Therapeutic antitumor vaccines are a matter of the near future
The term "therapeutic antitumor vaccines" covers a wide range of drugs based on DNA, cells or proteins designed to stimulate the immune system and trigger cytotoxic reactions directed against cancer cells. Currently, the topic of creating such vaccines is experiencing a renewed wave of interest from the public.
During the "World Vaccine Congress" held in Lyon on October 8-10, 2007, representatives of many companies working in this new but actively developing medical field expressed their opinion on the prospects for the introduction and use of antitumor vaccines.
In order to understand what is happening in this area at the present stage, it is enough to quote the words of the vice president of GlaxoSmithKline Biologicals (GSK), Dr. Vincent Brichard: "Many claim that the work on the creation of therapeutic antitumor vaccines is 20 years of continuous failures, however, I declare that this 20 years of valuable training, the results of which we are ready to use."
Dr. Jean-Yves Bonnefoy, Vice President of Research at Transgene, explains the rise in interest in investing in therapeutic antitumor vaccines to the market success of preventive vaccines such as Merck's Gardasil and GSK's Cervarix. In 2007, Roche received a license for the TG4001 cervical cancer vaccine developed by Transgene, and Sanofi-Aventis received a license for the TroVax therapeutic kidney cancer vaccine developed by Oxford Biomedica.
Thus, compared to the last five years, during which the members of the "big pharma" did not even admit the idea of producing therapeutic antitumor vaccines due to the conviction of their ineffectiveness, the situation has changed dramatically. However, despite the optimism of the representatives of Big Pharma, the official approval of the first therapeutic antitumor vaccine remains a matter of the future today.
During the last decade, the development of therapeutic antitumor vaccines was mainly carried out by small biotech companies, which, due to limited funds, conducted short-term clinical trials to quickly obtain results. This led to the simultaneous development of a large number of antitumor vaccines against melanoma, pancreatic cancer and prostate cancer.
Unfortunately, these diseases develop very quickly and their progression is recorded even before the formation of an effective immune response, so in such cases, the effectiveness of tested vaccines is difficult to assess using disease progression as a clinical parameter.
A good example is the vaccine developed by Dendreon for the treatment of prostate cancer Provenge (sipuleucel-T, Provenge), the active component of which are autologous antigen-presenting cells. Last year, the refusal of official approval for the use of this drug was widely covered in the press.
The head of Dendreon's information security service, Dr. David Ardal, compares the period during which the application for a Biologic License Application for Provenge was under consideration with a roller coaster ride. He claims that Provenge fell a little short of the main parameter of assessment – reducing the time to disease progression, however, when conducting clinical trials using a double-blind randomized method under placebo control, the vaccine demonstrated an increase in the life span of patients by an average of 4.5 months compared to the control group.
Despite the failure, this story brought a lot of new knowledge to the vaccine developers. According to Ardal, it turned out that the progression of metastatic androgen-independent prostate tumors occurs much faster than previously thought (within 8-10 weeks) and the change in the period before the progression of the disease is not quite an adequate parameter for evaluating the effectiveness of the drug, which takes time to form an immune response. The optimal parameter for evaluating such drugs in this case is the life expectancy measured in months.
Important information is also that chemotherapy with Doxitaxel after a course of Provenge also increases the survival rate of patients, which makes Provenge a potential means of increasing the effectiveness of Doxitaxel.
During the tests, the results of which are provided as part of the Application for a permit for a biopreparation, the Provenge is well tolerated and improves patient survival, so the company hopes that the US Food and Drug Administration (FDA) will allow the Application to include new data on the survival rate obtained as a result of the currently conducted additional phase III clinical trials. The first preliminary results will be obtained already in 2008, so the company does not lose hope that Provenge will still become the first therapeutic antitumor vaccine that has received official FDA approval.
Despite the failure of Dendreon, many biotech companies are still developing therapeutic vaccines for the treatment of tumors that do not respond well to immunotherapy. As an example, IMA901 is the main active ingredient in the arsenal of Immatics Biotechnologies, which is an aqueous solution of 10 tumor–specific peptides intended for intradermal administration together with GM-CSF (granulocyte-macrophage colony stimulating factor) as an adjuvant.
The head of the administrative service of Immatics, Dr. Niels Emmerich, explains that the company's specialists have identified more than 2,000 HLA-binding peptides of human kidney cancer tissue, from which peptides that are not associated with tumors, non-immunogenic, too hydrophobic, and also raising intellectual property issues have been excluded.
Of the remaining 5% of peptides, the researchers selected 10 that were part of the IMA901 drug that interacts with the HLA-A02 antigen and activates cytotoxic lymphocytes. The cost of production of IMA901 is very attractive, since solid-phase chemistry makes it possible to obtain a large amount of product at low cost without using cell cultures.
During the phase 1 clinical trials of IMA901, all 28 patients tolerated the administration of the drug well. At the same time, 75% of patients developed an immune response to at least one of the peptides included in IMA901 and a decrease in the size of tumors was observed. Based on these results, in September 2008, the company will begin phase II trials involving 70 patients with metastatic kidney cancer.
Progressive renal cell carcinoma is difficult to treat, so the ideal time to start therapy is the early stages of the disease. However, a company with limited funding and in need of quick results confirming the concept is taking a risk in the hope that it will be justified and the effectiveness of the proposed approach will be proven in early 2009.
Despite the fact that there are still doubts about the effectiveness of therapeutic antitumor vaccines, GSK and Roche believe in the promising direction and have already confirmed this in practice: Roche – by licensing the development of Transgene, and GSK – by licensing the recombinant melanoma antigen MAGE-A3, developed by the Ludwig Institute for Cancer Research.
Dr. Brichard, presenting information about the antigen-specific antitumor immunotherapy approach being developed by GSK for the treatment of non-small cell lung cancer using MAGE-A3, stated that MAGE-A3 express cells of many types of cancer, including non-small cell lung cancer, head and neck cancer and bladder cancer. At the same time, this antigen is absolutely not found on the surface of healthy cells, which makes it a unique therapeutic target.
The company's specialists chose the MAGE-A3 antigen, because its expression is registered in the cells of more than 50% of stage III non-small cell lung cancer tumors and is associated with a poor survival prognosis. The MAGE-A3-based vaccine is produced in a culture of E. coli (E.coli) modified using a patented gene vector technology. The production of this protein requires maintaining the stability of the technological process and a complex purification procedure, which makes it almost impossible to copy the technology. The MAGE-A3 antigen, administered in combination with the adjuvant system developed by GSK, stimulates the ability of CD4+ T-lymphocytes to recognize tumor cells and initiate an antitumor immune response.
Phase 2 clinical trials involving 182 patients with stages IB and II of non-small cell lung cancer showed that 28 months after the introduction of the vaccine, patients had a 27% reduction in the risk of postoperative recurrence of the disease compared with the control group. The company is already planning a phase III clinical trial involving 2,200 patients, with preliminary results expected by 2010.
Another vaccine being prepared for the start of a large-scale phase III clinical trial (800 participants from Europe and the USA) is the TG4001 vaccine (recently renamed R3484), developed by Transgene for the treatment of human papillomavirus. The vaccine contains a weakened form of a non-infectious strain of the cowpox virus, in whose DNA the genes of the papillomavirus antigens (E6 and E7) and interleukin-2 are embedded.
During phase II clinical trials, 12 months after vaccination, 10 of the 21 participants in the trials (aged 25 to 44 years) completely disappeared foci of cervical cancer. These results indicate that the R3484 vaccine is a promising alternative to surgical conization of the cervix, currently used to treat the disease.
There are still many difficulties to overcome before therapeutic antitumor vaccines appear on the market, the most difficult of which is proving their effectiveness. However, despite everything, all specialists working in this direction are optimistic about the future, especially considering that large pharmaceutical companies are beginning to join the work and finance large-scale clinical trials. According to the statement made within the framework of the congress, by 2010 doctors will have at their disposal a new class of drugs that practically has no side effects and can help a huge number of seriously ill patients.
Literature:
World Vaccine Congress
Jeffrey Schlom, Philip M. Arlen and James L. Gulley // Cancer Vaccines: Moving Beyond Current Paradigms – Clinical Cancer Research 13, 3776-3782, July 1, 2007.
Mark A Suckow; Julie Heinrich; Elliot D Rosen // Tissue Vaccines for Cancer – Expert Rev Vaccines. 2007;6(6):925-937.
Big step forward for cancer vaccine (Bernadette Tansey, San Francisco Chronicle, March 30, 2007).
Evgeniya Ryabtseva
Portal "Eternal youth" www.vechnayamolodost.ru
09.04.2008