A multicenter, randomized Phase II trial employing PROSTVAC-VF provided evidence of enhanced median overall survival (OS) (p = 0.0061) in patients with metastatic castration-resistant prostate cancer (mCRPC). In another trial using this same vaccine, 32 patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three costimulatory molecules. 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 versus no GM-CSF. Patients with a Halabi predicted survival of less than 18 months (median predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of greater than or equal to 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 of greater than or equal to 18 months) may best benefit from vaccine therapy. A recently completed study in mCRPC demonstrated that when ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) monoclonal antibody) was combined with PSA-TRICOM (PROSTVAC) at escalating doses, the median survival was 34 months, which compares favorably to previous vaccine trials in mCRPC that resulted in median survivals of approximately 26 months. These and other data support the rationale for randomized studies employing immune checkpoint inhibitors in combination with TRICOM-based vaccines. Two of the most widely studied human tumor-associated antigens (TAAs) are CEA and mucin-1 (MUC-1). CEA is overexpressed in a wide range of human carcinomas, including gastrointestinal, breast, lung, pancreatic, medullary thyroid, ovarian, and prostate. MUC-1 is a tumor-associated mucin, which is overexpressed and hypoglycosylated in all human carcinomas as well as in acute myeloid leukemia (AML) and multiple myeloma. Studies have demonstrated that the C-terminus of MUC-1 functions as an oncogene. A study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients with PANVAC (rV,rF-CEA-MUC1-TRICOM). Twenty-six patients were enrolled and given monthly vaccinations. These patients were heavily pretreated, with 21 of 26 patients having had three or more prior chemotherapy regimens. Side effects were largely limited to mild injection-site reactions. For the 12 breast cancer patients enrolled, median OS was 13.7 months. One patient had a complete response by RECIST and remained on study for over 37 months. Another patient with metastatic disease confined to the mediastinum had a 17% reduction in mediastinal mass and was on study for 10 months. Patients with stable or responding disease had fewer prior therapies and lower tumor marker levels than patients with no evidence of response. Patients were also monitored for generation of T-cell responses and antibody responses to tumor-associated antigens expressed by the vaccine. Further studies to confirm these results are warranted. A randomized multicenter study has been initiated evaluating docetaxel vs docetaxel plus PANVAC vaccine in patients (n=48) with metastatic breast carcinoma. Preliminary findings to date indicate a substantial increase in time to progression in the combination arm vs the docetaxel alone arm. A Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer has been completed. The primary end point of this study was to determine the safety and feasibility of intraprostatic administration of PSA-TRICOM vaccine in patients with locally recurrent or progressive prostate cancer. This trial was a standard 3 + 3 dose escalation with 6 patients each in cohorts 4 and 5 to gather more immunologic data. Nineteen of 21 patients enrolled had locally recurrent prostate cancer after definitive radiation therapy, and 2 had no local therapy. All cohorts received initial subcutaneous vaccination with rV-PSA-TRICOM and intraprostatic booster vaccinations with rF-PSA-TRICOM. There were no dose-limiting toxicities. Overall, 19 of 21 patients on trial had stable (10) or improved (9) PSA values. There was a marked increase in CD4+ (p = 0.0002) and CD8+ (p = 0.0002) tumor infiltrates in post- versus pre-treatment tumor biopsies. Four of 9 patients evaluated had peripheral immune responses to PSA or NGEP. Intraprostatic administration of PSA-TRICOM is safe and feasible and can generate a significant immunologic response. Improved serum PSA kinetics and intense post-vaccination inflammatory infiltrates were seen in the majority of patients. The interaction between CD27 and its ligand, CD70, has been implicated in regulating cellular immune responses to cancer. We have reported on the role of soluble CD27 (sCD27) in T cell activation and its elevation in the serum of cancer patients after immunotherapy. In vitro, sCD27 is preferentially derived from activated CD4+ T cells. Adding sCD27 to stimulated peripheral blood mononuclear cells (PBMCs) increases T-cell activation and proliferation, and is associated with the immunologic synapse-related proteins myosin IIA, high mobility group box 1, and the TCR Vbeta-chain. The pool of serum sCD27 is shown to be greater in healthy donors than in cancer patients. However, metastatic cancer patients treated with immunotherapy showed a significant increase in the serum sCD27-pool post-therapy (p 0.0005);there was also an increased trend toward an association between enhanced sCD27-pool post-therapy and overall survival (p = 0.022). The identification of sCD27 as an immune modulator associated with enhanced human T-cell activation in vitro and in vivo provides a rationale for developing new immunotherapeutic strategies aimed at enhancing sCD27 for treating cancer and potentially other diseases. Tumor cells can induce certain cytokines and soluble receptors that have a suppressive effect on the immune system. In this study, we showed that an extracellular portion of a membrane-bound ligand of CD40 (soluble CD40 ligand;sCD40L) was significantly elevated in the serum of cancer patients compared with healthy donors. In addition, PBMCs from cancer patients had a relatively larger population of myeloid-derived suppressor cells (MDSCs), defined as CD33posHLA-DRneg cells, and these cells expressed higher levels of CD40. T-cell proliferation and IFN-gamma production decreased when stimulated T cells were cocultured with an increased amount of autologous MDSCs. The addition of recombinant monomeric sCD40L enriched MDSCs and had an additive inhibitory effect on T-cell proliferation. PBMCs cultured in vitro with sCD40L also showed an expansion of regulatory T cells (CD4posCD25highFoxp3pos), as well as induction of cytokines, such as IL-10 and IL-6. Moreover, sCD40L-induced enrichment of programmed death-1-expressing T cells was greater in cancer patients than in healthy donors. Preexisting sCD40L also inhibited IL-12 production from monocytes on activation. These data suggest that the higher levels of sCD40L seen in cancer patients may have an immunosuppressive effect.

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Donahue, Renee N; Duncan, Brynn B; Fry, Terry J et al. (2014) A pan inhibitor of DASH family enzymes induces immunogenic modulation and sensitizes murine and human carcinoma cells to antigen-specific cytotoxic T lymphocyte killing: implications for combination therapy with cancer vaccines. Vaccine 32:3223-31
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