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

Richard P. Junghans, Qiangzhong Ma, Ritesh Rathore, Erica M. Gomes, Anthony J. Bais, Agnes S Y Lo, Mehrdad Abedi, Robin A. Davies, Howard J. Cabral, A. Samer Al-Homsi, Stephen I. Cohen

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1257-1270
Number of pages14
JournalProstate
Volume76
Issue number14
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

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T-Cell Antigen Receptor
Interleukin-2
Prostatic Neoplasms
T-Lymphocytes
Antigen Receptors
Neoplasms
Prostate
Therapeutics
Animal Models
Pharmacokinetics
Safety
Antigens
Drug Therapy

Keywords

  • CAR-T cells
  • designer T cells
  • gene therapy
  • immunotherapy
  • PSA delay

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Urology

Cite this

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. / 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.

In: Prostate, Vol. 76, No. 14, 01.10.2016, p. 1257-1270.

Research output: Contribution to journalArticle

Junghans, RP, Ma, Q, Rathore, R, Gomes, EM, Bais, AJ, Lo, ASY, Abedi, M, Davies, RA, Cabral, HJ, Al-Homsi, AS & Cohen, SI 2016, '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', Prostate, vol. 76, no. 14, pp. 1257-1270. https://doi.org/10.1002/pros.23214
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. / 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. In: Prostate. 2016 ; Vol. 76, No. 14. pp. 1257-1270.
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abstract = "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.",
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T1 - Phase I Trial of Anti-PSMA Designer CAR-T Cells in Prostate Cancer

T2 - Possible Role for Interacting Interleukin 2-T Cell Pharmacodynamics as a Determinant of Clinical Response

AU - Junghans, Richard P.

AU - Ma, Qiangzhong

AU - Rathore, Ritesh

AU - Gomes, Erica M.

AU - Bais, Anthony J.

AU - Lo, Agnes S Y

AU - Abedi, Mehrdad

AU - Davies, Robin A.

AU - Cabral, Howard J.

AU - Al-Homsi, A. Samer

AU - Cohen, Stephen I.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

KW - CAR-T cells

KW - designer T cells

KW - gene therapy

KW - immunotherapy

KW - PSA delay

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