Abstract
A chimeric antigen receptor (CAR) that responds to transforming growth factor beta (TGF‐β) enables the engineering of T cells that convert this immunosuppressive cytokine into a potent T‐cell stimulant. However, clinical translation of TGF‐β CAR‐T cells for cancer therapy requires the ability to productively combine TGF‐β responsiveness with tumor‐targeting specificity. Furthermore, the potential concern that contaminating, TGF‐β?producing regulatory T (Treg) cells may preferentially expand during TGF‐β CAR‐T cell manufacturing and suppress effector T (Teff) cells demands careful evaluation. Here, we demonstrate that TGF‐β CAR‐T cells significantly improve the anti‐tumor efficacy of neighboring cytotoxic T cells. Furthermore, the introduction of TGF‐β CARs into mixed T‐cell populations does not result in the preferential expansion of Treg cells, nor do TGF‐β CAR‐Treg cells cause CAR‐mediated suppression of Teff cells. These results support the utility of incorporating TGF‐β CARs in the development of adoptive T‐cell therapy for cancer.
Highlights
Adoptive T-cell immunotherapy has produced promising results in the treatment of advanced B-cell malignancies, leading to the approval of anti-CD19 chimeric antigen receptor (CAR)-T cell therapies by the United States Food and Drug Administration in 2017.1,2 successful treatment of solid tumors has been more elusive, in part due to the highly immunosuppressive nature of tumor microenvironments.[3]
Flow cytometry analysis revealed that transforming growth factor beta (TGF-b) CAR-transduced Treg cells, but not untransduced Treg cells, divided in response to TGF-b addition (Figure 7b,c), confirming TGF-b CAR signaling. This Treg population was unable to suppress Teff proliferation (Figure 7d), indicating that CAR-activated Tregs do not exert significant suppressive influence on nearby Teff cells. These results indicate that even if the starting population for therapeutic T-cell manufacturing contains Treg cells, FI G URE 5 TGF-b CAR expression and stimulation does not result in preferential expansion of FOXP31 Tregs among CD41/CD25hi/ CD127--sorted cells. (a) TGF-b CAR-transduced or untransduced CD41/CD25hi/CD127--sorted cells were expanded with Dynabeads only or Dynabeads plus 5 ng/mL TGF-b for 20 days
We previously demonstrated that TGF-b– binding CARs can be engineered to rewire Teff cells to proliferate and produce immunostimulatory cytokines in response to soluble TGF-b, effectively inverting an immunosuppressive signaling molecule to a potent T-cell stimulant that triggers immunosupportive functions.[14]
Summary
Adoptive T-cell immunotherapy has produced promising results in the treatment of advanced B-cell malignancies, leading to the approval of anti-CD19 chimeric antigen receptor (CAR)-T cell therapies by the United States Food and Drug Administration in 2017.1,2 successful treatment of solid tumors has been more elusive, in part due to the highly immunosuppressive nature of tumor microenvironments.[3]. Because of its suppressive role in the tumor microenvironment, TGF-b has been targeted in several studies seeking to boost antitumor immunity. We demonstrate that TGF-b CAR-T cells can protect neighboring immune cells from the suppressive effects of TGF-b by enabling tumor-targeted CD81 T cells to retain cytolytic activity in the presence of TGF-b, and by discouraging CD41 T cells from TGF-b– induced Treg differentiation. Our results suggest that the TGF-b CAR can safely and effectively boost the antitumor efficacy of T-cell therapy
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