Immunologie : recherche actuelle

Abstrait

Unlocking the potential of personal Cancer Vaccines: The Clinical ramifications of Antigen competition driven Immuno-editing

Michael G Hanna

Advances in the molecular characterization of tumors have led to a better understanding of the molecular pathways that underlie cancer. While the realization of intratumor heterogeneity has posed major limits to potential targeting of the mutated pathways and created limits to the central concept of personalized (targeted) medicine. The essential question is whether the approach to targeted medicine will result in any therapeutic strategy that will provide cure or long-term remission in the presence of genomic heterogeneity. The immune system has become a leading protagonist in successfully treating adenocarcinomas. However, with all of the accomplishments of the past two decades in the molecular characterization of tumors, the goal unfortunately was to obtain sustainable adaptive immune responses with agnostic cancer vaccines in advanced disease patients. This approach failed. For good reasons, the recent focus has been on achieving durable passive anticancer immunotherapy (check point inhibitors, tumor Infiltrating lymphocytes) in advanced disease patients with disseminated disease. In either case, cancer immunotherapy has proven to be a major challenge because it is an attempt to overcome those processes that evolved to mediate immune tolerance to self-antigens.

Advances in genomic sequencing and bioinformatics over the past decade have presented a clearer understanding at the molecular level, of the challenges for the immune response to cancer. In fact, during this decade of enlightenment, the development of better sequencing and laboratory tools have expanded our knowledge and capabilities of the neoantigens derived from somatic mutations produced in the repertoire of the tumor cells. In 2008, it was reported that there were between 75 and 125 coding mutations per tumor in lung, breast and colorectal adenocarcinomas. Only seven years later, with advanced sequencing technology and equipment, millions of mutations were discovered in a 3.5-cm squared segment of hepatocarcinoma. The summarized results were, they estimated millions of coding region mutations in this tumor and they estimated drug resistance to be 1 in 5000 tumor cells of any individual clone. Assuming that this is 12 to 13 cell divisions with the established somatic cell doubling time of 6 hours, that could be a loss of potential immune targets every 3 to 4 days. This off-target condition is a limitation of all forms of systemic drug, passive antibody as well as active immunotherapy and does not bode well for the “targeted therapy” movement. It is no longer logical to treat a heterogeneous disease with a homogeneous treatment.