P-PSMA-101 Elicits Encouraging Responses in Metastatic Castration-Resistant Prostate Cancer

Susan F. Slovin, MD, PhD

The autologous CAR T-cell therapy P-PSMA-101 elicited robust antitumor responses in patients with metastatic castration-resistant prostate cancer (mCRPC), according to preliminary findings from the phase 1 P-PSMA-101-001 trial (NCT04249947) that were virtually presented during the 6th Annual CAR-TCR Summit.¹

A total of 9 patients with mCRPC had been enrolled to the study; 5 of these patients received the product at Dose A, which was a single treatment of 0.25 x 10E6 cells/kg (an average of 20 million cells), and 4 patients were given the product at Dose B, which was a single treatment of 0.75 x 10E6 cells/kg (an average of 60 million cells). All participants were given a lymphodepletion regimen comprised of fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2.

Results indicated that 5 patients experienced measurable declines in prostate-specific antigen (PSA) levels. Additionally, 3 patients experienced a greater than 50% decline in PSA levels and had concordant improvements in PSMA-PET imaging. Notably, 1 patient showcased evidence suggestive of complete tumor elimination and continues to experience a response that has persisted for more than 5 months.

“This innovative Poseida PSMA-directed CAR T-cell platform has demonstrated a robust antitumor response in patients with mCRPC,” Susan F. Slovin, MD, PhD, associate vice chair of Academic Administration at Memorial Sloan Kettering Cancer Center and trial investigator, stated in a press release. “This is the first time that I have seen such impressive responses with an immunotherapy product. The responses of my patients in the trial are far beyond my expectations.”

P-PSMA-101 was designed to target prostate-specific membrane antigen, which is expressed on mCRPC cells.² The agent was developed using the piggyBac DNA Modification System, which manufactures products with a higher percentage of stem cell memory cells that can reconstruct T-cell subsets like effector T cells, which have a key role in tumor elimination.

One of the goals of the open-label, multicenter, 3+3 dose-escalating phase 1 trial was to identify the optimal dose of P-PSMA-101 that can safely be given to patients with mCRPC.³ Patients needed to have mCRPC that continued to progress despite prior treatment for advanced disease, an ECOG performance status of 0 or 1,⁴ and acceptable organ function within predetermined parameters. They could not still be experiencing serious toxicities from previous therapies.

The primary end points of the trial were to evaluate the safety of the CAR T-cell therapy, determine the maximum-tolerated dose, and examine the efficacy of the product. Participants were heavily pretreated, having received an average of 6 previous lines of therapy with a median time of 6.4 years since diagnosis.

Previously, in August 2020, the FDA placed a clinical hold on the P-PSMA-101-001 trial following notification of a patient death.⁵ The patient had previously progressed on various anticancer therapies prior to receiving treatment with the CAR T-cell product in late July 2020 and was reported to have had normal laboratory results after the first week of treatment; at that time point, no clinical symptoms indicative of an adverse effect (AE) were reported.

The patient, however, went on to miss his follow-up visits that were scheduled for days 10 and 14. During that time, the patient went on to experience symptoms that resulted in hospitalization. On day 19 following treatment with the CAR T-cell product, the patient died of hepatic failure. The direct cause of the hepatic failure had not been confirmed.

Specifically, the patient had presented with symptoms that proved to be consistent with macrophage activation syndrome (MAS), which is a serious overactivation of the immune system that has previously been associated with CAR T-cell products. However, MAS can also be caused by other events like autoimmune disease or infection. The patient also experienced blurred vision and had a diagnosis of uveitis. The severe toxicity was found to potentially be linked with P-PSMA-101 but warranted further investigation.

The hold on the trial was lifted in November 2020, and Poseida Therapeutics announced plans to resume the trial immediately having agreed to make amendments to the protocol to increase patient compliance and safety.⁶ Some of the modifications had to do with inclusion and exclusion criteria and frequency of monitoring and laboratory testing.

The CAR T-cell therapy was found to have favorable safety and tolerability in this population. Beyond the case of MAS that was exacerbated by patient non-compliance, only 3 cases of potential cytokine release syndrome were reported. However, all these cases were grade 1 or 2 and were managed effectively with early treatment. Notably, no neurotoxicity was reported with the product by the data cutoff date.

“We are excited about the preliminary data from our phase 1 trial of P-PSMA-101, which provides further evidence of the effectiveness of our CAR-T platform for solid tumor cancers,” Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc., stated in a press release. “To date, other CAR-T therapeutics have not had much success outside of hematologic malignancies. The deep and durable responses in our trial demonstrate that CAR-T products have the potential to work well against solid tumors, even at low doses, when using the appropriate technology platform.”

References

1. Poseida Therapeutics presents preliminary results from phase 1 trial of P-PSMA-101 at the 6th Annual CAR-TCR Summit. News release. Poseida Therapeutics, Inc. August 31, 2021. Accessed August 31, 2021. https://bit.ly/2WKV3lY
2. Poseida Therapeutics announces dosing of first patient on phase 1 clinical trial of P-PSMA-01 autologous CAR-T for metastatic castration-resistant prostate cancer. News release. Poseida Therapeutics, Inc. May 20, 2020. Accessed August 31, 2021. https://bit.ly/3kQVjY5
3. A phase I study of P-PSMA-01 CAR T-cell therapy in men with metastatic castration-resistant prostate cancer. Memorial Sloan Kettering Cancer Center. Accessed August 31, 2021. https://bit.ly/32iKLsn
4. P-PSMA-01 CAR-T cells in the treatment of subjects with metastatic castration-resistant prostate cancer (mCRPC). ClinicalTrials.gov. Updated July 13, 2020. Accessed August 31, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04249947
5. Gergen MJ. Form 8-L: Poseida Therapeutics, Inc. United States Securities Exchange Commission. August 17, 2020. Accessed August 31, 2021. https://bit.ly/2CEl4cR
6. Poseida Therapeutics announces clinical hold lifted on phase I autologous CAR-T study in prostate cancer. News release. Poseida Therapeutics, Inc. November 2, 2020. Accessed August 31, 2021. https://prn.to/385OmOE