Immune Modulation by Androgen Deprivation and Radiation Therapy: Implications for Prostate Cancer Immunotherapy

doi:10.3390/cancers9020013

Review

. 2017 Jan 27;9(2):13.

doi: 10.3390/cancers9020013.

Immune Modulation by Androgen Deprivation and Radiation Therapy: Implications for Prostate Cancer Immunotherapy

Jennifer L Kalina¹, David S Neilson^{2

3}, Alexandra P Comber^{4

5}, Jennifer M Rauw^{6

7}, Abraham S Alexander^{8

9}, Joanna Vergidis^{10

11}, Julian J Lum^{12

13}

Affiliations

¹ Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC V8R 6V5, Canada. Jennifer.Kalina@bccancer.bc.ca.
² Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC V8R 6V5, Canada. dneilson@bccrc.ca.
³ Department of Biochemistry & Microbiology, University of Victoria, Victoria, BC V8P 5C2, Canada. dneilson@bccrc.ca.
⁴ Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC V8R 6V5, Canada. acomber@bccrc.ca.
⁵ Department of Biochemistry & Microbiology, University of Victoria, Victoria, BC V8P 5C2, Canada. acomber@bccrc.ca.
⁶ British Columbia Cancer Agency, Victoria, BC, V8R 6V5, Canada. Jennifer.Rauw@bccancer.bc.ca.
⁷ Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada. Jennifer.Rauw@bccancer.bc.ca.
⁸ British Columbia Cancer Agency, Victoria, BC, V8R 6V5, Canada. AAlexander3@bccancer.bc.ca.
⁹ Department of Surgery, University of British Columbia, Vancouver, BC V5Z 1M9, Canada. AAlexander3@bccancer.bc.ca.
¹⁰ British Columbia Cancer Agency, Victoria, BC, V8R 6V5, Canada. JVergidis@bccancer.bc.ca.
¹¹ Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada. JVergidis@bccancer.bc.ca.
¹² Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC V8R 6V5, Canada. jjlum@bccancer.bc.ca.
¹³ Department of Biochemistry & Microbiology, University of Victoria, Victoria, BC V8P 5C2, Canada. jjlum@bccancer.bc.ca.

PMID: 28134800
PMCID: PMC5332936
DOI: 10.3390/cancers9020013

Review

Immune Modulation by Androgen Deprivation and Radiation Therapy: Implications for Prostate Cancer Immunotherapy

Jennifer L Kalina et al. Cancers (Basel). 2017.

. 2017 Jan 27;9(2):13.

doi: 10.3390/cancers9020013.

Authors

Jennifer L Kalina¹, David S Neilson^{2

3}, Alexandra P Comber^{4

5}, Jennifer M Rauw^{6

7}, Abraham S Alexander^{8

9}, Joanna Vergidis^{10

11}, Julian J Lum^{12

13}

Affiliations

¹ Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC V8R 6V5, Canada. Jennifer.Kalina@bccancer.bc.ca.
² Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC V8R 6V5, Canada. dneilson@bccrc.ca.
³ Department of Biochemistry & Microbiology, University of Victoria, Victoria, BC V8P 5C2, Canada. dneilson@bccrc.ca.
⁴ Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC V8R 6V5, Canada. acomber@bccrc.ca.
⁵ Department of Biochemistry & Microbiology, University of Victoria, Victoria, BC V8P 5C2, Canada. acomber@bccrc.ca.
⁶ British Columbia Cancer Agency, Victoria, BC, V8R 6V5, Canada. Jennifer.Rauw@bccancer.bc.ca.
⁷ Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada. Jennifer.Rauw@bccancer.bc.ca.
⁸ British Columbia Cancer Agency, Victoria, BC, V8R 6V5, Canada. AAlexander3@bccancer.bc.ca.
⁹ Department of Surgery, University of British Columbia, Vancouver, BC V5Z 1M9, Canada. AAlexander3@bccancer.bc.ca.
¹⁰ British Columbia Cancer Agency, Victoria, BC, V8R 6V5, Canada. JVergidis@bccancer.bc.ca.
¹¹ Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada. JVergidis@bccancer.bc.ca.
¹² Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC V8R 6V5, Canada. jjlum@bccancer.bc.ca.
¹³ Department of Biochemistry & Microbiology, University of Victoria, Victoria, BC V8P 5C2, Canada. jjlum@bccancer.bc.ca.

PMID: 28134800
PMCID: PMC5332936
DOI: 10.3390/cancers9020013

Abstract

Prostate cancer patients often receive androgen deprivation therapy (ADT) in combination with radiation therapy (RT). Recent evidence suggests that both ADT and RT have immune modulatory properties. First, ADT can cause inﬁltration of lymphocytes into the prostate, although it remains unclear whether the inﬂux of lymphocytes is beneﬁcial, particularly with the advent of new classes of androgen blockers. Second, in rare cases, radiation can elicit immune responses that mediate regression of metastatic lesions lying outside the ﬁeld of radiation, a phenomenon known as the abscopal response. In light of these ﬁndings, there is emerging interest in exploiting any potential synergy between ADT, RT, and immunotherapy. Here, we provide a comprehensive review of the rationale behind combining immunotherapy with ADT and RT for the treatment of prostate cancer, including an examination of the current clinical trials that employ this combination. The reported outcomes of several trials demonstrate the promise of this combination strategy; however, further scrutiny is needed to elucidate how these standard therapies interact with immune modulators. In addition, we discuss the importance of synchronizing immune modulation relative to ADT and RT, and provide insight into elements that may impact the ability to achieve maximum synergy between these treatments.

Keywords: androgen deprivation therapy; cancer vaccines; checkpoint inhibitors; immunotherapy; prostate cancer; radiation therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Cellular and molecular effects of ADT and RT as they relate to the development of anti-tumor immunity.

See this image and copyright information in PMC

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References

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1. Bolla M., Van Tienhoven G., Warde P., Dubois J.B., Mirimanoff R.O., Storme G., Bernier J., Kuten A., Sternberg C., Billiet I., et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-Year results of an EORTC randomised study. Lancet Oncol. 2010;11:1066–1073. doi: 10.1016/S1470-2045(10)70223-0. - DOI - PubMed
1. D’Amico A.V., Whittington R., Malkowicz S.B., Schultz D., Blank K., Broderick G.A., Tomaszewski J.E., Renshaw A.A., Kaplan I., Beard C.J., et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969–974. doi: 10.1001/jama.280.11.969. - DOI - PubMed
1. D’Amico A.V., Whittington R., Malkowicz S.B., Schultz D., Renshaw A.A., Tomaszewski J.E., Richie J.P., Wein A. Optimizing patient selection for dose escalation techniques using the prostate-specific antigen level, biopsy gleason score, and clinical T-stage. Int. J. Radiat. Oncol. Biol. Phys. 1999;45:1227–1233. doi: 10.1016/S0360-3016(99)00303-X. - DOI - PubMed
1. Hernandez D.J., Nielsen M.E., Han M., Partin A.W. Contemporary evaluation of the D’amico risk classification of prostate cancer. Urology. 2007;70:931–935. doi: 10.1016/j.urology.2007.08.055. - DOI - PubMed

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[1] Huggins C. Effect of Orchiectomy and Irradiation on Cancer of the Prostate. Ann. Surg. 1942;115:1192–1200. doi: 10.1097/00000658-194206000-00030. - DOI - PMC - PubMed

[2] Huggins C. Effect of Orchiectomy and Irradiation on Cancer of the Prostate. Ann. Surg. 1942;115:1192–1200. doi: 10.1097/00000658-194206000-00030. - DOI - PMC - PubMed

[3] Bolla M., Van Tienhoven G., Warde P., Dubois J.B., Mirimanoff R.O., Storme G., Bernier J., Kuten A., Sternberg C., Billiet I., et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-Year results of an EORTC randomised study. Lancet Oncol. 2010;11:1066–1073. doi: 10.1016/S1470-2045(10)70223-0. - DOI - PubMed

[4] Bolla M., Van Tienhoven G., Warde P., Dubois J.B., Mirimanoff R.O., Storme G., Bernier J., Kuten A., Sternberg C., Billiet I., et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-Year results of an EORTC randomised study. Lancet Oncol. 2010;11:1066–1073. doi: 10.1016/S1470-2045(10)70223-0. - DOI - PubMed

[5] D’Amico A.V., Whittington R., Malkowicz S.B., Schultz D., Blank K., Broderick G.A., Tomaszewski J.E., Renshaw A.A., Kaplan I., Beard C.J., et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969–974. doi: 10.1001/jama.280.11.969. - DOI - PubMed

[6] D’Amico A.V., Whittington R., Malkowicz S.B., Schultz D., Blank K., Broderick G.A., Tomaszewski J.E., Renshaw A.A., Kaplan I., Beard C.J., et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969–974. doi: 10.1001/jama.280.11.969. - DOI - PubMed

[7] D’Amico A.V., Whittington R., Malkowicz S.B., Schultz D., Renshaw A.A., Tomaszewski J.E., Richie J.P., Wein A. Optimizing patient selection for dose escalation techniques using the prostate-specific antigen level, biopsy gleason score, and clinical T-stage. Int. J. Radiat. Oncol. Biol. Phys. 1999;45:1227–1233. doi: 10.1016/S0360-3016(99)00303-X. - DOI - PubMed

[8] D’Amico A.V., Whittington R., Malkowicz S.B., Schultz D., Renshaw A.A., Tomaszewski J.E., Richie J.P., Wein A. Optimizing patient selection for dose escalation techniques using the prostate-specific antigen level, biopsy gleason score, and clinical T-stage. Int. J. Radiat. Oncol. Biol. Phys. 1999;45:1227–1233. doi: 10.1016/S0360-3016(99)00303-X. - DOI - PubMed

[9] Hernandez D.J., Nielsen M.E., Han M., Partin A.W. Contemporary evaluation of the D’amico risk classification of prostate cancer. Urology. 2007;70:931–935. doi: 10.1016/j.urology.2007.08.055. - DOI - PubMed

[10] Hernandez D.J., Nielsen M.E., Han M., Partin A.W. Contemporary evaluation of the D’amico risk classification of prostate cancer. Urology. 2007;70:931–935. doi: 10.1016/j.urology.2007.08.055. - DOI - PubMed

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Immune Modulation by Androgen Deprivation and Radiation Therapy: Implications for Prostate Cancer Immunotherapy

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Immune Modulation by Androgen Deprivation and Radiation Therapy: Implications for Prostate Cancer Immunotherapy

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Conflict of interest statement

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