Phase I Trial of Anti-PSMA Designer CAR-T Cells in Prostate Cancer: Possible Role for Interacting Interleukin 2-T Cell Pharmacodynamics as a Determinant of Clinical Response

• Published in: The Prostate Vol. 76; no. 14; pp. 1257 - 1270
• Main Authors: Junghans, Richard P., Ma, Qiangzhong, Rathore, Ritesh, Gomes, Erica M., Bais, Anthony J., Lo, Agnes S.Y., Abedi, Mehrdad, Davies, Robin A., Cabral, Howard J., Al-Homsi, A. Samer, Cohen, Stephen I.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.10.2016; Wiley Subscription Services, Inc
• Subjects: Aged; Antigens; Antigens, Surface - blood; CAR-T cells; Cytokines; designer T cells; Drug dosages; gene therapy; Glutamate Carboxypeptidase II - antagonists & inhibitors; Glutamate Carboxypeptidase II - blood; Humans; immunotherapy; Interleukin-2 - administration & dosage; Lymphocytes; Male; Middle Aged; Prostate cancer; Prostatic Neoplasms - blood; Prostatic Neoplasms - diagnosis; Prostatic Neoplasms - therapy; PSA delay; Receptors, Antigen, T-Cell - administration & dosage; T-Lymphocytes - transplantation; Transplantation, Autologous - methods; Treatment Outcome; Tumors; gene therapy; designer T cells; PSA delay; CAR-T cells; immunotherapy
• DOI: 10.1002/pros.23214
• ISSN: 0270-4137

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 under­went chemotherapy condi­tion­ing, 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 109 or 1010 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 pharmaco­dynamics 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.