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The commercial potential of its alphavaccine system in cancer immunotherapy. is one of AlphaVax's current areas of focus. The development of immunotherapeutic treatments for cancer is a rapidly growing area in which AlphaVax will be taking a lead position in developing new treatment modalities utilizing its proprietary technology. The objective of AlphaVax is to develop our portfolio of vaccines towards the treatment and management of various cancers. The goal of the immunotherapy strategy will be to position cancer as a manageable disease. To this end, initial clinical testing of the Company’s first alphavaccines for immunotherapeutic treatment of colon cancer and breast cancer have been completed, with encouraging safety and immunogenicity results (see below) as well as signals related to survival and the breaking of tolerance.
The molecular identities of many tumor-associated antigens have been identified and this knowledge has provided a major stimulus for the development of new immunotherapies for the treatment of patients with cancers. In the field of cancer immunotherapy, significant enthusiasm has been directed at the use of cancer vaccines in patients in order to elicit specific immune responses to target tumors. The decision to initiate a cancer immunotherapy program for solid tumors was based on a careful analysis of current cancer therapies and developing strategies. This analysis has provided a multifold response. Promising safety and immunogenicity results from the Company’s five Phase I clinical studies that evaluated four different alphavaccines, have provided a considerable knowledge base of immunologic information as well as a theoretical framework for immunization against cancer antigens. There are also practical reasons for the attractiveness of therapeutic cancer vaccines—they are easily administered to outpatients and generally do not cause significant side effects. Investigators have been enthusiastic about the use of active immunization for patients with solid tumors because of an over-reliance on surrogate and subjective endpoints, such as histologic evidence of tumor necrosis or lymphocyte infiltration, rather than objective cancer regressions. Finally, the encouraging results from the CEA alphavaccine Phase I trial in Stage IV colon cancer patients suggest that the alphavaccine vector technology may play an important role in cancer immunotherapy.
As noted above, an alphavaccine has been developed for treating CEA expressing colon cancer and has completed an initial round of clinical evaluation. In collaboration with the Duke University Medical Center in a Phase I/II clinical trial in patients with Stage IV CEA-expressing colon cancer, we found that treatment with our CEA alphavaccine resulted in two key outcomes: (i) the vaccine was able to “break self-tolerance” and (ii) a trend for enhanced survival in patients in the high-dose cohort with measurable T cell responses. Based on comparison to previously published results, the trial’s principal investigator noted that the CEA alphavaccine compared favorably to treatment of similar patients with Erbitux, the current standard of care in treating colon cancer. A statistical analysis of the associated "survival data" has been carried out and the results show a trend that is suggestive of enhanced survival - further details may be obtained upon request. A presentation on the results was given at 2015's November SITC meeting.
To follow up the success and key outcomes from the Company’s first cancer immunotherapy trial in patients with Stage IV CEA+ colon cancer, the CEA alphavaccine has been evaluated in earlier stage colon cancer patients (i.e., Stage III) to test the hypothesis that the vaccine elicits clinically relevant CEA-specific immune responses of greater magnitude and frequency than those measured in the Stage IV patients. Positive T-cell responses and antibodies against CEA have been seen. This trial was subsequently extended and the final patient was recruited earlier in 2017 - details pertaining to this study may be found on the following link: http://clinicaltrials.gov/ct2/show/NCT01890213?term=cea+duke&rank=1
Results of the Stage III colon cancer trial were published in the Journal for ImmunoTherapy for Cancer in November 2020, and full details may be accessed under https://immunology.duke.edu/node/15893 . The summary data showed a 5-year survival rate of 17% in Stage IV cancer, and 100% in Stage III, with a relapse-free rate in the latter group of 75%. CEA-specific humoral immunity was seen in all patients. The CD8+ effector memory T cell to Treg ratio was also raised.
AlphaVax is developing a HER2 alphavaccine for breast cancer patients with HER2-expressing tumors. HER2 blockade has been used successfully against malignant breast cancer and the humanized monoclonal antibody Trastuzumab (Genentech, CA, marketed as Herceptin®) is currently approved for therapeutic use as first-line treatment of HER2-overexpressing metastatic breast cancer. A Phase I trial was initiated in October 2012 in collaboration with the Duke University Medical Center. The trial was sponsored by the Department of Defense, Breast Cancer Research Program. Two patient cohorts were enrolled in this trial: comprised of 4 patients in the first, and 18 patients in the second (a number greater than that first planned). Data from this trial https://clinicaltrials.gov/ct2/show/NCT01526473?term=her+2+duke pertaining to immunological results featured in a poster presentation shown at the 2015 ASCO meeting: http://meeting.ascopubs.org/cgi/content/short/33/15_suppl/3081?rss=1 . The January 11th 2019 edition of Clinical Cancer Research shows the results and discusses the anti-tumor effect of the vaccine candidate (http://clincancerres.aacrjournals.org/content/early/2019/01/11/1078-0432.CCR-18-3102). A Phase II trial (NCT 03632941) is underway in a three-armed randomized study that seeks to compare our vaccine candidate versus pembrolizumab, and versus our vaccine plus pembrolizumab. February 2023's Cancer Gene Therapy discusses early data in patients in this Phase II trial - concluding that Her2-specific immunity was induced by the candidate vaccine, and that systemic immunity was enhanced.
In collaboration with Memorial Sloan-Kettering Cancer Center (MSK), studies identified a potent therapeutic VRP vaccine encoding the melanoma differentiation antigen TRP-2. Treatment with the TRP2 VRP vaccine demonstrated durable anti-tumor effects in a rigorous murine melanoma tumor model. The investigators at MSK had noted, from comparative studies in the murine model, that the alphavaccine platform appeared to be superior to all others previously tested; these findings accordingly support further investigation on the efficacy of a TRP-2 alphavaccine in melanoma patients. A later publication describes the combination of immunomodulatory monoclonal antibodies and our vaccine candidate in showing the therapeutic anti-tumor response in mouse models; and that the immunogenicity and efficacy could be increased. Additional pre-clinical trials have recently been completed.