Principles and Prospects of Cancer Immunotherapy

Principles and Prospects of Cancer Immunotherapy

The specific component of our immune system involves two types of lymphocytes: B cells and T cells. B cells produce antibodies and some T cells, called T helper cells, collaborate in this process. Other T cells destroy cells that are infected by viruses by a lytic process. They are named cytolytic T lymphocytes (CTL).

The presence in human tumors of tumor-specific antigens that can be recognized by CTL of the cancer patients was definitively demonstrated about 25 years ago. These tumor-specific antigens arise through two main mechanisms. The first is the occurrence in the genes of tumor cells of many point mutations that are not present in normal cells. Many of these mutations change the sequence of the protein produced by the mutated gene. This results in the production of a new short peptide which is presented on the surface of the tumor cell by specialized molecules called MHC class I molecules. These peptide-MHC complexes are recognized by CTL which can destroy the tumor cells. These CTL spare the normal cells of the body as these cells do not harbour the mutation and hence do not present the antigen. The second mechanism is the activation in tumor cells of the transcription of a number of genes that are not expressed in normal adult cells. The genes of this group, the first of which was named Mage, are usually located on the X chromosome. Their activation results from a demethylation process which activates the promoter of the gene. This demethylation occurs at random in tumor cells and not in normal cells with the exception of early germ cells, but these germ cells do not present the relevant antigen because they do not bear class I MHC molecules on their surface, hence the tumor-specificity of the antigens encoded by these “cancer-germline” genes. In addition to these two main mechanisms, a host of anomalous transcription and translation processes found to occur only in tumor cells produce tumor-specific antigenic peptides.

The tumor-specific antigens resulting from mutations are highly individual for each patient. This made their exploitation for cancer immunotherapy nearly impossible in the early days. However recent considerable progress reducing both the time and the cost of the sequencing of human genomes is now beginning to make their exploitation practical. In contrast, Mage-type antigens are shared by significant proportions of cancer patients but they may be less potent antigens than those resulting from mutations.

Almost two decades of trials involving immunization with tumor-specific antigens have not led to a medical breakthrough: responses were observed in only 10% of the patients, a percentage too low for medical use. In contrast, the use of antibodies that block inhibitory receptors of T lymphocytes has led to a much larger fraction of responding patients with many long-term responses. It is through this approach that immunotherapy is now having a considerable impact on cancer treatment. However, this procedure is activating all T lymphocytes and not just the anti-tumor lymphocytes. This result in a significant proportion of patients who undergo severe autoimmune side-effects harming essential normal cells. But these side-effects are better and better managed by the clinical cancer therapists.

I do hope that at one point an improved vaccination procedure will lead to a cancer therapy which is both highly effective and safe. Combining vaccination with a low dose of T lymphocyte activators represents an attractive possibility. We should bear in mind that our immune mechanisms, which are quite successful in curing us from bacterial and viral diseases, are rather clumsy, involving an enormous number of activating and inhibitory agents. Perhaps we should be prepared to be equally complex in our approaches by combining vaccination with several local and systemic agents adapted to the profile of the tumor.

At this point, I cannot avoid mentioning that the European authorities have promulgated regulations regarding clinical trials that are well adapted to guarantee the quality of the large phase-three trials, which are managed by pharmaceutical firms to obtain authorizations to market new drugs. Unfortunately, these regulations are totally unsuited for innovative exploratory trials involving very small number of patients who should be extensively tested to understand the processes at play. This, in my opinion, has all but killed innovative clinical research pursued in European Universities, often increasing the delays by tenfold and the cost by hundredfold. Ill-conceived privacy regulations also prevent the collection of samples from patients at the time of relevant clinical observations. I can personally testify how the extensive analysis of blood and tumor samples of less than five patients provided 90% of the knowledge we have of tumor-specific antigens.

We know now that most metastatic cancer patients for which we are trying to induce a strong anti-tumoral response have previously mounted a spontaneous response against their tumor. But extraordinarily, this response has stalled. It seems amazing that for such a vital issue, the immune system that is so effective at freeing us from viruses and bacteria that would otherwise kill us within a few days fails to achieve the apparently easy task of eliminating the relatively slow growing tumor cells. The explanation probably rests on the fact that defending young persons against bacteria and viruses had an enormous selective impact during human evolution. On the contrary, cancer kills mostly old people well past their reproductive age and there is therefore little selective value for resistance to cancer.

Finally, what about the consequences of improved cancer treatment for society? When faced, as we were until recently, with the imminent and inexorable death of women in their thirties leaving behind very young children, it is difficult to doubt the validity of one’s purpose. I can understand the concern that cancer improvement will extend lives in a way that imposes a considerable burden to society, especially if little progress is made in the area of diseases such as Alzheimer’s disease. However, I am confident that ways can be found to manage this situation, by combining technical progress and the pursuit of an inclusive society as, I believe, is occurring in Japan. I fear the prospect of having too many old people much less than I fear the continuous accumulation of a greater and greater share of mankind in monstrously large cities where most of the people live in conditions that are incompatible with human nature.