Outlining Novel Cellular Adjuvant Products for Therapeutic Vaccines Against Cancer

Josianne Nitcheu Tefit; Vincent Serra

Disclosures

Expert Rev Vaccines. 2011;10(8):1207-1220. 

In This Article

Conclusion

Despite the failure of most randomized trials, there have been some encouraging advances in vaccine therapies against cancer. Sipuleucel-T (Provenge®, Dendreon Corporation, not discussed in this article) is an encouraging advance in the field of cancer immunotherapy. The Phase III trial of the DC-based vaccine loaded with a recombinant fusion protein containing prostatic acid phosphatase and GM-CSF has recently demonstrated a significantly longer OS in asymptomatic metastatic prostate cancer patients, leading to its approval in April 2010 by the FDA for the treatment of advanced prostate cancer. However, the modest increase in survival time (4.1 months) and the exorbitant cost per patient (approximately US$93,000) for three doses of the vaccine emphasize the need to find novel yet economical ways to achieve positive clinical results, perhaps by combining the best tumor antigens with the most effective immunotherapy agents. Various compounds and vaccine delivery systems have been used to induce CD8+ cytotoxic T lymphocytes that include live vectors (attenuated or nonpathogenic live virus or bacteria – not discussed in this article) such as vaccinia virus and other poxviruses.[143,144] These vectors may generate superior antitumor immune responses when used as priming agents, followed by boosting with other agents.[145] In clinical studies, a recombinant vaccinia virus vector expressing single or multiple T-cell costimulatory molecules induced effective clinical responses in patients with metastatic malignant melanoma,[146] and other poxvirus-based vaccines are currently under evaluation (PANVAC-VF [Therion Biologics Corp, USA and under investigation in studies sponsored by the National Cancer Institute], PSA-TRICOM vaccine [Therion Biologics Corp., and under investigation in studies sponsored by the NIH]). The development of 'new' delivery systems such as nanoparticles as effective vaccine adjuvants for cancer therapy will improve the prospects of cancer vaccine development. For example, microencapsulated DNA vaccine has been used in a Phase I–II clinical trial in patients for the treatment of HPV-associated malignancies and resulted in generation of antigen-specific T cells.[147]

However, as reported earlier, although some studies showed significant correlations between clinical benefits and immunological responses, generating a biologically meaningful response has proven to be more challenging, and many cancer vaccines were dropped at different stages of development. While the reasons for discontinuation are sometimes difficult to interpret, it will be critical to address the issues raised to facilitate cancer vaccine development. In many cases, cancer vaccines were dropped owing to a lack of efficacy in Phase II and III trials combined with some safety concerns. In particular, Canvaxin was undergoing a Phase III trial following Phase II trials and was closed prematurely on the advice of independent data and safety monitoring board recommendations that a survival benefit was unlikely to achieved. In some cases, the design of the trial, at least in part may have masked the benefit of the cancer vaccine. This may be the case with whole tumor vaccine strategies with detrimental outcome, such as GVAX immunotherapy, an allogeneic form of active cellular immunotherapy using human prostate cancer cell lines secreting GM-CSF (not discussed in this article). It is highly possible that T cells against irrelevant antigens that are expressed only on the allogeneic tumor cells, but not on the host tumor cells, might dominate the adequate response to real antigens expressed on the host tumor cells.[148] More careful selection of patients based on tumor genotype or phenotype might help determine the responsiveness of particular tumors. In addition, the observation that Melacine vaccine showed no benefit for the total study population but a strong benefit for patients with the relevant HLA also demonstrates that patient selection is important to identify which vaccine could be effective in which population. Therefore more robust design of Phase II trials and immune monitoring (identification of markers that might predict a host antitumor immune response) may augment vaccine efficacy and avoid ineffective and time consuming Phase III studies being conducted.

Finally, it became apparent that there is a need for combining adjuvants in order to achieve good therapeutic responses. Therefore, larger multicenter adjuvant vaccine clinical trials in cancer patients are needed in order to establish the efficacy of adjuvants in cancer therapeutic vaccines. The best example illustrating adjuvant combination therapies is the MAGE-A3 vaccination, for which international Phase III studies are currently evaluating the clinical efficacy of adjuvant AS15, a mixture of CpG, MPL and QS-21. Ongoing and future preclinical and clinical studies offer hope for the future in this regard.

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