January 1, 2007 (Vol. 27, No. 1)

VC Hesitation Is Largely Unfounded

Safety and quality of life are becoming more important to patients, and because of this the field of therapeutic cancer vaccines should be moving a lot faster than it is, said Jean-Yves Bonnefoy, Ph.D., vp R&D, Transgene (www.transgene.fr) at the recent “World Vaccine Congress” in Lyon, France.

Therapeutic cancer vaccines, a broad term for a DNA-, cell-, or protein-based drug designed to stimulate the immune system and initiate a cytotoxic reaction against cancer cells, have not yet enjoyed the clinical success of prophylactic cancer vaccines.

“There are 15 to 20 therapeutic cancer vaccines in late-stage development, but big pharma is still hesitant about licensing this class of drugs because they are so safe and well-tolerated that many believe they don’t actually work,” said Dr. Bonnefoy.

Clinical Results

To dispute the point of poor efficacy, speakers from Transgene, Onyvax (www.onyvax.com), and Oxxon Therapeutics (www.oxti.com) presented encouraging clinical trial data on their vaccines. Dr. Bonnefoy discussed TG 4001, Transgene’s human papilloma virus (HPV) vaccine to treat cervical cancer. This has a modified virus ankara (MVA) nonpropagating, attenuated vaccinia virus backbone into which is engineered DNA for cervical cancer-associated antigens (HPV16) and interleukin 2 (IL2), a cytokine adjuvant that stimulates immune responses.

In a Phase II trial of 21 women with cervical cancer lesions, six months post-TG 40101 vaccination, 10 women had no lesions and did not need surgery, according to Dr. Bonnefoy. “If we can avoid doing cone biopsies, as this study indicates, then TG 4001 will be a great product.”

Joerg Schneider, Ph.D., vp of research and cofounder of Oxxon Therapeutics, presented the firm’s Hi-8™ MEL DNA vaccine for the treatment of melanoma. This vaccine is a two-step process where a plasmid DNA vaccine (DNA.mel3) expressing seven epitopes derived from five melanoma antigens is injected, followed by a second injection of an MVA based vector (MVA.mel3) expressing the same epitopes as the plasmid.

Using this two-step prime boost approach increases the immune response by as much as 10 times, says Dr. Schneider. In a Phase II trial, where 41 patients were given both DNA vaccines sequentially, 27 patients had an immune response, and those that responded had a median survival of 86 weeks compared to 37 weeks for nonresponders.

Stephen Ward, Ph.D., head of process development at Onyvax, talked about a cell-based vaccine, ONY-P1, for treating hormone-resistant prostate cancer. ONY-P1 contains nonpatient-specific prostate cancer cells mixed with the vaccine BCG (used for the treatment of superficial bladder cancer as well as controlling tuberculosis) as an adjuvant. Dr. Ward presented Phase II data that showed that among the 26 patients treated with ONY-P1, there was a median of 58 weeks progression-free survival compared to historical controls of approximately 29 weeks without treatment, and 11 of these patients showed a decrease in their prostate-specific antigen levels over time.“On the basis of these encouraging results, we are going ahead with a further randomized Phase II, placebo-controlled trial of 75 patients,” said Dr. Ward.

The Wrong Indication

Despite these success stories, speakers at the World Vaccine Congress believe that venture capitalists are wary of investing in cancer vaccine companies because there have been too many high-profile failures in trials. Many also state that this is an unfair situation, as the therapeutic cancer vaccines that have failed in trials may have been used to treat cancers that would not respond well to this type of drug.

“Most failed cancer vaccines have been to treat melanoma or pancreatic cancers,” explained Angus Dalgleish, Ph.D., foundation chair in clinical oncology, St. George’s Hospital Medical School, London. “Melanoma prophylactic vaccines fail as the disease is capable of rapid replication and mutation and can outrun even a polyepitope vaccine. Pancreatic vaccines tend to be used in the presence of high-volume tumors, which inhibit immune response and can progress before an effective immune response is generated.”

“Biotechs have difficulty selling cancer vaccine propositions to VCs because VCs want to see trial results in months not years,” points out Dr. Schneider. “Therapeutic cancer vaccines are sometimes tested in indications that are suboptimal for an early proof-of-concept. Biotechs should be in a position to use their cancer vaccines in the indication with the best chance of success, for example, early-stage disease with longer survival follow-up, and not just because the trials will take months rather than years to complete.”

According to Dr. Dalgleish, VCs need to understand that overall survival is not the only measure of a vaccine’s efficacy, and if good biomarkers could be identified, there could be surrogate end points to show the drug was working effectively. This may give VCs the confidence to invest in longer trials.

“If we had decent biomarkers that indicated success earlier in trials, many cancer vaccines would be in clinic, and it would be a much rosier world for cancer patients,” agreed Dr. Ward.

Combination Therapy

A strategy for getting around the efficacy issues is to use therapeutic cancer vaccines in combination with chemotherapy. “An appropriate chemotherapy produces tumor cell lysis and a burst of antigenic material, which associated with immunostimulation gives a better chance of the drug working,” said Frederic Triebel, M.D., Ph.D., scientific and medical director of Immutep (www.immutep.com).

This is exactly what Immutep is doing with IMP 321, its LAG-3-based (lymphocyte activation gene-3) protein vaccine for treating metastatic breast cancer. IMP 321 is being administered with paclitaxel in a Phase I study of 16 women.

“So far the results are encouraging. The women are not suffering from neutropenia or alopecia and the low-dose chemotherapy regimen means that there is good patient compliance in this trial,” said Dr. Triebel.

According to Reiner Laus, M.D, president and CEO of BN ImmunoTherapeutics (www.bn-immunotherapeutics.com), the company’s recombinant MVA-based vaccine, MVA-BN®-HER2 to treat breast cancer will also be used in Phase I combination trials with docetaxel or Herceptin. “In metastatic disease settings, multimodality approaches are more promising then single agents. In experimental settings, both Herceptin and docetaxel have shown utility in combination with other immunotherapies. Also, chemotherapy can enhance the immune response by several mechanisms, such as eliminating regulatory T cells. We want to determine how to get the best synergistic effects with this vaccine.”

Dr. Bonnefoy presented the results of a Phase II chemotherapy combination trial of TG 4010 (MVA-MUC1-IL2), Transgene’s vaccine for non-small-cell-lung cancer. In this study, TG 4010 was administered simultaneously with cisplatin and vinorelbine in 44 patients. Tumor response was seen in 32 patients, and 22 patients had a median survival of 12 months, with one patient surviving 30 months.

“Combination therapy is contra-intuitive thinking, but in many trials, we see chemotherapy boosts the immune response to allow more clinical development. Instead of having a patient who is refractory to everything on the planet, you have a responder. Because we have had good Phase II results, TG4010 is now in a Phase IIb combination trial of 140 patients,” reported Dr. Bonnefoy.

Where to Next?

Speakers at the “World Vaccine Congress” agreed that therapeutic vaccines still have a number of hoops to jump through before reaching the market, including proving efficacy, finding good biomarkers to demonstrate drug effectiveness, and obtaining enough funding to finance longer drug trials. “Therapeutic cancer vaccines are perfect drugs—the only thing being debated is their efficacy. Once we can prove they are effective this drug class will be a winner because of its lack of side effects. I believe the future for therapeutic cancer vaccine is in combination therapy. This will make cancer vaccines attractive to pharma partners for cofunded trials or in-licensing.”

Dr. Bonnefoy believes that, “we live or die by randomized data. Our drugs have to be used in the right patient population. We should be driven by this rather than finances or we may throw promising candidates out unnecessarily. Combination therapy is a way forward for showing robust clinical efficacy.”

Despite these obstacles, delegates at the congress are upbeat about the future. “In the next year, we will see the first BLA for therapeutic cancer vaccines.

This will begin to open the floodgates of acceptance for this type of drug and with sufficient funding in 10 years time, therapeutic cancer vaccines could be as successful as antibody drugs are now,” concludes Dr. Bonnefoy.

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