Study launches of CAR T therapy for bone metastatic prostate cancer

The first patient has been treated in a phase 1 study (NCT06193486) exploring the safety and preliminary efficacy of a delta gamma chimeric antigen receptor T-cell (CAR T) therapy for adult patients with end-stage bone metastatic castration-resistant prostate cancer (mCRPC).¹

The primary end point for the trial is the maximum tolerated dose of the CAR T cell therapy.

The study is being conducted by investigators at H. Lee Moffitt Cancer Center in Tampa, Florida.

“We are hopeful that this therapy will help patients with prostate cancer and that this study will be just the first step towards the effective treatment of other bone tumors,” said Daniel Abate-Daga, PhD, scientific director of Cell Therapies Core, in a news release on the study.¹ Abate-Daga’s lab at Moffitt Cancer Center developed the CAR T therapy in early 2023.

The therapy utilizes gamma delta T cells to target prostate stem cell antigen, a tumor biomarker that is highly expressed in prostate cancer that has metastasized to the bone. Patients are eligible for the study if they have exhausted standard of care options and are on zoledronate for bone metastases.²

The single-center, dose-escalation trial of the therapy will be conducted in a 3+3 design, with 3 patients enrolled into each cohort. The study will include 5 dose levels at 1x10^5 cells/kg, 3x10^5 cells/kg, 1x10^6 cells/kg, 3x10^6 cells/kg, and 1x10^6 cells/kg.

Patients included in the phase 1 study will have their T cells harvested through apheresis. The cells will then be engineered to include chimeric antigen receptor. Patients will also undergo lymphodepletion chemotherapy prior to infusion, which will consist of 500 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine administered over 3 days. On average, the process from cell collection to infusion will take 14 days.

The primary end point for the trial is the maximum tolerated dose (MTD) of the CAR T cell therapy. The secondary end points are best prostate-specific antigen response rate, radiographic progression-free survival, and the percentage of circulating tumor cell count conversions from above 5/mL to below 5/mL.

The dose escalation phase of the trial will be followed by the dose expansion phase upon determination of the MTD.

Preclinical data on the CAR T cell therapy

In 2023, preclinical data was published in the journal Science Advances on γδ-enriched CAR T cells in combination with zoledronate for mCRPC. Overall, the combination therapy was shown to induce rapid and significant regression of established tumors in a preclinical murine model of bone mCRPC.³

Further, pretreatment with zoledronate led to activation of γδ-enriched CAR T cells, independent of CAR, as well as increased cytokine secretion and enhance anti-tumor activity. The authors concluded that the findings supported the use of γδ CAR T-cell therapy in the management of mCRPC.

References

1. Moffitt treats first clinical trial patient with gamma delta CAR T for bone metastatic prostate cancer. News release. Moffitt Cancer Center. April 16, 2024. Accessed April 18, 2024. https://www.moffitt.org/newsroom/news-releases/moffitt-treats-first-clinical-trial-patient-with-gamma-delta-car-t-for-bone-metastatic-prostate-cancer/

2. Autologous gamma delta T cells to target prostate stem cell antigen in mCRPC. ClinicalTrials.gov. Last updated March 13, 2024. Accessed April 18, 2024. https://clinicaltrials.gov/study/NCT06193486

3. Frieling JS, Tordesillas L, Bustos XE, et al. γδ-Enriched CAR-T cell therapy for bone metastatic castrate-resistant prostate cancer. Sci Adv. 2023;9(18):eadf0108. doi:10.1126/sciadv.adf0108