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Cancer Immunotherapy: lights and shadows

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Cancer immunotherapy has recently emerged as the fourth treatment modality, in addition to surgery, chemotherapy and radiotherapy. These advances are the result of important discoveries in the field of regulation of the immune response, specially on the mechanisms which turn "on" and "off" immune ...

Cancer immunotherapy has recently emerged as the fourth treatment modality, in addition to surgery, chemotherapy and radiotherapy. These advances are the result of important discoveries in the field of regulation of the immune response, specially on the mechanisms which turn "on" and "off" immune responses. A disease which has proved to be a canonical model to test therapeutic immunotherapy approaches is the immunogenic cutaneous melanoma. So far, "passive" immunotherapy with monoclonal antibodies has outpaced "active" immunotherapy with antitumor vaccines, and monoclonal antibodies which antagonize the "off" responses have been recently introduced in clinical practice.

In spite of these recent successes, many unresolved practical and theoretical questions remain to be answered. An example of such questions is that lymphocytes specificity, apparently CD8 cells, which execute tumor cells death, has not yet been established, neither the question as to why those lymphocytes have not been centrally deleted in the thymus has been answered. Another topic that must be answered is which white cells enter into tumors, through which endothelium, in which order, and how they perform their task. It is yet unknown which is the tumor size, and its location, in which an immune response may be sufficient to eradicate the tumor. Understanding these questions could help to increment an appropriate lymphocytes entrance into tumors, and such increase would probably enhance efficacy.

Divergent to those recent advances with monoclonal antibodies, the development of antitumor vaccines has been lagging behind. One of the main reasons is the multiplicity of antigens that must be targeted to achieve significant clinical responses, specially in melanoma, one of the most diversely mutated tumors. Another factor that hampers the results obtained by vaccination is that tumor elimination by the immune system is the result of a race play by two different runners: a tumor on one hand, with widely different growth rates, sometimes quite explosive, and the slow development of the adaptive immune response. In this regard, enhancement of the native arm of the immune response and previous administration of chemotherapy to slow down a rapid tumor development are reasonable approaches that should be put to test.

Finally, criteria to analyze the responses to immune treatments must be perfected, and the populations of patients that may benefit the more from immunotherapeutic approaches should be better defined. In this respect, aplication of systems biology to understand the immune responses to tumors may offer a broader landscape.


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