Optimizing gamma/delta CAR-T-cell therapy for bone metastatic castration-resistant prostate cancer
Project Summary/Abstract Metastatic castrate resistant prostate cancer (mCRPC) remains an incurable condition, associated with high mortality and morbidity. As part of a previous R01-funded program, we have established the proof of concept, obtained investigational new drug (IND) clearance by the FDA, and started a Phase 1 clinical trial of a novel immunotherapy for bone mCRPC (NCT06193486). The treatment involves adoptive transfer of autologous ãä- enriched chimeric antigen receptor (CAR-)T cells, in mCRPC patients who receive zoledronate (ZOL) as standard-of-care treatment for bone deterioration. Zoledronate is a key element in this therapy, because it polyclonally stimulates a subtype of ãä T-cell called Vã9Vä2 (herein named Vd2), through their T-cell receptor (TCR). Simultaneous activation of the CAR (by its target antigen, PSCA) and the endogenous TCR (induced by ZOL treatment) increases the activity of CAR-T cells, resulting in enhanced antitumor efficacy. Importantly, when the infusions of ZOL and CAR-T cells are staggered, the boosting effect of ZOL is localized to the bone, due to its rapid clearance from circulation and soft tissues and long-term accumulation in bone, thus reducing the risk of off-tumor toxicities. As we advance the clinical testing of this strategy, we seek to leverage clinical samples from patients to further our understanding of the biology of Vd2 T cells and to improve our strategy through evidence-based interventions. Our overarching goal is to maximize the therapeutic benefit provided by Vd2 CART cells to patients with bone mCRPC. More specifically, we aim to study two processes initiated by ZOL exposure that may impact the efficacy of the therapy. We will also test a new strategy to enhance the performance of CAR-T cells, while inducing long-term immunity through vaccination. First, we will study the role of ZOL-induced TXNIP upregulation on the establishment of a suboptimal metabolic phenotype identified in our preliminary studies. Second, we will test if ZOL-induced antigen presentation by Vd2 CAR-T cells is part of the mechanism of action of Vd2 CAR-T cells. Finally, we will test a new CAR product designed to shield Vd2 T-cells from the deleterious effects of TXNIP while priming ab T-cell responses against the tumor. This innovative design differs from other prime-boost strategies where CAR-T cell administration is followed by vaccination and simplifies its implementation by condensing all the functions in a single cell product. Through this study, we will gain a deeper understanding of factors that condition the therapeutic success of Vd2 CAR-T cells. While this project relies heavily on human systems (correlative analysis of samples from patients receiving Vd2 CAR-T cells), we still need to include limited animal modeling to study processes that cannot be modelled in vitro or studied directly from human subjects. More specifically, we will use a murine model to analyze the effects of biological interventions on the in vivo persistence of T cells in a complex organism, and on the process of immunization. Upon successful completion of the proposes studies, we will be well positioned to initiate clinical testing of a new generation of 𝛾𝛿 CAR-T cell-based immunotherapies.
4/6 complete
Imported from NIH RePORTER | Grant 1R01CA301640-01A1.
Open sourceOverview
Grant agreement 1R01CA301640-01A1
Open sourceProject Summary/Abstract Metastatic castrate resistant prostate cancer (mCRPC) remains an incurable condition, associated with high mortality and morbidity. As part of a previous R01-funded program, we have established the proof of concept, obtained investigational new drug (IND) clearance by the FDA, and started a Phase 1 clinical trial of a novel immunotherapy for bone mCRPC (NCT06193486). The treatment involves adoptive transfer of autologous ãä- enriched chimeric antigen receptor (CAR-)T cells, in mCRPC patients who receive zoledronate (ZOL) as standard-of-care treatment for bone deterioration. Zoledronate is a key element in this therapy, because it polyclonally stimulates a subtype of ãä T-cell called Vã9Vä2 (herein named Vd2), through their T-cell receptor (TCR). Simultaneous activation of the CAR (by its target antigen, PSCA) and the endogenous TCR (induced by ZOL treatment) increases the activity of CAR-T cells, resulting in enhanced antitumor efficacy. Importantly, when the infusions of ZOL and CAR-T cells are staggered, the boosting effect of ZOL is localized to the bone, due to its rapid clearance from circulation and soft tissues and long-term accumulation in bone, thus reducing the risk of off-tumor toxicities. As we advance the clinical testing of this strategy, we seek to leverage clinical samples from patients to further our understanding of the biology of Vd2 T cells and to improve our strategy through evidence-based interventions. Our overarching goal is to maximize the therapeutic benefit provided by Vd2 CART cells to patients with bone mCRPC. More specifically, we aim to study two processes initiated by ZOL exposure that may impact the efficacy of the therapy. We will also test a new strategy to enhance the performance of CAR-T cells, while inducing long-term immunity through vaccination. First, we will study the role of ZOL-induced TXNIP upregulation on the establishment of a suboptimal metabolic phenotype identified in our preliminary studies. Second, we will test if ZOL-induced antigen presentation by Vd2 CAR-T cells is part of the mechanism of action of Vd2 CAR-T cells. Finally, we will test a new CAR product designed to shield Vd2 T-cells from the deleterious effects of TXNIP while priming ab T-cell responses against the tumor. This innovative design differs from other prime-boost strategies where CAR-T cell administration is followed by vaccination and simplifies its implementation by condensing all the functions in a single cell product. Through this study, we will gain a deeper understanding of factors that condition the therapeutic success of Vd2 CAR-T cells. While this project relies heavily on human systems (correlative analysis of samples from patients receiving Vd2 CAR-T cells), we still need to include limited animal modeling to study processes that cannot be modelled in vitro or studied directly from human subjects. More specifically, we will use a murine model to analyze the effects of biological interventions on the in vivo persistence of T cells in a complex organism, and on the process of immunization. Upon successful completion of the proposes studies, we will be well positioned to initiate clinical testing of a new generation of 𝛾𝛿 CAR-T cell-based immunotherapies.