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.

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Acknowledgements

AER and this work, was supported by Prostate Cancer Foundation Young Investigator Award. AER is supported by a DOD PRTA W81XWH-13- 1-0445 grant. Cryoablation probes were a generous gift from HeathTronics. We also thank to Mr. Robert Lee Blosser for his expert help with flow cytometry.

Author information

Affiliations

  1. Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Benjamin Benzon
    • , Stephanie A. Glavaris
    • , Brian W. Simons
    • , Robert M. Hughes
    • , Kamyar Ghabili
    • , Patrick Mullane
    • , Rebecca Miller
    • , Brian Shinder
    • , Jeffrey Tosoian
    • , Phuoc T. Tran
    • , Paula J. Hurley
    • , Charles G. Drake
    •  & Ashley E. Ross
  2. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Hospital School of Medicine, Baltimore, MD, USA

    • Katriana Nugent
    •  & Phuoc T. Tran
  3. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital School of Medicine, Baltimore, MD, USA

    • Ephraim J. Fuchs
    • , Phuoc T. Tran
    • , Charles G. Drake
    •  & Ashley E. Ross
  4. Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA

    • Milena Vuica-Ross
  5. Department of Urology, Northwestern Feinberg School of Medicine, Chicago, IL, USA

    • Edward M. Schaeffer

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Conflicts of interest

AER has served as an advisor and speaker for HeathTronics. AER and CGD are the principal and co-principal investigators of NCT02489357 who studied the combination of anti-PD-1 therapy, androgen deprivation, and cryoablation in oligo-metastatic newly diagnosed prostate cancer. AER and this work, was supported by Prostate Cancer Foundation Young Investigator Award. AER is supported by a DOD PRTA W81XWH-13- 1-0445 grant. AER has served as an advisor and speaker for Healthtronics. Cryoablation probes were a generous gift from Healthronics. The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Benjamin Benzon.

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DOI

https://doi.org/10.1038/s41391-018-0035-z

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