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Human / Clinical Studies

    Table 2. Studies of NDV Oncolysates in Which Therapeutic Benefit Was Assesseda,b continued...

    One additional clinical study evaluated the effect of vaccine quality on the survival of patients who were treated with NDV-infected, autologous tumor cells.[17] In this retrospective study, survival was estimated separately for three groups of patients who had early breast cancer (n = 63), metastatic breast cancer (n = 27), or metastatic ovarian cancer (n = 31) and who had sufficient numbers of recovered tumor cells to allow at least two vaccinations. Most of the patients who had early breast cancer were treated after surgery with conventional adjuvant therapies (chemotherapy, radiation therapy, and/or hormonal therapy) in addition to vaccine therapy. The patients who had metastatic breast or ovarian cancer had failed to respond to conventional treatments before the start of vaccine therapy. In addition to receiving tumor cell vaccines, these latter patients were treated with oral indomethacin and cimetidine, intravenous cyclophosphamide and epirubicin, and subcutaneous low-dose recombinant interleukin-2 and interferon-alpha. The indomethacin, cimetidine, cyclophosphamide, and epirubicin were given in an attempt to prevent the suppression of desired immune system responses. The autologous vaccines were classified as either high quality or low quality on the basis of the following two parameters: the ratio of tumor cells to other types of cells and the percentage of live tumor cells. The median times from surgery to the start of immunotherapy were 13 days, 27 days, and 28 days for the patients who had early breast cancer, metastatic breast cancer, and metastatic ovarian cancer, respectively.

    Overall survival 4 years after surgery was estimated to be 96% for the patients with early breast cancer who had received a high-quality vaccine (n = 32), compared with an overall survival of 68% for those who had received a low-quality vaccine (n = 31). For the patients with metastatic breast cancer, the median survival time was estimated to be 1.75 years from the start of immunotherapy for those who had received a high-quality vaccine (n = 13), compared with a median survival time of 0.75 years for those who had received a low-quality vaccine (n = 14) (median follow-up time = 1.4 years). For patients with metastatic ovarian cancer, the median survival time was estimated to be 1.16 years from the start of immunotherapy for those who had received a high-quality vaccine (n = 18), compared with a median survival time of 0.84 years for those who had received a low-quality vaccine (n = 13) (median follow-up time = 1.23 years). The only survival difference that was statistically significant was the one for the patients who had early breast cancer. The retrospective nature of this study and the small numbers of patients in each treatment group should be viewed as major weaknesses.

    In two of the above-mentioned studies, the phase I colorectal cancer study [19,20] and the phase II ovarian cancer study,[23] histologic examination of several vaccination sites revealed the presence of infiltrating immune system cells. These infiltrating cells, however, consisted primarily of helper T cells (CD4 antigen–positive cells); cytotoxic T cells (CD8 antigen–positive cells) were present, but only as a minor component. In another study,[27] vaccination sites from five cancer patients (two with colon cancer, two with melanoma, and one with ovarian cancer) also contained infiltrates of predominantly helper T cells. In fact, CD8 antigen–positive T cells could not be detected in the lymphocytes cultured from vaccination sites of two of these five patients.[27] Reviewed in [22] The presence of small numbers of cytotoxic T cells at vaccination sites may be an important factor to consider when evaluating the results of the whole cell vaccine trials because animal studies [54,55,56,57] Reviewed in [16,19,58,59,60,61,62,63,64,65,66] and human studies [1] have suggested that this class of T cells is required for effective, long-term anticancer immunity. It should also be noted that, in another study,[67] increases in NK cell activity were measured in blood samples from two patients with colorectal cancer who exhibited delayed-type hypersensitivity responses at vaccination sites, but cytotoxic T cells directed against tumor-specific antigens could not be detected. Overall, these results indicate that NDV-infected, autologous, whole cell vaccines may be able to stimulate NK cell activity, which may have contributed the clinical outcomes described above, but also that these vaccines may be ineffective in promoting at least one additional immune system response (i.e., the production of tumor-specific antigen-targeted cytotoxic T cells) thought to be important to establishing long-term anticancer immunity. Whether the inclusion of bispecific monoclonal antibodies (refer to the Laboratory/Animal/Preclinical Studies section of this summary for more information) in the whole cell vaccines will make them more effective remains to be determined.

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