Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer

Abstract

A concurrent multicenter, randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of enhanced median overall survival (OS) (p=0.0061) in patients with metastatic castrate-resistant prostate cancer (mCRPC). The study reported here employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. Thirty-two patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three costimulatory molecules (TRICOM). Patients received boosters with recombinant fowlpox containing the same four transgenes. Twelve of 32 patients showed declines in serum PSA post-vaccination and 2/12 showed decreases in index lesions. Median OS was 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). Patients with greater PSA-specific T-cell responses showed a trend (p=0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF vs no GM-CSF. Patients with a Halabi predicted survival of < 18 months (median predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of ≥ 18 months (median predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p=0.035). Treg suppressive function was shown to decrease following vaccine in patients surviving longer than predicted, and increase in patients surviving less than predicted. This hypothesis-generating study provides evidence that patients with more indolent mCRPC (Halabi predicted survival ≥ 18 months) may best benefit from vaccine therapy.

Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer

“…8,9 In addition, other approaches including vaccines that decrease the frequency and function of Tregs have also shown limited clinical benefits for cancer patients. 10,11 However, the role of Tregs in human CRC patients is still controversial. [12][13][14][15][16] Given the inconsistent results concerning the prognostic value of Tregs in patients with CRC, it is not surprising that there is to date no clinical trial reporting effective immunotherapies targeting Tregs in CRC.…”

Research Highlights

“…This is based on the hypothesis that immune boosting of peptide-specific CTLs will be more effective than priming of naive T cells in inducing immunologic response. Other studies of PPV therapy, given concurrently with hormone therapy and low-dose EMP, have shown promising clinical and immunologic activity [1,2]. In the current study by Uemura et al [3], PPV monotherapy was assessed in 23 HLA-A24+ or A2+ patients with CRPC in a single arm study, to evaluate PPV monotherapy without concurrent EMP or hormone therapy.…”

“…Evaluation of a randomized Phase II trial of a poxviral-based PSA-targeted immunotherapy in patients with minimally symptomatic metastatic CRPC Recombinant vaccinia vector containing the entire PSA transgene with agonist epitope (rV-PSA) is a novel immunotherapy platform that has demonstrated activity in a Phase I trial in men with CRPC [1]. Preclinical studies have shown activity with first the addition of three costimulatory molecules along with the PSA transgene (rV-PSA-TRICOM) and second use of GM-CSF as an adjuvant to recruit dendritic cells [2,3]. A randomized Phase II trial previously demonstrated that a vaccinia vector prime (rV) followed by multiple fowlpox (rF) boosts had improved progression-free survival (PFS) compared with all-vaccinia or allfowlpox vaccination [4].…”

“…A pivotal Phase III trial of PROSTVAC-VF is being planned, as confirmation of the findings seen in this study. PROSTVAC-VF, and activity in a more advanced disease setting including those requiring narcotic use, higher Gleason score, and visceral metastases [2]. In this trial by Gulley et al, 32 chemotherapy-naive men with CRPC, who were HLA-A2+, were randomized to one of four cohorts:…”

“…Immunotherapy, in which the host's immune system is induced to attack prostate cancer cells, is currently under investigation as an alternative or addition to cytotoxic chemotherapy for castration-resistant prostate cancer (CRPC), especially in light of the recent US FDA approval of the dendritic cell-based vaccine, sipuleucel-T, based on an overall survival (OS) benefit demonstrated in several Phase III trials [1,2]. Other immunologic techniques currently being investigated include tumor cell-based vaccines, recombinant viral vectors and CTLA-4 blockade [3][4][5][6].…”