teaser
Bruce Acres
PhD
Head of Clinical Immunology and Translational Research
Jean-Yves Bonnefoy
PhD
Vice President
Research and Development
Transgene SA
Strasbourg
France
E:[email protected]
The lymphocytes in our bloodstream have the potential to recognise and destroy any pathogen. The problem is that lymphocytes with any one specificity are usually present in very small numbers, such that only an encounter with the pathogen will stimulate these cells first to expand in numbers, then to destroy the pathogen and, finally, to establish protective immunity. This way, a second encounter with the same pathogen leads to easy elimination with no symptoms of the disease. Therefore, before the invention of vaccines, in order to establish immunity an individual first had to have the disease. If he/she survived, and many didn’t, immunity was established. With the discovery of vaccination, it was found that the body’s natural defences could be deceived into believing that a pathogen had been encountered and, thus, establish protective immunity. The use of vaccines to “fool Mother Nature” into believing that a pathogen has been encountered, such that protective immunity is established, represents the single most important leap in medical care … ever.
Cancer caused by viruses
Some diseases, such as most cancers, however, do not involve a readily identified pathogenic entity. Therefore, other than virally associated cancers (see below), it is unlikely that most cancers can be prevented by a prophylactic vaccine. Nevertheless, with the knowledge of the immune system gained over the last 50 years, it may be possible to stimulate an immune response to cancer after the disease has started and after it has been diagnosed. The immune system can occasionally run rampant and become very destructive, as evidenced by autoimmune disorders such as rheumatoid arthritis and Crohn’s disease. It is now the goal of immunologists to harness this destructive capacity of the immune system to treat cancer by using “therapeutic cancer vaccines”.(1)
There is now a body of evidence indicating that a cancer patient’s immune response has tried to eliminate the cancer. In fact, it has been proposed that many cancers do not even make it to the stage of symptoms and diagnosis because they are eliminated by the immune system. However, the cancers which do get to the stage of causing pathology have done so by avoiding or suppressing the immune response. Thus a therapeutic cancer vaccine must not only be able to stimulate the cancer-specific lymphocytes, but it must also be able to reboot the immune system such that proliferation and therapeutic activity of the specific lymphocytes can occur.
It has been shown that some cancers can, in fact, be caused by viruses, such as human papilloma virus (HPV). This virus, which is associated with anogenital cancers such as cervical cancer, has recently received much attention. Two prophylactic vaccines have now been approved and it is hoped that vaccination of adolescents against HPV infection will eventually prevent most cervical cancers. However, there are millions of people who are already infected with HPV without any symptoms. These people are at risk of either developing cervical or other anogenital cancers or transmitting HPV to their partner who will then be at risk of developing an anogenital cancer. Therefore, there is still a need for a therapeutic, HPV-specific cancer vaccine and the need for a therapeutic vaccine will persist at least for another 30–40 years. The advantage of this vaccine is that it involves a pathogenic agent so it should be straightforward for the immune system to attack cells expressing parts of the virus and there should be no issues for the immune system to distinguish “self” from “nonself”. Three therapeutic HPV-specific cancer vaccines are currently being tested in post-phase II clinical studies.
Other cancer types
Most cancers, however, do not appear to be caused by a known virus. Nevertheless, over the past 20 years, several cancer-associated proteins, called “antigens”, have been identified. It is generally agreed that these antigens can be incorporated into a strong therapeutic vaccine so as to generate an immune response to an existing cancer. These tumour-associated antigens (TAA) can be divided into several groups:
- Mutated regulatory genes (p53, ras, etc). These genes are involved in the control of cell division. If they are inactivated or uncontrolled, they can cause unlimited cell division and result in cancer. Since they are mutated, they have an unusual structure that could be recognised by the immune system.
- Cancer/testis antigens are a series of antigens that are expressed in some cancers and on some cells in the testis. It is felt that since these cells do not express major histocompatibility complex I (MHCI) cell surface structures, there is no danger of immune damage to the cells of the testis. MHCI structures are required for a cytotoxic T lymphocyte (CTL) to recognise and kill a target cell.
- Embryonic antigens are antigens expressed during embryogenesis to produce the proteins required during fetal life but which are shut down postpartum. Some cancers re-express these antigens, the most common of which is carcinoembryonic antigen (CEA), which is often associated with colon carcinoma.
- Overexpressed/modified antigens. This group of antigens represents cell surface proteins normally present in a particular tissue in low amounts but, in cancer cells, their expression rate increases by orders of magnitude.In addition, they are often modified to make them attractive to an immune response. The best example of this type of antigen is mucin-1 (MUC1), which is produced in great abundance in most epithelial cancers (which represents over two-thirds of all cancer cases) and is underglycosylated. Normal MUC1 is a highly glycosylated molecule and its function is to protect epithelial cells lining secretory ducts and lubricate the passage of materials along the ducts. Possibly due to its overexpression,the cancer-associated MUC1 is much less glycosylated. This exposes the protein core of the molecule. Since the immune system is unaccustomed to exposure to this MUC1 protein structure, and this provides another handle for the immune response to MUC1.
Initial efforts to look for tumour antigens were focused on tumour-“specific” antigens rather than tumour-“associated” antigens (TAA), under the belief that the generation of an immune response to a “self-antigen” (such as TAA), no matter how overexpressed on tumours, would result in life-threatening autoimmunity. This appears not to be the case. Once again, the immune system is more complex than initially believed.
An elegant and insightful hypothesis was published by Polly Matzinger several years ago.(2) This hypothesis states that CTLs capable of responding to self-antigens will not respond to their cogniscent antigen unless they are in a “danger” situation, such as inflammation or tissue necrosis. This hypothesis is now supported by experimental evidence. Mice which are made to express a gene and, therefore, an antigen not normally expressed (transgenic mice) can be infused with CTLs that are specific for that antigen. No autoimmunity occurs. However, if a tumour expressing that antigen is then transplanted into the mouse, immune rejection of the tumour occurs.(3)
Evidence is also now coming from clinical trials. Several hundred patients have been immunised with the antigen MUC1. Only one case of slight autoimmunity to secretory glands was noted and these symptoms resolved as soon as vaccination stopped.(4)
In contrast, about half the patients assessed showed MUC1-specific CTL activity and this activity was associated with better survival.(5,6) Therefore, it would appear that rather than tumour-specific antigens, successful therapeutic cancer vaccines can be based on TAA.
Various therapeutic cancer vaccines based on TAA are now in phase III clinical trials. What is becoming clear is that while the vaccines are very well tolerated and have some modest success alone, their strength at this point is realised when they are combined with standard therapies, such as chemotherapy, or when they are combined with strategies to boost the immune response.
Future prospects
That being said, however, clinically significant results of a therapeutic vaccine have been announced this year.(7) A vaccine called TG4001 was used to treat women with high-grade cervical intraepithelial neoplasia (CIN 2/3). CIN 2/3 is a precancerous lesion of the cervix caused by HPV. Treatment with the vaccine, which targets the oncogenic proteins of HPV, so-called E6 and E7, was shown to eliminate CIN 2/3 and evidence of HPV RNA in nine out of 18 of the women vaccinated. This allowed surgery, the most common treatment for CIN 2/3, to be avoided in responding vaccinated women.
Even though this is a vaccine targeting viral antigens in patients with precancerous lesions, this study demonstrates that the concept of therapeutic vaccines is viable and provides hope for successful therapies of the more common epithelial cancers, such as lung, breast and colon, using therapeutic vaccines.
References
- Expert Opin Ther Targets 2004;8:521-5.
- Science 2002;296:301-5.
- J Immunol 2001;166:2863-70.
- J Biomed Biotech 2003;2003(3):194-201.
- J Clin Oncol 2006;24 Suppl:Abstract 2581.
- J Clin Oncol 2005;23 Suppl:Abstract 7132.
- Bory J-P, Leveque J, Brun J-L, et al. In a phase II study with HPV16 CIN2/3 patients, Transgene’s TG4001 induces clinical regression and HPV16 transcription inhibition. Presented at Eurogyn 2006, Paris, France; 2006.
