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Published on: February 17, 2022
Phase I Trial of Anti-PSMA Designer CAR-T Cells in Prostate Cancer: Possible Role for Interacting Interleukin 2-T
Richard P Junghans1,2, Qiangzhong Ma1,2, Ritesh Rathore1
1Division of Hematology-Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
Background:
Chimeric antigen receptor (CAR)-modified "designer" T cells (dTc, CAR-T) against PSMA selectively target antigen-expressing cells in vitro and eliminate tumors in vivo. Interleukin 2 (IL2), widely used in adoptive therapies, was proven essential in animal models for dTc to eradicate established solid tumors.
Methods:
Patients under-went chemotherapy condi-tion-ing, followed by dTc dosing under a Phase I escalation with continuous infusion low dose IL2 (LDI). A target of dTc escalation was to achieve ≥20% engraftment of infused activated T cells.
Results:
Six patients enrolled with doses prepared of whom five were treated. Patients received 10(9) or 10(10) autologous T cells, achieving expansions of 20-560-fold over 2 weeks and engraftments of 5-56%. Pharmacokinetic and pharmacodynamic analyses established the impact of conditioning to promote expansion and engraftment of the infused T cells. Unexpectedly, administered IL2 was depleted up to 20-fold with high engraftments of activated T cells (aTc) in an inverse correlation (P < 0.01). Clinically, no anti-PSMA toxicities were noted, and no anti-CAR reactivities were detected post-treatment. Two-of-five patients achieved clinical partial responses (PR), with PSA declines of 50% and 70% and PSA delays of 78 and 150 days, plus a minor response in a third patient. Responses were unrelated to dose size (P = 0.6), instead correlating inversely with engraftment (P = 0.06) and directly with plasma IL2 (P = 0.03), suggesting insufficient IL2 with our LDI protocol to support dTc anti-tumor activity under optimal (high) dTc engraftments.
Conclusions:
Under a Phase I dose escalation in prostate cancer, a 20% engraftment target was met or exceeded in three subjects with adequate safety, leading to study conclusion. Clinical responses were obtained but were suggested to be restrained by low plasma IL2 when depleted by high levels of engrafted activated T cells. This report presents a unique example of how the pharmaco-dynamics of "drug-drug" interactions may have a critical impact on the efficacy of their co-application. A new Pilot/Phase II trial is planned to test moderate dose IL2 (MDI) together with high dTc engraftments for anticipated improved therapeutic efficacy. Prostate 76:1257-1270, 2016. © 2016 Wiley Periodicals, Inc.
Insights
Chimeric antigen receptor T-cell (CAR-T) therapy shows promise for prostate cancer, but low Interleukin 2 (IL2) levels with high CAR-T cell engraftment may limit efficacy. Future trials will explore moderate dose IL2 to improve therapeutic outcomes.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR)-modified T cells (CAR-T) target PSMA-expressing cells.
- Interleukin 2 (IL2) is crucial for CAR-T cell efficacy in eradicating solid tumors.
Purpose of the Study:
- To evaluate the safety and efficacy of CAR-T therapy combined with low-dose IL2 (LDI) in prostate cancer patients.
- To determine optimal CAR-T cell engraftment and assess the impact of IL2 pharmacodynamics on treatment outcomes.
Main Methods:
- Phase I dose escalation study involving chemotherapy conditioning followed by CAR-T cell infusion and continuous LDI.
- Monitoring of CAR-T cell expansion, engraftment, IL2 levels, and clinical responses in enrolled patients.
Main Results:
- Five patients were treated, achieving significant CAR-T cell expansion (20-560-fold) and engraftment (5-56%).
- High CAR-T cell engraftment correlated with significant IL2 depletion, inversely impacting clinical responses.
- Two partial responses and one minor response were observed, unrelated to CAR-T dose but linked to IL2 levels.
Conclusions:
- CAR-T therapy with LDI is safe and can achieve target engraftment in prostate cancer patients.
- Low plasma IL2, due to depletion by high CAR-T cell engraftment, may limit therapeutic efficacy.
- A new trial will investigate moderate dose IL2 (MDI) with high CAR-T engraftment to enhance treatment outcomes.
