Therapeutic cancer vaccines have gained new momentum in the clinic and gotten serious attention from previously wary investors. While development remains extremely challenging, the April approval of prostate cancer vaccine Provenge (sipleucel-T) for metastatic prostate cancer effectively changed the treatment paradigm for patients with hormone-refractory tumors.
Additionally, acceptance of individually prepared therapies like Provenge has increased. And as clinical successes for one-off therapies accumulate, uncertainty about costs have also diminished as health insurance providers including Aetna, Humana, Kaiser Permanente, some of the Blues, and Medicare have stepped up to support them; Provenge costs $93,000 a year. In an October 13 report, Canaccord Genuity analyst George Farmer, Ph.D., commented, “Reimbursement is happening and appears consistent with what would be expected during launch of a premium-priced new product.”
The results of Dendreon’s IMPACT study, published in the July 29 issue of The New England Journal of Medicine, demonstrated that among 512 patients, Provenge extended median survival by 4.1 months compared to control (25.8 months vs. 21.7 months) and reduced the risk of death by 22.5%. Provenge is administered as a one-time treatment and has fewer side effects compared to the only other approved drug, Taxotere (docetaxel), which in clinical trials extended lives by 2–3 months.
A Kalorama report released this year noted, “With a couple prophylactic vaccines for cervical cancer on the market, a few select therapeutic vaccine approvals, and several therapeutic vaccines on a promising path to commercialization, the market could see a surge of regulatory activity and an influx of market opportunities.”
Coming Down the Pike
In late-stage autologous vaccine development is Biovest’s BiovaxID for follicular non-Hodgkin lymphoma. The company reported preliminary Phase III results at last year’s ASCO and expects to reveal further analysis later this year. It also plans to report on long-term follow-up studies of a BiovaxID Phase II trial in patients with mantle cell lymphoma.
Investigators analyzed a group of 117 randomized patients who maintained a complete response to chemotherapy for at least six months and who received active (n=76) or control (n=41) vaccine. After a median follow-up of 4.71 years (range: 12.6–89.3 months), the median disease-free survival in the BiovaxID arm was 44.2 months compared with 30.6 months in the control arm.
Larry Kwak, M.D., Ph.D., professor and chair of the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center and the vaccine’s developer, commented that several patients from an earlier trial of the vaccine are still in remission after 12 years of follow-up. “These patients have not needed anything else—not even rituximab, which is often given as maintenance therapy for lymphoma.”
The BiovaxID vaccine is manufactured through a process known as rescue fusion hybridization in which individual tumor cells obtained through biopsy are fused with an antibody-secreting cell to form a heterohybridoma. This cell then secretes the unique idiotype, or immunoglobulin antigen characteristic of the individual tumor, which is purified for use as the vaccine. The vaccine is administered as a subcutaneous injection along with granulocyte-macrophage colony-stimulating factor (GM-CSF) and keyhole limpet hemocyanin (KLH) as a carrier protein and adjuvant.
Two other companies, Favrille and Genitope, failed in their attempts to develop an autologous vaccine for follicular lymphoma. These companies sought to shorten production time from six months to two months by cloning the patient-specific genes that encoded the tumor-specific idiotype protein and then expressing that protein in either mouse or insect cell lines. The cloned idiotype was then bound to KLH and given along with GM-CSF.
Commenting on the Phase III failures of both company’s vaccines, Biovest’s CSO, Carlos Santos, Ph.D., told GEN, “In both recombinant efforts, the variable region of an antibody was cloned, in effect capturing only a fragment of the original tumor’s antigen. We believe that rescue hybridization yields a higher-fidelity idiotype than cloning. The approach employs the tumor cells themselves to produce a true, full-length idiotype rather than a fragment of the protein. We feel this profound difference in tumor antigen manufacture translates to treatment benefit in lymphoma.”
In early clinical studies, the BioVaxID prototype vaccine required approximately six months to manufacture, but Dr. Santos told GEN that mostly as a result of streamlined tumor collection and cell culture technology, the company has reduced production time to three months.
Dr. Santos further noted that “the patients that are most amenable to active immunotherapy are probably patients in complete remission who have been treated with chemotherapies. Due to the need for the immune system to fully recover from the assault produced by chemotherapy, all vaccines require a waiting period for the immune system to recover. Even if you could manufacture the vaccine in 24 hours, you still have to wait three to six months before you can vaccinate a patient.”
In other autologous cancer vaccine developments, Geron’s autologous cancer vaccine candidate, GRNVAC1, is a dendritic cell product. It has been studied in Phase I trials at Duke University and currently is in a multicenter Phase II study of acute myelogenous leukemia patients in remission.
It is distinct from Dendreon’s Provenge as Geron transfects immature dendritic cells through electroporation with mRNA encoding the sequences for the human telomerase catalytic subunit (hTERT), linked to a lysosomal targeting sequence (LAMP). The transfected cells express hTERT-LAMP as protein prior to processing to peptides, which can be presented in the context of each patient’s specific HLA.
The transfected cells are then matured in medium containing a cytokine mix. Cryopreserved aliquots of the final mature DC preparations are ultimately supplied to the clinic for intradermal injections.
Lastly, Australian company Prima Biomed is developing an autologous dendritic cell vaccine for ovarian cancer treatment. CVac™ incorporates the MUC-1 antigen that is overexpressed in some cancers like epithelial ovarian carcinoma. Phase I and II studies conducted in Australia in heavily pretreated, advanced-stage patients showed minimal toxicities and prolonged disease stabilization, according to the company.
Prima Biomed announced in September that it is seeking a listing on NASDAQ. Managing director Martin Rogers said that the proposed NASDAQ listing is timely, following a number of important developments. “We have recently commenced patient recruitment for our Phase IIb trial with the FDA, received orphan drug designation from the FDA, and are well under way with preparations for a Phase III trial in Europe to commence in 2011.”
Changing Tides for Autologous Vaccines
Investors and potential partners have traditionally favored nonautologous cancer vaccines, which don’t require one-off manufacturing and are likely to cost less than custom-made vaccines. These vaccines, however, generally use an antigen or antigen-like molecule characteristic of a specific tumor type, not a patient’s specific tumor, to provoke an antitumor response.
“If we were to rewind to two years ago I would agree that financing active immunotherapy had its challenges due to multiple failures reported in the space,” Dr. Santos stated. “But there has been a renaissance in this therapy based on Provenge.” After presentations at ASCO 2009, Biovest received multiple expressions of interest from partnering candidates, he added.
As more vaccines go through clinical development, whether the most effective prove to be autologous, nonautologous, or need to be used with other treatment modalities, patients stand to gain longer survival times with fewer side effects than those inflicted by conventional chemotherapies.