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.
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.



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.



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.



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.
Division of Hematology-Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.|Division of Hematology-Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
Richard P
RP
Junghans
Division of Hematology-Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.|Division of Hematology-Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
Qiangzhong
Q
Ma
Division of Hematology-Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
Ritesh
R
Rathore
Division of Hematology-Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
Erica M
EM
Gomes
Division of Hematology-Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
Anthony J
AJ
Bais
Division of Hematology-Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.|Division of Hematology-Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
Agnes S Y
AS
Lo
Division of Hematology-Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
Mehrdad
M
Abedi
Protocol Office, Roger Williams Medical Center, Providence, Rhode Island.
Robin A
RA
Davies
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
Howard J
HJ
Cabral
Division of Hematologic Malignancies and Blood and Marrow Transplantation, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
A Samer
AS
Al-Homsi
Division of Urology, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
Stephen I
SI
Cohen
D000368:Aged; D000954:Antigens, Surface / Q000097:blood; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000097:blood; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000637:transplantation*; D014182:Transplantation, Autologous / Q000379:methods; D016896:Treatment Outcome
D000954:Antigens, Surface; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
CAR-T cells; PSA delay; designer T cells; gene therapy; immunotherapy