Engineered Cytokine Signaling to Improve CAR T Cell Effector Function

Bell, Matthew; Gottschalk, Stephen

doi:10.3389/fimmu.2021.684642

Cited by 85 publications

(56 citation statements)

References 180 publications

(208 reference statements)

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“…They contain an inducible gene expression cassette coding for a transgenic cytokine, such as IL-12 (IL-8, IL-9, IL-15, and IL-18 are still under investigation), to be delivered into the targeted tissue ( Figure 3D ) ( 91 , 93 ). The accumulation of IL-12 can effectively recruit innate immune cells to the TME and attack antigen-negative cancer cells that CAR-T cells cannot recognize ( 94 , 95 ). Recently, fifth-generation CARs have been studied and engineered based on the second-generation CARs.…”

Section: Strategies To Improve the Persistence Of Car-t Cellsmentioning

confidence: 99%

CAR-T Cell Performance: How to Improve Their Persistence?

López-Cantillo¹,

Urueña

Camacho³

et al. 2022

Front. Immunol.

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Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs.

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Section: Strategies To Improve the Persistence Of Car-t Cellsmentioning

confidence: 99%

CAR-T Cell Performance: How to Improve Their Persistence?

López-Cantillo¹,

Urueña

Camacho³

et al. 2022

Front. Immunol.

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“…For example, CXCR2-modified GPC3-CART had improved trafficking in a hepatocellular carcinoma model ( 92 ), while a CXCR1/2-modified CD70-CART enhanced CART trafficking and efficacy in murine GBM, ovarian cancer and pancreatic cancer models ( 93 ). Many groups have also sought to generate a more “fit” ACT through enhanced cytokine secretion [thoroughly reviewed by Bell and Gottschalk ( 94 )]. Additional modifications include creation of ACT which is resistant to exhaustion [e.g.…”

Section: Discussion: Overcoming the Immune-suppressive Tme In Act For...mentioning

confidence: 99%

Adoptive Cell Therapy in Pediatric and Young Adult Solid Tumors: Current Status and Future Directions

et al. 2022

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Advances from novel adoptive cellular therapies have yet to be fully realized for the treatment of children and young adults with solid tumors. This review discusses the strategies and preliminary results, including T-cell, NK-cell and myeloid cell-based therapies. While each of these approaches have shown some early promise, there remain challenges. These include poor trafficking to the tumor as well as a hostile tumor microenvironment with numerous immunosuppressive mechanisms which result in exhaustion of cellular therapies. We then turn our attention to new strategies proposed to address these challenges including novel clinical trials that are ongoing and in development.

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“…Limited 41BB.z CAR T cell activation could potentially also be overcome by including a second zeta domain with the CAR [ 48 ]. Finally, additional genetic modifications, including the transgenic expression of cytokines and/or deletion of negative regulators, are attractive strategies to further enhance the anti-tumor activity of CD28.z or 41BB.z CAR T cells [ 49 ]. Based on our studies, it seems advisable to explore their benefits in EM- and CM-enriched CAR T cell populations.…”

Section: Discussionmentioning

confidence: 99%

Cytolytic Activity of CAR T Cells and Maintenance of Their CD4+ Subset Is Critical for Optimal Antitumor Activity in Preclinical Solid Tumor Models

Csaplár

Szöllősi

Vereb

et al. 2021

Cancers

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Correlative studies of clinical studies for hematological malignancies have implicated that less differentiated, CD8+-dominant CAR T cell products have greater antitumor activity. Here, we have investigated whether the differentiation status of CAR T cell products affects their antitumor activity in preclinical models of solid tumors. We explored if different activation/expansion protocols, as well as different co-stimulatory domains in the CAR construct, influence the short- and long-term efficacy of CAR T cells against HER2-positive tumors. We generated T cell products that range from the most differentiated (CD28.z; OKT3-antiCD28/RPMI expansion) to the least differentiated (41BB.z; OKT3-RetroNectin/LymphoONE expansion), as judged by cell surface expression of the differentiation markers CCR7 and CD45RA. While the effect of differentiation status was variable with regard to antigen-specific cytokine production, the most differentiated CD28.z CAR T cell products, which were enriched in effector memory T cells, had the greatest target-specific cytolytic activity in vitro. These products also had a greater proliferative capacity and maintained CD4+ T cells upon repeated stimulation in vitro. In vivo, differentiated CD28.z CAR T cells also had the greatest antitumor activity, resulting in complete response. Our results highlight that it is critical to optimize CAR T cell production and that optimal product characteristics might depend on the targeted antigen and/or cancer.

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Engineered Cytokine Signaling to Improve CAR T Cell Effector Function

Cited by 85 publications

References 180 publications

CAR-T Cell Performance: How to Improve Their Persistence?

CAR-T Cell Performance: How to Improve Their Persistence?

Adoptive Cell Therapy in Pediatric and Young Adult Solid Tumors: Current Status and Future Directions

Cytolytic Activity of CAR T Cells and Maintenance of Their CD4+ Subset Is Critical for Optimal Antitumor Activity in Preclinical Solid Tumor Models

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