A therapeutic cancer vaccine being developed by an international team of cancer immunologists working within the Cancer Research Institute/Ludwig Institute for Cancer Research Cancer Vaccine Collaborative (CVC) successfully induced a comprehensive, tumor-specific immune response in patients with late-stage metastatic disease, with results indicating that the vaccine had a favorable impact on disease progression in some patients, according to a paper to be published on September 26 in the scientific journal, Proceedings of the National Academy of Sciences USA. The paper is currently available in the journal's online advance edition.
In a two-part, open-label cohort study, patients whose tumors expressed the immunogenic NY-ESO-1 antigen, most with melanoma, received at least four monthly doses of recombinant vaccinia-NY-ESO-1 and recombinant fowlpox-NY-ESO-1 vaccine, administered alone and together in a prime-boost setting. In a large proportion of the 23 evaluable patients, the vaccine was shown to stimulate both humoral and cellular immune responses consisting of antibodies, CD8+ and CD4+ T cells specific to a broad range of NY-ESO-1 antigenic epitopes. Of nine melanoma patients with progressive stage III/IV disease at the onset of vaccinations, seven have survived 17-63+ months. One patient with melanoma showed a complete response with total regression of lesions and remains disease-free 32 months out; another melanoma patient continues to show disease stabilization 31 months out; and several others showed disease stability with delayed progression. The only side-effect observed in the study was temporary redness, swelling, and itching at the injection site.
AdvertisementAs a follow-up to this prime-boost vaccination strategy study, a prospective phase II prime-boost vaccine study in metastatic melanoma is underway. Therion Biologics Corporation of Cambridge, MA, produced the recombinant vaccinia and fowlpox for both studies.
"These results are very encouraging," says Dr. Lloyd J. Old, director of the Cancer Vaccine Collaborative and chairman of the Ludwig Institute for Cancer Research, and a contributing author to the paper. "While this study cannot tell us definitively about the potential, overall benefit induced by this vaccination strategy, it does give a strong impression that, in patients with advanced metastatic melanoma at least, vaccination altered the expected course of the disease."
Jill O'Donnell-Tormey, Ph.D., executive director of the Cancer Research Institute, which provides funding for Cancer Vaccine Collaborative studies like this one, hailed the study as another successful step forward in her organization's efforts to develop immune-based approaches to the treatment, control, and prevention of cancer.
"Evidence is mounting that the cancer vaccines we are studying in the Cancer Vaccine Collaborative are having significant clinical benefit for some patients," Dr. O-Donnell-Tormey says. "While these are at present a small number of individuals, we see real potential for broader-scale impact. The data we are amassing from this and other CVC studies continue to support the rationale for further exploration of the potential of immune-based cancer therapy. In the process, CVC studies are teaching us some extremely valuable lessons about the fundamentals of cancer vaccination."
The Cancer Vaccine Collaborative has previously reported on trials testing several NY-ESO-1 peptides and whole-protein, and is currently evaluating DNA, viral vector, and bacterial vector-based NY-ESO-1 vaccines. Most notably, a CVC team based in Melbourne reported last year on the efficacy of a NY-ESO-1 peptide vaccine used in combination with ISCOMATRIX™ adjuvant which seemed to delay recurrence in melanoma patients. That trial prompted the CVC to open a randomized phase II study of the vaccine, which is currently accruing patients in Australia and the UK in order to determine more solidly the vaccine's impact on overall clinical course.
Dr. Elke Jaeger of Krankenhaus Nordwest in Frankfurt, Germany, the paper's primary author, says this study is the first within the CVC to report on the effectiveness of recombinant viral-vector antigen delivery mechanisms. "Our results show this vaccination strategy is effective and requires further investigation." Dr. Jaeger, a member of the Cancer Vaccine Collaborative, will share the details of her team's findings with other CVC researchers at their annual meeting in New York City in early October.
In addition to reporting the specific study results, the authors of the PNAS paper also call for a reevaluation of the benchmarks of success currently applied to cancer vaccine studies.
"Many cancer immunologists would argue that the success criteria that have been applied to chemotherapeutic investigational new drugs, for instance, are not necessarily those by which immunotherapies should be judged," Dr. Old says.
"Yes, the ultimate endpoint would be complete, long-lasting remission, as sometimes happens in these vaccine studies," Dr. Old says. "However, such cases are at present few and far between. Rather, we are coming to realize and, more importantly, to accept that a more realistic benchmark of clinical success with immunotherapy is disease stabilization—that is, control of cancer's growth." According to Dr. Old, from what scientists currently understand about cancer immunosurveillance and immunoediting, vaccine-related stabilization of cancer would correspond to returning the body from a state of tumor escape to a state of tumor equilibrium.
"Disease stabilization as a successful clinical outcome makes sense when talking about immunotherapy," Dr. O'Donnell-Tormey says, "especially at this early stage in the development of this new approach to treating cancer. We have a long way to go, and the Cancer Vaccine Collaborative is doing a lot to move us along as quickly as possible, but we've got to take things one step at a time."
"We can't say for certain until further studies are carried out," Dr. O'Donnell-Tormey says, "but it does seem that cancer vaccines like those being studied in the Cancer Vaccine Collaborative are potentially extending lives for many patients. Given the negligible toxicity of these therapies and the relative ease with which they're administered to the patient, I'm betting that any cancer patient you talk to would consider any delay in disease progression a success, too."
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