There is no denying the potential of cancer vaccines. The strategy of an injected therapeutic designed to boost the body's natural ability to protect itself, through the immune system, against abnormal cancer cells has captured the attention of researchers and companies alike for decades.

Following a number of setbacks, it appeared that the long awaited breakthrough had been made in the field when Seattle-based Dendreon Corp.'s Provenge (sipuleucel-T) became the first example of the therapeutic class to receive FDA approval for treatment of advanced asymptomatic or minimally symptomatic prostate cancer that is resistant to standard hormone treatment. (See BioWorld Today, April 30, 2010.)

During a conference call to discuss the approval, Dendreon President and CEO at the time Mitchell Gold (now a director of the firm) hailed the achievement as representing "the dawn of an entirely new era in medicine" and "the Holy Grail of oncology."

At that time hopes were indeed high that other vaccines and cancer immunotherapies, targeting a range of cancer types, would follow and create an approximately $8 billion market for cancer vaccines by 2015 (Kalorama Information report, 2010). Unfortunately the "Holy Grail" for the nascent cancer vaccine industry continues to remain elusive.

Fast Forward

Fast forward to today. Dendreon's share price has plummeted 88 percent from its lofty $54.06 value on the day it received approval for Provenge. The reason for the precipitous decline is that sales for the cancer vaccine have continued to fall well short of predictions. In its third quarter 2012 financial results Provenge revenues, for example, were well short of consensus, at $78 million, vs. $80.7 million. The vaccine's sales fell 2.5 percent in the third quarter, the second sequential quarter of decreasing sales, although that was an increase of 27 percent compared to the third quarter of 2011, at $61 million. (See BioWorld Today, Nov. 5, 2012.)

Dendreon revealed that it was in the process of restructuring and said it believed it could achieve positive cash flow soon by looking forward to continued growth in community urology centers and possible European approval in mid-2013.

"We will continue to make urologists a key area of focus," said Dendreon CEO John H. Johnson commenting on the company's financial performance.

This strategy appears to be bearing fruit and causing investors to take notice once again. Heading into the J. P. Morgan Healthcare conference Jan. 7, the company provided preliminary fourth quarter 2012 revenues.

Net product revenue for the quarter is expected to be approximately $85.5 million, a figure that will beat estimates. The higher revenues are attributable to continued strong performance in community urology accounts, which grew 25 percent overall quarter over quarter.

"We have focused our commercial efforts on growing our community accounts, where we see the greatest long-term revenue opportunity. Having achieved our highest quarter ever for community sales, we believe that our community strategy is working," said Johnson.

Mark Schoenebaum, analyst at ISI Group, views 4Q12 net sales disclosure as an incremental positive for the company. The caveat is that Dendreon needs to grow its Provenge sales to around $100 million per quarter in order to reach a cash flow break even point, he noted.

A Rocky Road

The ups and downs in the cancer vaccine space, however, continues. At the end of the year Oncothyreon Inc.'s shares lost more than half their value after partner Merck KgaA disclosed that its cancer vaccine, L-BLP25 (Stimuvax), failed to meet the primary endpoint of overall survival in a pivotal Phase III trial in non-small-cell lung cancer (NSCLC). (See BioWorld Today, Dec. 26, 2012.)

The study recruited more than 1,500 patients with nonresectable Stage IIIA or Stage IIIB NSCLC who were stable or who had responded to primary chemoradiotherapy. In addition to best supportive care, patients received either placebo or a single infusion of cyclophosphamide, followed by eight weekly subcutaneous vaccinations of L-BLP25 and maintenance doses every six weeks until disease progression.

L-BLP25 contains a 25 amino acid sequence derived from the mucin 1 (MUC-1) antigen, which is overexpressed in many tumors and plays roles in tumor-associated immune suppression, in mediating resistance to chemotherapy and in preventing apoptosis. It is administered in a liposomal formulation, which also contains the monophosphoryl lipid A, (MPL) adjuvant, and elicits a T-cell response only.

The cancer vaccine space is no stranger to its share of product candidate failures. In addition to Oncothyreon/Merck KgaA the list of companies that failed in late-stage trials with immunotherapies includes Antigenics Inc., CancerVax Corp., Cell Genesys Inc., Favrille Inc., Genitope Corp., Progenics Pharmaceuticals Inc. and Therion Biologics Corp.

The future for the space still remains bright, however, with more than 20 compounds currently in clinical development with many more just starting out on their development cycle.

There are a number of promising vaccines in late-stage clinical trials. In June, NovaRx Corp., of San Diego, completed enrollment in its Phase III trial testing Lucanix (belagenpumatucel-L), a whole tumor cell vaccine, in post-front-line maintenance in NSCLC. The 506-patient study is being conducted under a special protocol assessment from the FDA.

Also in Phase III in NSCLC is BV-NSCLC-001, a cancer vaccine developed by Aberdeen, Scotland-based Bioven (Europe) Ltd. That product, which targets epithelial growth factor, was in-licensed from the Center of Molecular Immunology in Havana, Cuba.

Money No Problem

Investors are certainly supporting cancer vaccine developers. CureVac GmbH (Tuebingen, Germany), for example, closed what was, according to BioWorld Snapshots, one of the largest private equity rounds for a European biotechnology company in 2012. It realized an €80 million (US$104.9 million) investment from dievini Hopp BioTech Holding GmbH & Co. KG, to assist it in taking forward two mRNA-based therapeutic cancer vaccines, in clinical development for prostate cancer and NSCLC respectively. (See BioWorld Today, Sept. 19, 2012.)

The deal represented a major endorsement of CureVac's RNActive platform technology, which already has generated two promising therapeutic candidates – CV9103 is its prostate cancer vaccine that will enter into a European Phase IIb trial shortly; and CV9201, a NSCLC vaccine undergoing a smaller-scale mechanism-of-action study.

CureVac has developed methods for modifying mRNA sequences to improve their stability and boost their translation levels. It also has developed a process for formulating mRNA molecules with protamine, a histone-like protein obtained from the sperm of salmon, which acts as an immunostimulatory adjuvant.

CV9103 comprises four individual mRNA molecules, which encode prostate-specific antigen, prostate stem cell antigen, prostate-specific membrane antigen and six transmembrane epithelial antigene of the prostate 1, respectively.

In December, Galena Biopharma Inc., of Lake Oswego, Ore., priced an underwritten public offering of about 15.2 million units priced at $1.60 apiece for gross proceeds of $24.25 million. Some of the funds will be used to conduct the firm's ongoing Phase III trial of its investigational breast cancer vaccine NeuVax (nelipepimut-S). Galena has partnered with Teva Pharmaceutical Industries Ltd., of Petach Tikva, Israel, to commercialize the vaccine in Israel. Teva will take responsibility for regulatory registration in Israel, and support local development and commercialization.

Investor enthusiasm has also carried over into the New Year with Gradalis Inc. closing a $24 million Series B round to move its autologous vaccine platform, Furin-ANd-GMCSF (FANG), forward. Its ovarian cancer vaccine is in Phase II trials.