference statements)

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“…IL-15 maintains a naive and central memory phenotype with increased expression of anti-apoptotic proteins and reduced PD-1 expression [ 152 ]. Many other cytokines including IL-7, IL-18, IL-21, and IL-23 have now been tested for their ability to enhance CAR T cell antitumor responses and an overview can be consulted in the recent review of Glover and colleagues [ 153 ].…”

Section: Adoptive T Cell Transfer Therapy—a Focus On Car T Cellsmentioning

confidence: 99%

T Cell Engaging Immunotherapies, Highlighting Chimeric Antigen Receptor (CAR) T Cell Therapy

Bousser

Callewaert

Festjens

2021

Cancers

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In the past decade, chimeric antigen receptor (CAR) T cell technology has revolutionized cancer immunotherapy. This strategy uses synthetic CARs to redirect the patient’s own immune cells to recognize specific antigens expressed on the surface of tumor cells. The unprecedented success of anti-CD19 CAR T cell therapy against B cell malignancies has resulted in its approval by the US Food and Drug Administration (FDA) in 2017. However, major scientific challenges still remain to be addressed for the broad use of CAR T cell therapy. These include severe toxicities, limited efficacy against solid tumors, and immune suppression in the hostile tumor microenvironment. Furthermore, CAR T cell therapy is a personalized medicine of which the production is time- and resource-intensive, which makes it very expensive. All these factors drive new innovations to engineer more powerful CAR T cells with improved antitumor activity, which are reviewed in this manuscript.

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Section: Adoptive T Cell Transfer Therapy—a Focus On Car T Cellsmentioning

confidence: 99%

T Cell Engaging Immunotherapies, Highlighting Chimeric Antigen Receptor (CAR) T Cell Therapy

Bousser

Callewaert

Festjens

2021

Cancers

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“…A summary of clinical trial activity in the solid tumour arena has recently been published (Adami and Maher 2021 ). Increasing efforts are being applied to address relevant obstacles in this quest, including target heterogeneity and lack of cancer selectivity, inadequate homing to and penetration of CAR-engineered cells within malignant lesions and the profoundly immunosuppressive nature of the tumour microenvironment (Glover et al 2021 ; Hull and Maher 2021 ). These efforts are likely to make an impact in the near future, as evidenced by recent successes in selected solid tumour types (Glover et al 2021 ; Hull and Maher 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Increasing efforts are being applied to address relevant obstacles in this quest, including target heterogeneity and lack of cancer selectivity, inadequate homing to and penetration of CAR-engineered cells within malignant lesions and the profoundly immunosuppressive nature of the tumour microenvironment (Glover et al 2021 ; Hull and Maher 2021 ). These efforts are likely to make an impact in the near future, as evidenced by recent successes in selected solid tumour types (Glover et al 2021 ; Hull and Maher 2021 ). Given that over 90% of human cancers are solid tumours, the development of an effective CAR-based solution that can impact in this arena will prove profoundly disruptive, but will also impose an substantial drug delivery challenge which autologous solutions are unlikely to overcome.…”

Section: Introductionmentioning

confidence: 99%

Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies

Mazza

Maher

2021

Arch. Immunol. Ther. Exp.

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Technologies required to generate induced pluripotent stem cells (iPSC) were first described 15 years ago, providing a strong impetus to the field of regenerative medicine. In parallel, immunotherapy has finally emerged as a clinically meaningful modality of cancer therapy. In particular, impressive efficacy has been achieved in patients with selected haematological malignancies using ex vivo expanded autologous T cells engineered to express chimeric antigen receptors (CARs). While solid tumours account for over 90% of human cancer, they currently are largely refractory to this therapeutic approach. Nonetheless, given the considerable innovation taking place worldwide in the CAR field, it is likely that effective solutions for common solid tumours will emerge in the near future. Such a development will create significant new challenges in the scalable delivery of these complex, costly and individualised therapies. CAR-engineered immune cell products that originate from iPSCs offer the potential to generate unlimited numbers of homogeneous, standardised cell products in which multiple defined gene modification events have been introduced to ensure safety, potency and reproducibility. Here, we review some of the emerging strategies in use to engineer CAR-expressing iPSC-derived drug products.

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“…proliferation. 1 Chimeric antigen receptor T-cell therapy (CART) directed against CD19 has shown remarkable efficacy in patients with relapsed acute lymphoblastic leukemia (ALL), and more recently, in patients with refractory diffuse large B-cell lymphoma (DLBCL). 2,3 Despite frequent durable remissions induced by CART in hematologic malignancies, about 60% of patients show a lack of response or eventually relapse, which is a major barrier to improve the outcome of the disease.…”

mentioning

confidence: 99%

“…Chimeric antigen receptor (CAR) T cells are genetically engineered T cells bearing a particular surface receptor composed of an extracellular single-chain variable fragment capable of direct recognition of a specific antigen 1. This immunotherapy represents a powerful weapon against various tumor cells since its action is independent of the major histocompatibility complex but instead relies on an intracellular CD3z domain eliciting the T-cell activation signal and a CD28 or 4-1BB domain triggering a costimulatory signal to allow CAR T-cell proliferation 1. Chimeric antigen receptor T-cell therapy (CART) directed against CD19 has shown remarkable efficacy in patients with relapsed acute lymphoblastic leukemia (ALL), and more recently, in patients with refractory diffuse large B-cell lymphoma (DLBCL) 2,3…”

mentioning

confidence: 99%

Resistance of B-Cell Lymphomas to CAR T-Cell Therapy Is Associated With Genomic Tumor Changes Which Can Result in Transdifferentiation

Laurent

Syrykh

Hamon³

et al. 2021

American Journal of Surgical Pathology

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Despite the impressive efficacy of chimeric antigen receptor (CAR) T-cell therapy (CART) in B-cell non-Hodgkin lymphomas, durable responses are uncommon. The histopathologic and molecular features associated with treatment failure are still largely unknown. Therefore, we have analyzed 19 sequential tumor samples from 9 patients, prior anti-CD19 CART (pre-CART) and at relapse (post-CART), using immunohistochemistry, fluorescence in situ hybridization, array comparative genomic hybridization, next-generation DNA and RNA sequencing, and genome-scale DNA methylation. The initial diagnosis was diffuse large B-cell lymphoma (n = 6), double-hit high-grade B-cell lymphoma (n = 1), and Burkitt lymphoma (n = 2). Histopathologic features were mostly retained at relapse in 7/9 patients, except the frequent loss of 1 or several B-cell markers. The remaining 2 cases (1 diffuse large B-cell lymphoma and 1 Burkitt lymphoma) displayed a dramatic phenotypic shift in post-CART tumors, with the drastic downfall of B-cell markers and emergence of T-cell or histiocytic markers, despite the persistence of identical clonal immunoglobulin gene rearrangements. The post-CART tumor with aberrant T-cell phenotype showed reduced mRNA expression of most B-cell genes with increased methylation of their promoter. Fluorescence in situ hybridization and comparative genomic hybridization showed global stability of chromosomal alterations in all paired samples, including 17p/TP53 deletions. New pathogenic variants acquired in post-CART samples included mutations triggering the PI3K pathway (PIK3R1, PIK3R2, PIK3C2G) or associated with tumor aggressiveness (KRAS, INPP4B, SF3B1, SYNE1, TBL1XR1). These results indicate that CART-resistant B-cell non-Hodgkin lymphomas display genetic remodeling, which may result in profound dysregulation of B-cell differentiation. Acquired mutations in the PI3K and KRAS pathways suggest that some targeted therapies could be useful to overcome CART resistance.

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How Can We Engineer CAR T Cells to Overcome Resistance?

Cited by 14 publications

References 245 publications

T Cell Engaging Immunotherapies, Highlighting Chimeric Antigen Receptor (CAR) T Cell Therapy

T Cell Engaging Immunotherapies, Highlighting Chimeric Antigen Receptor (CAR) T Cell Therapy

Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies

Resistance of B-Cell Lymphomas to CAR T-Cell Therapy Is Associated With Genomic Tumor Changes Which Can Result in Transdifferentiation

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