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Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer

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Abstract

CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles, 3 months apart, in which they received bicalutamide 150 mg daily days 1–28 and tremelimumab on day 29. The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.

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Acknowledgments

This work was supported by funding from Pfizer Corporation, for Heath A. Smith by DOD W81XWH-10-1-0495, and for Joshua M. Lang by NIH T32CA009614.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. University of Wisconsin Carbone Cancer Center, Madison, WI, 53792, USA

    Douglas G. McNeel, Heath A. Smith, Jens C. Eickhoff, Joshua M. Lang, Mary Jane Staab, George Wilding & Glenn Liu

  2. Department of Medicine, University of Wisconsin, Madison, WI, 53792, USA

    Douglas G. McNeel, Joshua M. Lang, George Wilding & Glenn Liu

  3. Department of Biostatistics, University of Wisconsin, Madison, WI, 53792, USA

    Jens C. Eickhoff

  4. 7007 Wisconsin Institutes for Medical Research, 1111 Highland Ave., Madison, WI, 53705, USA

    Douglas G. McNeel

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  1. Douglas G. McNeel
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Correspondence to Douglas G. McNeel.

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262_2011_1193_MOESM1_ESM.tif

Supplemental Figure 1: Example of High-Throughput Immunoblot Analysis: Sera were obtained from a subject (#2) pretreatment and at study conclusion and were used to probe a panel of phage-encoded antigens, as previously described [32, 33]. The red arrows indicate immunoreactive proteins recognized by IgG after treatment that were not present prior to treatment. Supplementary material 1 (TIFF 6,559 kb)

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McNeel, D.G., Smith, H.A., Eickhoff, J.C. et al. Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. Cancer Immunol Immunother 61, 1137–1147 (2012). https://doi.org/10.1007/s00262-011-1193-1

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