Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization

Koh, Yi Ting; Gray, Andrew; Higgins, Sean; Hubby, Bolyn; Kast, W. Martin

doi:10.1002/pros.20906

Cited by 92 publications

(72 citation statements)

References 60 publications

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“…The findings of this study are consistent with preclinical prostate cancer models (7,12) and a small randomized trial involving men with nonmetastatic castrate-resistant prostate cancer, in which survival was longer in patients vaccinated with a PSAencoding poxviral vaccine prior to second-line ADT (nilutamide) versus those receiving ADT prior to vaccination (13).…”

Section: Discussionsupporting

confidence: 85%

“…ADT has been shown to augment antitumor immune responses in animal models (5-7) and in patients with prostate cancer (6,(8)(9)(10), especially when combined with immunotherapies (11). Several (but not all) studies have shown superior immunologic and antitumor responses when immunotherapy was administered prior to ADT (7,12,13). However, although there is a clear rationale for combining ADT with immunologic therapies in men with prostate cancer (14), optimal sequencing remains unresolved.…”

Section: Introductionmentioning

confidence: 99%

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Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

Investigators

2017

Clinical Cancer Research

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Purpose: STAND, a randomized, phase II, open-label trial (NCT01431391), assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC) patients at high risk for metastasis.Experimental Design: Men with BRPC following prostatectomy and/or radiotherapy, a PSA doubling time 12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T-cell response [enzyme-linked immunospot (ELISPOT)] over time.Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-T!ADT versus ADT!sipuleucel-T (P ¼ 0.013). PA2024-specific T-cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-T!ADT versus ADT!sipuleucel-T (P ¼ 0.001). PA2024-specific cellular and humoral responses and prostatic acid phosphatase-specific humoral responses increased significantly versus baseline (P < 0.001) and were maintained for 24 months (both arms). Median time-to-PSA recurrence was similar between arms (21.8 vs. 22.6 months, P ¼ 0.357). Development of a PA2024-specific humoral response correlated with prolonged time-to-PSA progression (HR, 0.22; 95% CI, 0.08-0.67; P ¼ 0.007). Sipuleucel-T with ADT was generally well tolerated.Conclusions: Sipuleucel-T!ADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine whether this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

Investigators

2017

Clinical Cancer Research

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“…The rationale for a reciprocal potentiating action of ADT and immunotherapy is promising, but the results have not been convincing so far (33,41,42). Here, we have investigated the immune protection of combination treatment since having observed a promising synergistic effect of immunotherapy combined with orchiectomy.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse

Liang

et al. 2016

Sci. Transl. Med.

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Surgical and medical androgen deprivation therapy (ADT) is a cornerstone for prostate cancer treatment, but relapse usually occurs. We herein show that orchiectomy synergizes with immunotherapy, whereas the more widely used treatment of medical ADT involving androgen receptor (AR) antagonists suppresses immunotherapy. Furthermore, we observed that the use of medical ADT could unexpectedly impair the adaptive immune responses through interference with initial T cell priming rather than in the reactivation or expansion phases. Mechanistically, we have revealed that inadvertent immunosuppression might be potentially mediated by a receptor shared with g-aminobutyric acid. Our data demonstrate that the timing and dosing of antiandrogens are critical to maximizing the antitumor effects of combination therapy. This study highlights an underappreciated mechanism of AR antagonist-mediated immunosuppression and provides a new strategy to enhance immune response and prevent the relapse of advanced prostate cancer.

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“…Using abiraterone in combination with sipuleucel-T would yield more immediate antitumor effects and thus allow time for the sipuleucel-T anticancer response to develop. Furthermore, suppression of testosterone has been demonstrated to have immunostimulatory properties (4)(5)(6)(7)(8)(9). Thus, reduction of testosterone levels with AA plus prednisone (AA þ P) may enhance the immunologic effects of sipuleucel-T. To date, because AA requires the coadministration of prednisone, which may have immunosuppressive effects, there is concern that this treatment could interfere with sipuleucel-T manufacture and/or dampen its immunologic effects if used in combination (10).…”

Section: Introductionmentioning

confidence: 99%

A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer

Small

Lance

Gardner

et al. 2015

Clinical Cancer Research

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Purpose: This phase II open-label study evaluated the effect of concurrent or sequential administration of abiraterone acetate plus prednisone (AA þ P) on sipuleucel-T manufacture and immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients.Experimental Design: mCRPC patients received sipuleucel-T followed by AA þ P 1 day (concurrent) or 10 weeks (sequential) after the first sipuleucel-T infusion. AA þ P treatment continued for 26 weeks. The primary endpoint was cumulative antigen presenting cell (APC) activation, and secondary endpoints included cumulative APC number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) as well as safety.Results: Sixty-nine mCRPC patients were enrolled, with 35 and 34 patients randomized to the concurrent and sequential arms, respectively. Ex vivo APC activation was significantly greater at the second and third infusions compared with baseline in both arms (P < 0.05), indicative of an immunologic prime-boost effect. In both arms, sipuleucel-T product parameter profiles and peripheral immune responses were consistent with previously conducted sipuleucel-T phase III trials. Antigen spread was similarly observed in both arms and consistent with the other immunologic endpoints.Conclusions: These data suggest that sipuleucel-T can be successfully manufactured during concurrent administration of AA þ P without blunting immunologic effects or altering immune parameters that correlate with sipuleucel-T's clinical benefit. Combination of these agents was well tolerated, with no new safety signals emerging.

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Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization

Cited by 92 publications

References 60 publications

Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse

A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer

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