Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Some incremental progress has been made in an area that has seen its share of failures.

This year, Science Magazine designated cancer immunotherapy “Breakthrough of the Year” for 2013, owing to reports of some stunning clinical successes in some patients. None of the named successes include a therapeutic cancer vaccine. To date, only one immunotherapeutic that could be considered a vaccine, Dendreon’s Provenge, has gained U.S. marketing approval.

But even as multiple late-stage clinical trial failures accrue, cancer vaccine developers soldier on, as every clinical trial provides a wealth of immunological information about the immune responses needed for successful antitumor activity.

The accumulated knowledge that has emerged from these and other studies has pointed toward strategies to improve the clinical efficacy of cancer vaccines including patient selection based on gene signature or preexisting immunity, vaccine administration as combination therapy with standard of care or new agents that disrupt immune-inhibiting pathways, and the utilization of more immunogenic vaccine platforms and target antigens associated with tumor-initiating cells that escape the process of central and peripheral immune tolerance.

Meanwhile, new enterprises are being founded and clinical trials are ongoing in a number of difficult-to-treat cancers including pancreatic, breast, and prostate cancers.

One Virtual Developer’s Endeavor

As a case in point, virtual drug developer Madison Vaccines Inc. (MVI) says it raised $8 million to further its efforts to advance its MVI-816 DNA vaccine for prostate cancer beyond basic research and has completed Phase I in early-stage patients. The trial demonstrated that MVI-816 was safe and that the product induced antigen-specific CD8+ cytotoxic T-cell immunological responses and prostatic acid phosphatase (PSA) doubling times in more than 30% of patients.

The company further intends to use the proceeds to support ongoing development of its pipeline, including completion of an expanded Phase II clinical trial for its MVI-816 DNA vaccine that targets PSA in nonmetastatic prostate cancer patients with rapidly rising PSA before the need for surgical or chemical castration (androgen deprivation therapy or ADT) arises.

A Shield against Breast Cancer

And while some advances have been made in the treatment of difficult breast cancers, treatment often involves surgery, months of chemotherapy, then more months of radiation. However, there are still patients whose cancer recurs, and most of these patients will die of their disease. One potential option is breast cancer vaccines.

Last September, Cleveland Clinic Innovations announced it had created a spin-off company to develop a preventive breast cancer vaccine based on research from Cleveland Clinic’s Lerner Research Institute.

The new company, Shield Biotech, will complete preclinical development and seek permission from the FDA to test the vaccine as an investigational new drug in proof-of-concept, first-in-human clinical trials. The trials are expected to start within two years and will take about three years to complete.

“The mission of Shield Biotech will be to translate the scientific research on a breast cancer vaccine, led by Vincent Tuohy, Ph.D., at Cleveland Clinic, into a viable preventive alternative for the patients who may benefit,” said Thomas Graham, M.D., Cleveland Clinic’s CIO. “We believe that the vaccine has the potential to stop the more lethal forms of breast cancer, as well as inhibiting the recurrence of triple-negative breast cancer in women after they have recovered from their initial disease.”

The vaccine is based on work published in Nature by Dr. Tuohy and his colleagues, who noted in their paper that “the difficulty in developing prophylactic cancer vaccines is primarily due to the fact that tumor antigens are variations of self-proteins and would probably mediate profound autoimmune complications if used in a preventive vaccine setting. Here we use several mouse breast cancer models to define a prototypic strategy for prophylactic cancer vaccination, selecting α-lactalbumin as our target vaccine autoantigen because it is a breast-specific differentiation protein expressed in high amounts in the majority of human breast carcinomas and in mammary epithelial cells only during lactation.”

The investigators found that immunoreactivity against α-lactalbumin provides substantial protection and therapy against growth of autochthonous tumors in transgenic mouse models of breast cancer and against 4T1 transplantable breast tumors in BALB/c mice.

Because, they said, that α-lactalbumin is conditionally expressed only during lactation, vaccination-induced prophylaxis occurs without any detectable inflammation in normal nonlactating breast tissue, potentially providing safe and effective protection against the development of breast cancer for women in their postchildbearing, premenopausal years when lactation is readily avoidable and risk for developing breast cancer is high.

Failures and Disappointments

But as 2013 closed, it remains clear that success in cancer vaccine development remains few and far between. Although analysts who follow the field made optimistic predictions based on data available in September 2013, some key potential players have not made the cut.

Based on data available at the time, predictions were that three immunotherapy products could reach the market in the 2014–2015 timeframe including Biovest International’s BiovaxID, an autologous idiotype lymphoma cancer vaccine (Id-KLH/GM-CSF), projected to be approved in Canada and the EU in 2013–2014 and in the U.S. in 2017. Other potentially successful candidates in late-stage clinical development included, among others, GlaxoSmithKline’s MAGE A3 in NSCLC and potentially melanoma, New Link’s HyperAcute in pancreatic cancer, Vical’s Allovectin-7 in melanoma, and Bavarian Nordic’s Prostvac in prostate cancer.

In 2012, the FDA denied marketing approval for BioVaxID, requiring that the vaccine undergo another Phase III trial. But this January, Biovest announced that the European Medicines Agency (EMA) accepted its marketing authorization application for BiovaxID (submitted to EMA under the name Dasiprotimut-T Biovest), thus beginning the review process intended to secure approval to market BiovaxID in the EU and to allow prescription and sale of BiovaxID for the treatment of non-Hodgkin’s follicular lymphoma in patients who have achieved a first complete remission.

And Vical announced last August that its Allovectin (velimogene aliplasmid) failed to meet key endpoints in a Phase III trial in patients with stage III/IV metastatic melanoma and that it will not develop the vaccine further. The vaccine failed to demonstrate a statistically significant improvement in objective response rate at greater than or equal to 24 weeks, its primary endpoint, or in overall survival, the secondary endpoint, when compared with first-line chemotherapy, the company said.

Allovectin is a plasmid-based immunotherapeutic that expresses the HLA-B7 and β2 microglobulin genes, forming a major histocompatibility class I complex. Investigators had hoped that the vaccine, through multiple mechanisms of action, could provoke immune responses that target treated and distal lesions.

Last September, GlaxoSmithKline (GSK) reported that its targeted cancer immunotherapy MAGE-A3, incorporating recombinant MAGE-A3 protein and a novel immunostimulant, AS15 (a combination of QS-21 Stimulon adjuvant, monophosphoryl lipid A, and CpG7909, a TLR-9 agonist), failed its first co-primary endpoint in a Phase III study for melanoma, failing to produce better results than a placebo in enhancing disease-free survival. The company says it will carry on with the study to determine whether the second primary endpoint—testing the immunotherapy in a genetically defined subpopulation—will provide better efficacy, with data expected in 2015.

“We remain committed to identifying a patient subpopulation who may benefit from this investigational treatment,” said Vincent Brichard, head of immunotherapeutics at GSK Vaccines.

Hope Lies in Phase II

But tantalizing potential Phase II successes have occurred. Just about the same time that GSK reported that MAGE-A3 had failed, Agenus announced last September that an analysis from a Phase II trial in patients with newly diagnosed glioblastoma multiforme (GBM) treated with the company’s Prophage Series G-100 (HSPPC-96), a vaccine used in combination with the current standard of care (radiation and temozolomide), showed an almost 18-month median progression-free survival, representing a 160% increase versus current standard of care alone. Prophage Series cancer vaccines are autologous therapies derived from cells extracted from the patient’s tumor.

On January 14, Aduro Biotech announced safety and efficacy data from its Phase II clinical trial of a two-vaccine approach, suggesting that patients with advanced pancreatic cancer may live a little longer when treated with two therapeutic vaccines. In a study that enrolled 93 pancreatic cancer patients, results demonstrated a statistically significant survival benefit in patients receiving the combination of GVAX Pancreas and CRS-207 cancer vaccines compared to GVAX Pancreas vaccine alone.

The median overall survival of the patients receiving the combination was 6.1 months compared to 3.9 months for those receiving GVAX monotherapy, and the trial was stopped early for meeting the primary efficacy endpoint at a preplanned interim analysis.

With regard to overly enthusiastic responses to Phase II clinical results, however, biotech analyst Joseph Pantginis, Ph.D., of Roth Capital Partners sounded a cautionary note in an interview with The Life Sciences Report: “It is a pet peeve of mine that some investors focus on the statistics of a Phase II trial. These studies are not powered to deal with statistical significance—they are designed to see if there is any activity from the drug.”

That maxim will continue to hold true as cancer vaccine development companies continue to report trial data, positive or otherwise.

Patricia Fitzpatrick Dimond, Ph.D. ([email protected]), is technical editor at Genetic Engineering & Biotechnology News.

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