Improved efficacy of mitoxantrone in patients with castration-resistant prostate cancer after vaccination with GM-CSF-transduced allogeneic prostate cancer cells

Abstract

Previous vaccination studies in patients with castration-resistant prostate cancer (CRPC) showed improved survival without prolongation of progression-free survival (PFS). This might be explained by enhanced efficacy of subsequent therapies because of heightened immune status. We therefore evaluated the efficacy of chemotherapy in CRPC patients after immunotherapy. We retrospectively analyzed 28 patients who were treated with ipilimumab and GVAX, an allogeneic vaccine, and 21 patients who were randomized to GVAX or no vaccination. To study whether immune status was related to the efficacy of chemotherapy, frequencies of myeloid and lymphocyte subsets were determined. Of 28 patients treated with GVAX and ipilimumab, 23 patients received docetaxel and 13 patients mitoxantrone. Median PFS after docetaxel was 6.4 mo (range 0.8-11.2), while median PFS after mitoxantrone was markedly longer than expected (4.8 mo; range 1.4-13.7). High CD8⁺ICOS⁺ Tcell/Treg and pDC/mMDSC ratios were associated with relatively long PFS after mitoxantrone, suggesting a correlation between activated immune status and benefit of mitoxantrone. Analysis of 21 patients, randomized to GVAX or not, revealed a median PFS after docetaxel of 9.9 mo for vaccinated patients and 7.1 mo for unvaccinated patients. Interestingly, PFS after mitoxantrone (n = 14) was significantly longer in vaccinated patients as compared to controls (5.9 vs. 1.6 mo, p = 0.0048). In conclusion, mitoxantrone seems more effective in CRPC patients after immunotherapy, which may be related to the immune-stimulating effect of mitoxantrone in patients with heightened antitumor immunity. As this was a retrospective study with limited sample size, prospective studies are warranted to definitively show proof of principle.

Keywords: Cancer vaccines; GVAX; chemotherapy; docetaxel; immunotherapy; mitoxantrone; prostate cancer.

Figure 1.

Kaplan–Meier curves of progression-free survival after docetaxel and mitoxantrone of study subjects from the VITAL1 or VITAL2 study. Kaplan–Meier curves of progression-free survival (PFS) after docetaxel (A) and mitoxantrone (B) treatment for subjects with (solid line) or without (dotted line) prior prostate GVAX treatment. Number of patients and corresponding median PFS for each group is given. Statistical significance of the survival distribution was analyzed by log-rank testing..

Figure 2.

High Tact/Treg ratios after prostate GVAX/ipilimumab therapy are associated with significantly longer PFS following mitoxantrone. Kaplan–Meier curves of progression-free survival (PFS) following (A) mitoxantrone or (B) docetaxel treatment for prostate GVAX/ipilimumab-treated patients with high vs. low CD8⁺ICOS⁺/Treg ratios. Number of patients and corresponding median PFS for each group is given. Statistical significance of the survival distribution was analyzed by log-rank testing.