Combining immune check-point blockade and cryoablation in an immunocompetent hormone sensitive murine model of prostate cancer

Benjamin Benzon, Stephanie A. Glavaris, Brian W. Simons, Robert M. Hughes, Kamyar Ghabili, Patrick Mullane, Rebecca Miller, Katriana Nugent, Brian Shinder, Jeffrey Tosoian, Ephraim J Fuchs, Phuoc T Tran, Paula Hurley, Milena Vuica-Ross, Edward M. Schaeffer, Charles G. Drake, Ashley E. Ross

Research output: Contribution to journalArticle

Abstract

Background: Prostate cancer remains the second leading cause of cancer related death in men. Immune check point blocking antibodies have revolutionized treatment of multiple solid tumors, but results in prostate cancer remain marginal. Previous reports have suggested that local therapies, in particular cryoablation might increase tumor immunogenicity. In this work, we examine potential synergism between tumor cryoabalation and check point blocking antibodies. Methods: FVB/NJ mice were injected subcutaneously into each flank with either 1 × 106 or 0.2 × 106 isogenic hormone sensitive Myc-Cap cells to establish synchronous grafts. Mice were treated with four intraperitoneal injections of anti-PD-1 (10 mg/kg), anti-CTLA-4 (1 mg/kg), or isotype control antibody with or without adjuvant cryoablation of the larger tumor graft and with or without neo-adjuvant androgen deprivation with degarelix (ADT). Mouse survival and growth rates of tumor grafts were measured. The immune dependency of observed oncological effects was evaluated by T cell depletion experiments. Results: Treatment with anti-CTLA-4 antibody and cryoablation delayed the growth of the distant tumor by 14.8 days (p = 0.0006) and decreased the mortality rate by factor of 4 (p = 0.0003) when compared to cryoablation alone. This synergy was found to be dependent on CD3+ and CD8+ cells. Combining PD-1 blockade with cryoablation did not show a benefit over use of either treatment alone. Addition of ADT to anti-PD1 therapy and cryoablation doubled the time to accelerated growth in the untreated tumors (p = 0.0021) and extended survival when compared to cryoablation combined with ADT in 25% of the mice. Effects of combining anti-PD1 with ADT and cryoablation on mouse survival were obviated by T cell depletion. Conclusion: Trimodal therapy consisting of androgen deprivation, cryoablation and PD-1 blockade, as well as the combination of cryoablation and low dose anti-CTLA-4 blockade showed that local therapies with cryoablation could be considered to augment the effects of checkpoint blockade in prostate cancer.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalProstate Cancer and Prostatic Diseases
DOIs
StateAccepted/In press - Mar 20 2018

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Cryosurgery
Prostatic Neoplasms
Hormones
Neoplasms
Blocking Antibodies
Transplants
Therapeutics
Androgens
Growth
T-Lymphocytes
Antibodies
Intraperitoneal Injections
Survival Rate

ASJC Scopus subject areas

  • Oncology
  • Urology
  • Cancer Research

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Combining immune check-point blockade and cryoablation in an immunocompetent hormone sensitive murine model of prostate cancer. / Benzon, Benjamin; Glavaris, Stephanie A.; Simons, Brian W.; Hughes, Robert M.; Ghabili, Kamyar; Mullane, Patrick; Miller, Rebecca; Nugent, Katriana; Shinder, Brian; Tosoian, Jeffrey; Fuchs, Ephraim J; Tran, Phuoc T; Hurley, Paula; Vuica-Ross, Milena; Schaeffer, Edward M.; Drake, Charles G.; Ross, Ashley E.

In: Prostate Cancer and Prostatic Diseases, 20.03.2018, p. 1-11.

Research output: Contribution to journalArticle

Benzon, B, Glavaris, SA, Simons, BW, Hughes, RM, Ghabili, K, Mullane, P, Miller, R, Nugent, K, Shinder, B, Tosoian, J, Fuchs, EJ, Tran, PT, Hurley, P, Vuica-Ross, M, Schaeffer, EM, Drake, CG & Ross, AE 2018, 'Combining immune check-point blockade and cryoablation in an immunocompetent hormone sensitive murine model of prostate cancer', Prostate Cancer and Prostatic Diseases, pp. 1-11. https://doi.org/10.1038/s41391-018-0035-z
Benzon, Benjamin ; Glavaris, Stephanie A. ; Simons, Brian W. ; Hughes, Robert M. ; Ghabili, Kamyar ; Mullane, Patrick ; Miller, Rebecca ; Nugent, Katriana ; Shinder, Brian ; Tosoian, Jeffrey ; Fuchs, Ephraim J ; Tran, Phuoc T ; Hurley, Paula ; Vuica-Ross, Milena ; Schaeffer, Edward M. ; Drake, Charles G. ; Ross, Ashley E. / Combining immune check-point blockade and cryoablation in an immunocompetent hormone sensitive murine model of prostate cancer. In: Prostate Cancer and Prostatic Diseases. 2018 ; pp. 1-11.
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author = "Benjamin Benzon and Glavaris, {Stephanie A.} and Simons, {Brian W.} and Hughes, {Robert M.} and Kamyar Ghabili and Patrick Mullane and Rebecca Miller and Katriana Nugent and Brian Shinder and Jeffrey Tosoian and Fuchs, {Ephraim J} and Tran, {Phuoc T} and Paula Hurley and Milena Vuica-Ross and Schaeffer, {Edward M.} and Drake, {Charles G.} and Ross, {Ashley E.}",
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T1 - Combining immune check-point blockade and cryoablation in an immunocompetent hormone sensitive murine model of prostate cancer

AU - Benzon, Benjamin

AU - Glavaris, Stephanie A.

AU - Simons, Brian W.

AU - Hughes, Robert M.

AU - Ghabili, Kamyar

AU - Mullane, Patrick

AU - Miller, Rebecca

AU - Nugent, Katriana

AU - Shinder, Brian

AU - Tosoian, Jeffrey

AU - Fuchs, Ephraim J

AU - Tran, Phuoc T

AU - Hurley, Paula

AU - Vuica-Ross, Milena

AU - Schaeffer, Edward M.

AU - Drake, Charles G.

AU - Ross, Ashley E.

PY - 2018/3/20

Y1 - 2018/3/20

N2 - Background: Prostate cancer remains the second leading cause of cancer related death in men. Immune check point blocking antibodies have revolutionized treatment of multiple solid tumors, but results in prostate cancer remain marginal. Previous reports have suggested that local therapies, in particular cryoablation might increase tumor immunogenicity. In this work, we examine potential synergism between tumor cryoabalation and check point blocking antibodies. Methods: FVB/NJ mice were injected subcutaneously into each flank with either 1 × 106 or 0.2 × 106 isogenic hormone sensitive Myc-Cap cells to establish synchronous grafts. Mice were treated with four intraperitoneal injections of anti-PD-1 (10 mg/kg), anti-CTLA-4 (1 mg/kg), or isotype control antibody with or without adjuvant cryoablation of the larger tumor graft and with or without neo-adjuvant androgen deprivation with degarelix (ADT). Mouse survival and growth rates of tumor grafts were measured. The immune dependency of observed oncological effects was evaluated by T cell depletion experiments. Results: Treatment with anti-CTLA-4 antibody and cryoablation delayed the growth of the distant tumor by 14.8 days (p = 0.0006) and decreased the mortality rate by factor of 4 (p = 0.0003) when compared to cryoablation alone. This synergy was found to be dependent on CD3+ and CD8+ cells. Combining PD-1 blockade with cryoablation did not show a benefit over use of either treatment alone. Addition of ADT to anti-PD1 therapy and cryoablation doubled the time to accelerated growth in the untreated tumors (p = 0.0021) and extended survival when compared to cryoablation combined with ADT in 25% of the mice. Effects of combining anti-PD1 with ADT and cryoablation on mouse survival were obviated by T cell depletion. Conclusion: Trimodal therapy consisting of androgen deprivation, cryoablation and PD-1 blockade, as well as the combination of cryoablation and low dose anti-CTLA-4 blockade showed that local therapies with cryoablation could be considered to augment the effects of checkpoint blockade in prostate cancer.

AB - Background: Prostate cancer remains the second leading cause of cancer related death in men. Immune check point blocking antibodies have revolutionized treatment of multiple solid tumors, but results in prostate cancer remain marginal. Previous reports have suggested that local therapies, in particular cryoablation might increase tumor immunogenicity. In this work, we examine potential synergism between tumor cryoabalation and check point blocking antibodies. Methods: FVB/NJ mice were injected subcutaneously into each flank with either 1 × 106 or 0.2 × 106 isogenic hormone sensitive Myc-Cap cells to establish synchronous grafts. Mice were treated with four intraperitoneal injections of anti-PD-1 (10 mg/kg), anti-CTLA-4 (1 mg/kg), or isotype control antibody with or without adjuvant cryoablation of the larger tumor graft and with or without neo-adjuvant androgen deprivation with degarelix (ADT). Mouse survival and growth rates of tumor grafts were measured. The immune dependency of observed oncological effects was evaluated by T cell depletion experiments. Results: Treatment with anti-CTLA-4 antibody and cryoablation delayed the growth of the distant tumor by 14.8 days (p = 0.0006) and decreased the mortality rate by factor of 4 (p = 0.0003) when compared to cryoablation alone. This synergy was found to be dependent on CD3+ and CD8+ cells. Combining PD-1 blockade with cryoablation did not show a benefit over use of either treatment alone. Addition of ADT to anti-PD1 therapy and cryoablation doubled the time to accelerated growth in the untreated tumors (p = 0.0021) and extended survival when compared to cryoablation combined with ADT in 25% of the mice. Effects of combining anti-PD1 with ADT and cryoablation on mouse survival were obviated by T cell depletion. Conclusion: Trimodal therapy consisting of androgen deprivation, cryoablation and PD-1 blockade, as well as the combination of cryoablation and low dose anti-CTLA-4 blockade showed that local therapies with cryoablation could be considered to augment the effects of checkpoint blockade in prostate cancer.

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