Dominant-Negative TGF-β Receptor Enhances PSMA-Targeted Human CAR T Cell Proliferation And Augments Prostate Cancer Eradication
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Published on: October 27, 2020
Christopher C Kloss1, Jihyun Lee2, Aaron Zhang2
1Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-5156, USA; Smilow Center for Translational Research, 3400 Civic Center Blvd., Philadelphia, PA 19104-5156, USA.
Abstract:
Cancer has an impressive ability to evolve multiple processes to evade therapies. While immunotherapies and vaccines have shown great promise, particularly in certain solid tumors such as prostate cancer, they have been met with resistance from tumors that use a multitude of mechanisms of immunosuppression to limit effectiveness. Prostate cancer, in particular, secretes transforming growth factor β (TGF-β) as a means to inhibit immunity while allowing for cancer progression. Blocking TGF-β signaling in T cells increases their ability to infiltrate, proliferate, and mediate antitumor responses in prostate cancer models. We tested whether the potency of chimeric antigen receptor (CAR) T cells directed to prostate-specific membrane antigen (PSMA) could be enhanced by the co-expression of a dominant-negative TGF-βRII (dnTGF-βRII). Upon expression of the dominant-negative TGF-βRII in CAR T cells, we observed increased proliferation of these lymphocytes, enhanced cytokine secretion, resistance to exhaustion, long-term in vivo persistence, and the induction of tumor eradication in aggressive human prostate cancer mouse models. Based on our observations, we initiated a phase I clinical trial to assess these CAR T cells as a novel approach for patients with relapsed and refractory metastatic prostate cancer (ClinicalTrials.gov: NCT03089203).
Insights
Chimeric antigen receptor (CAR) T-cells targeting prostate-specific membrane antigen (PSMA) were engineered to resist immunosuppression by incorporating a dominant-negative TGF-β receptor. This enhanced CAR T-cell therapy demonstrated potent anti-tumor activity in prostate cancer models, leading to a clinical trial.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Prostate cancer utilizes immunosuppressive mechanisms, like transforming growth factor β (TGF-β) secretion, to evade immune responses and therapies.
- While immunotherapies show promise, tumor resistance limits their effectiveness, necessitating novel strategies for advanced prostate cancer.
Purpose of the Study:
- To enhance the efficacy of prostate-specific membrane antigen (PSMA)-targeted chimeric antigen receptor (CAR) T-cells by co-expressing a dominant-negative TGF-β receptor II (dnTGF-βRII).
- To evaluate the therapeutic potential of dnTGF-βRII-engineered CAR T-cells in aggressive prostate cancer models and initiate clinical investigation.
Main Methods:
- CAR T-cells targeting PSMA were engineered to co-express dnTGF-βRII.
- The functional capacity of engineered CAR T-cells, including proliferation, cytokine secretion, and in vivo persistence, was assessed in aggressive human prostate cancer mouse models.
- A Phase I clinical trial was initiated to evaluate safety and efficacy in patients with relapsed/refractory metastatic prostate cancer.
Main Results:
- Co-expression of dnTGF-βRII significantly enhanced CAR T-cell proliferation, cytokine secretion, and resistance to exhaustion.
- Engineered CAR T-cells exhibited improved long-term in vivo persistence and demonstrated potent anti-tumor activity, leading to tumor eradication in preclinical models.
- These promising preclinical findings supported the initiation of a Phase I clinical trial (NCT03089203).
Conclusions:
- Engineering CAR T-cells with dnTGF-βRII overcomes TGF-β-mediated immunosuppression, enhancing anti-tumor activity against prostate cancer.
- This strategy represents a promising novel approach for treating patients with advanced, refractory prostate cancer.
- The ongoing Phase I clinical trial will further assess the safety and efficacy of this enhanced CAR T-cell therapy.
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