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Experimental & Clinical Evidence

Animal studies performed using a murine model of non-Hodgkin’s lymphoma and CLL demonstrated that a vaccine made on the Aggregon® technology platform induced a strong and effective immune response against tumor cells (Kwak et al., 1998; Popescu et al., 2007; see Publications). This predominately Th1-type response was shown in depletion experiments to depend on both CD4+ helper and CD8+ killer T cells and was specific for the tumor cell line from which the antigenic material was derived. Mice inoculated with the vaccine were able to survive a challenge with tumor cells at 50-100 times the lethal dose. Furthermore, dose response experiments demonstrated that the Aggregon® vaccine was effective at an antigen level 50-fold lower than that needed in a conventional vaccine (antigen coupled to carrier protein). Vaccines in which the antigenic component and IL-2 were included in the same Aggregon® liposomal unit structure were more effective than ones in which the components were mixed after incorporation into separate liposomal structures. These preclinical studies demonstrated the superiority of the Aggregon® vaccine technology for active specific tumor immunotherapy and supported the vaccine testing in a clinical setting.

Clinical Evidence

Evidence for safety and indication of efficacy was obtained in two completed Phase I clinical trials at the US National Institute of Health (National Cancer Institute) performed on patients with non-Hodgkin’s B-cell lymphoma (Neelapu et al., 2004 and 2007; see Publications). The two studies (one for 5.5 years) indicated that XEME vaccines are safe, non-toxic and able to induce strong durable anti-tumor immune responses (Th1 type). In a minimal residual disease setting (Phase Ia) the tumor-free survival was doubled for the majority of patients. In the manifested disease (with high tumor burden)-setting, the predicted tumor-induced immunosuppression was reversed as indicated by Th1 type responses in the majority of patients. Thus, XEME’s vaccines seemed able to rebut immune check point modulators. Among the eligible patients accrued in these studies, two (10%) achieved complete clinical responses (no tumor) that coincided with the peak of their anti-tumor immunity.

The Phase Ia clinical trial was done with a single tumor specific antigen (TSA ) represented by the surface immunoglobulin idiotype (IgId) found on the patient’s lymphoma cells (these are unique antigens that are uniform, i.e. all cancer cells from the same patient have the same immunoglobulin or idiotype, Id) (Neelapu et al., 2004; see Publications). The main purpose of the study was to determine safety and the ability of the vaccine to induce a specific immune response. Ten follicular lymphoma patients with chemotherapy (CHOP)-induced clinical remission, were chosen for this study. The remissions were expected to last for about 2.5 years. The vaccine was administered subcutaneously 5 times at monthly intervals. The vaccine was safe, with all patients having only minor local reactions and occasional flu-like symptoms. No general toxicity and no sign of autoimmunity was seen during 5.5 years of observation when the study was closed. Of the 10 patients, 7 survived without any sign of disease during the 5.5 year observation period, i.e. more than twice the duration of clinical remission expected for these patients. Complete remission (CR) was documented in one patient who had relapsed following chemotherapy. The patient was still symptom free at the end of the study with no additional treatment. All 10 patients had documented cellular immunity that was specific for the patient’s own tumor antigen (IgId) and all tested patients mounted a specific cytotoxic response against their own tumor cells. Importantly, anti-tumor immunity was observed for at least 18 months beyond the completion of vaccination.

In the Phase Ib clinical trial, Aggregon® vaccines were derived directly from the patient’s tumor biopsy and contained not only the cell surface idiotype (IgId), but also the entire cell membrane material, which served as a source of additional tumor antigens (Neelapu et al., 2007; see Publications). The study accrued 10 patients with non-Hodgkin’s follicular lymphoma. Of these, 3 patients were treatment naive (i.e. previously untreated). All patients had advanced stage III or IV disease, with a significant tumor load and high probability of tumor-induced immune suppression. In these patients again, minor local reactions and some flu-like symptoms were observed after vaccine inoculation, but no systemic toxicity or autoimmunity. Vaccination induced specific cellular immunity in most patients (6/10), despite their high tumor burden and expected tumor-induced immune-suppression. One complete objective remission was observed and one patient experienced disease stabilization.

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