Dominant-Negative TGF-β Receptor Enhances PSMA-Targeted Human CAR T Cell Proliferation And Augments Prostate Cancer Eradication

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).

Chimeric antigen receptors designed to overcome transforming growth factor‐β‐mediated repression in the adoptive T‐cell therapy of solid tumors

“…In contrast to CD28-f CAR, T cells with the 4-1BB-f CAR are sensitive to repression by TGF-b, which makes an alternative strategy necessary. The strategy established by Kloss et al (2018) 24 was that co-expressing a dominant-negative (dn) TGF-bRII along with a PSMA-specific CAR in T cells results in enhanced infiltration, proliferation, persistence and efficiency in the presence of TGFb. 24 The dnTGF-bRII thereby acts as a decoy receptor binding TGF-b without downstream signalling.…”

“…The strategy established by Kloss et al (2018) 24 was that co-expressing a dominant-negative (dn) TGF-bRII along with a PSMA-specific CAR in T cells results in enhanced infiltration, proliferation, persistence and efficiency in the presence of TGFb. 24 The dnTGF-bRII thereby acts as a decoy receptor binding TGF-b without downstream signalling. The study also identified a distinct transcriptional programme in the T cells expressing PSMA CAR and the dnTGF-bRll in the presence of TGF-b, indicating a successful protection from TGF-b-mediated repression of T cell effector functions.…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Conversely, other investigators are testing dual constructs requiring both targets to be expressed on tumor cells in order to exert their cytotoxic activity (114) and inhibitory CARs able to redirect T cells activity from healthy tissues (115), with the aim of increasing CAR specificity and of preventing off-tumor side effects. Furthermore, many efforts are being made to optimize co-stimulatory molecules and to improve the structure of CARs (116), and new constructs able to locally deliver immune-modulating cytokines (117)(118)(119)(120), bearing modified cytokine receptors (121) or targeting tumor matrix components (122,123) are being developed to overcome environmental barriers. Some groups are also exploring the possibility of combing CAR T cells with oncolytic viruses (124) or with checkpoint inhibitors (125)(126)(127).…”

Advances in Chimeric Antigen Receptor T‐Cell Therapies for Solid Tumors

“…An alternative approach is to abrogate TGFβ signaling by incorporating a dominant negative receptor. Using a CAR targeting the prostate-specific membrane antigen (PSMA), Kloss et al 39 created a T cell that expresses both the CAR and the dominant negative TGFβ receptor. Insensitivity to TGFβ promoted a significant increase in proliferative capacity relative to conventional CAR T cells, 39 suggesting that the lack of persistence observed in CAR T-cell-treated solid tumors stems from TME-mediated immune suppression and that the potential to achieve the persistence observed in CD19-directed CAR T cells is possible with appropriate immune cell modulation.…”