Proof-of-principle Phase I results of combining nivolumab with brachytherapy and external beam radiation therapy for Grade Group 5 prostate cancer: safety, feasibility, and exploratory analysis.
Journal
Prostate cancer and prostatic diseases
ISSN: 1476-5608
Titre abrégé: Prostate Cancer Prostatic Dis
Pays: England
ID NLM: 9815755
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
12
04
2020
accepted:
02
07
2020
revised:
05
06
2020
pubmed:
12
7
2020
medline:
25
11
2021
entrez:
12
7
2020
Statut:
ppublish
Résumé
To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa. Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189). Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post-HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders. Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.
Sections du résumé
BACKGROUND
To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa.
METHODS
Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189).
RESULTS
Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post-HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders.
CONCLUSION
Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.
Identifiants
pubmed: 32651467
doi: 10.1038/s41391-020-0254-y
pii: 10.1038/s41391-020-0254-y
pmc: PMC7882397
mid: NIHMS1655461
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
Nivolumab
31YO63LBSN
Banques de données
ClinicalTrials.gov
['NCT03543189']
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
140-149Subventions
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Références
Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl J Med. 2017;377:1345–56.
pubmed: 28889792
pmcid: 5706778
doi: 10.1056/NEJMoa1709684
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl J Med. 2015;372:2018–28.
pubmed: 25891174
doi: 10.1056/NEJMoa1501824
Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl J Med. 2018;378:1277–90.
pubmed: 29562145
pmcid: 5972549
doi: 10.1056/NEJMoa1712126
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl J Med. 2017;376:1015–26.
pubmed: 28212060
pmcid: 5635424
doi: 10.1056/NEJMoa1613683
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl J Med. 2012;366:2443–54.
pubmed: 22658127
pmcid: 3544539
doi: 10.1056/NEJMoa1200690
Graff JN, Alumkal JJ, Drake CG, Thomas GV, Redmond WL, Farhad M, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget. 2016;7:52810–7.
pubmed: 27429197
pmcid: 5288150
doi: 10.18632/oncotarget.10547
D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008;299:289–95.
pubmed: 18212313
doi: 10.1001/jama.299.3.289
Denham JW, Steigler A, Lamb DS, Joseph D, Turner S, Matthews J, et al. Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol. 2011;12:451–9.
pubmed: 21440505
doi: 10.1016/S1470-2045(11)70063-8
D’Amico AV. Is Gleason grade 5 prostate cancer resistant to conventional androgen deprivation therapy? Eur Urol. 2016;69:761–3.
pubmed: 26364550
doi: 10.1016/j.eururo.2015.08.057
Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res. 2004;64:4328–37.
pubmed: 15205348
pmcid: 15205348
doi: 10.1158/0008-5472.CAN-04-0073
Gameiro SR, Malamas AS, Bernstein MB, Tsang KY, Vassantachart A, Sahoo N, et al. Tumor cells surviving exposure to proton or photon radiation share a common immunogenic modulation signature, rendering them more sensitive to T cell-mediated killing. Int J Radiat Oncol Biol Phys. 2016;95:120–30.
pubmed: 27084634
pmcid: 4834148
doi: 10.1016/j.ijrobp.2016.02.022
Gameiro SR, Ardiani A, Kwilas A, Hodge JW. Radiation-induced survival responses promote immunogenic modulation to enhance immunotherapy in combinatorial regimens. Oncoimmunology. 2014;3:e28643.
pubmed: 25097803
pmcid: 4091054
doi: 10.4161/onci.28643
Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–7.
pubmed: 25754329
doi: 10.1038/nature14292
Patel RB, Baniel CC, Sriramaneni RN, Bradley K, Markovina S, Morris ZS. Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities. Brachytherapy. 2018;17:995–1003.
pubmed: 30078541
doi: 10.1016/j.brachy.2018.07.004
Walle T, Martinez Monge R, Cerwenka A, Ajona D, Melero I, Lecanda F. Radiation effects on antitumor immune responses: current perspectives and challenges. Therapeutic Adv Med Oncol. 2018;10:1758834017742575.
Koh YT, Gray A, Higgins SA, Hubby B, Kast WM. Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization. Prostate. 2009;69:571–84.
pubmed: 19143030
pmcid: 2732563
doi: 10.1002/pros.20906
Roden AC, Moser MT, Tri SD, Mercader M, Kuntz SM, Dong H, et al. Augmentation of T cell levels and responses induced by androgen deprivation. J Immunol. 2004;173:6098–108.
pubmed: 15528346
doi: 10.4049/jimmunol.173.10.6098
Aragon-Ching JB, Williams KM, Gulley JL. Impact of androgen-deprivation therapy on the immune system: implications for combination therapy of prostate cancer. Front Biosci: a J virtual Libr. 2007;12:4957–71.
doi: 10.2741/2441
Sanda MG, Smith DC, Charles LG, Hwang C, Pienta KJ, Schlom J, et al. Recombinant vaccinia-PSA (PROSTVAC) can induce a prostate-specific immune response in androgen-modulated human prostate cancer. Urology. 1999;53:260–6.
pubmed: 9933036
doi: 10.1016/S0090-4295(98)00539-1
George DJ, Nabhan C, DeVries T, Whitmore JB, Gomella LG. Survival outcomes of sipuleucel-T phase III studies: impact of control-arm cross-over to salvage immunotherapy. Cancer Immunol Res. 2015;3:1063–9.
pubmed: 25943532
doi: 10.1158/2326-6066.CIR-15-0006
Small EJ, Lance RS, Gardner TA, Karsh LI, Fong L, McCoy C, et al. A randomized phase II trial of sipuleucel-T with concurrent versus sequential abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2015;21:3862–9.
pubmed: 25925891
doi: 10.1158/1078-0432.CCR-15-0079
Mercader M, Bodner BK, Moser MT, Kwon PS, Park ES, Manecke RG, et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad Sci USA. 2001;98:14565–70.
pubmed: 11734652
doi: 10.1073/pnas.251140998
Epstein JI, Zelefsky MJ, Sjoberg DD, Nelson JB, Egevad L, Magi-Galluzzi C, et al. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol. 2016;69:428–35.
pubmed: 26166626
doi: 10.1016/j.eururo.2015.06.046
Nabid A, Carrier N, Martin AG, Bahary JP, Lemaire C, Vass S, et al. Duration of androgen deprivation therapy in high-risk prostate cancer: a randomized phase III trial. Eur Urol. 2018;74:432–41.
pubmed: 29980331
doi: 10.1016/j.eururo.2018.06.018
Matta R, Chapple CR, Fisch M, Heidenreich A, Herschorn S, Kodama RT, et al. Pelvic complications after prostate cancer radiation therapy and their management: an international collaborative narrative review. Eur Urol. 2019;75:464–76.
pubmed: 30573316
doi: 10.1016/j.eururo.2018.12.003
Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, Malhotra N, et al. Immune checkpoint inhibitor-induced colitis: a comprehensive review. World J Clin Cases. 2019;7:405–18.
pubmed: 30842952
pmcid: 6397821
doi: 10.12998/wjcc.v7.i4.405
Wang Y, Abu-Sbeih H, Mao E, Ali N, Ali FS, Qiao W, et al. Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson. J Immunother Cancer. 2018;6:37.
pubmed: 29747688
pmcid: 5946546
doi: 10.1186/s40425-018-0346-6
Mahoney KM, Atkins MB. Prognostic and predictive markers for the new immunotherapies. Oncology. 2014;28:39–48.
pubmed: 25384886
Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214–8.
pubmed: 23770567
pmcid: 3919509
doi: 10.1038/nature12213
Bilusic M, Madan RA, Gulley JL. Immunotherapy of prostate cancer: facts and hopes. Clin Cancer Res. 2017;23:6764–70.
pubmed: 28663235
pmcid: 5690854
doi: 10.1158/1078-0432.CCR-17-0019
Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C, Gravis G, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2017;35:40–7.
doi: 10.1200/JCO.2016.69.1584
Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700–12.
pubmed: 24831977
pmcid: 24831977
doi: 10.1016/S1470-2045(14)70189-5
Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 Study. J Clin Oncol 2019;38:395–405.
Gorbet MJ, Ranjan A. Cancer immunotherapy with immunoadjuvants, nanoparticles, and checkpoint inhibitors: recent progress and challenges in treatment and tracking response to immunotherapy. Pharmacol Ther 2019;207:107456.
Geara FB, Bulbul M, Khauli RB, Andraos TY, Abboud M, Al Mousa A, et al. Nadir PSA is a strong predictor of treatment outcome in intermediate and high risk localized prostate cancer patients treated by definitive external beam radiotherapy and androgen deprivation. Radiat Oncol. 2017;12:149.
pubmed: 28882187
pmcid: 5590195
doi: 10.1186/s13014-017-0884-y
Verma V, Shrimali RK, Ahmad S, Dai W, Wang H, Lu S, et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1(+)CD38(hi) cells and anti-PD-1 resistance. Nat Immunol. 2019;20:1231–43.
pubmed: 31358999
pmcid: 7472661
doi: 10.1038/s41590-019-0441-y