Immunothérapie génique du cancer : bilan et perspectives.

Abstract

L’immunothérapie génique du cancer repose essentiellement sur des protocoles de transfert de gène dans les cellules tumorales ou fibroblastiques. Le consensus est acquis sur la nécessité d’améliorer le transfert de gène in vivo dans les tumeurs. Les approches cherchant à augmenter l’immunogénicité tumorale devraient être associées à une neutralisation des effets immunosuppresseurs de la tumeur. La variabilité antigénique tumorale demeure un écueil important et implique que l’immunothérapie du cancer cible d’emblée plusieurs antigènes tumoraux ou soit utilisée dans d’autres thérapeutiques anticancéreuses. L’emploi des cellules dendritiques génétiquement modifiées reste cependant une perspective majeure du fait de leurs propriétés en tant que cellules présentatrices d’antigène. La voie et le site d’injection, la capacité des cellules dendritiques humaines de migrer vers les organes lymphoïdes périphériques, la quantité de cellules à injecter et le nombre d’injections chez l’homme sont autant de questions encore sans réponse.

New biological cancer treatments are based on specific immunotherapy including cell and gene therapies. Although attempts are made to develop adoptive immunotherapy of cancer, through for example the genetic modification of tumor infiltrating lymphocytes, the major hopes are located in the active immunotherapy of cancer, also designated "vaccine" strategies. More than 1800 patients have been included in 228 clinical trials based on gene therapy of cancer, with more than half based on immune strategies. The major target of these immunotherapeutic trials are patients with melanoma, and viral vectors have been used in more than 50% of them. The therapeutic strategies are based on the transfer of genes such as those coding for cytokines (mainly interleukin-2), HLA allo-molecules, costimulatory molecules, or antigens, used either alone or in combination. These transfers have been performed ex vivo, mostly in autologous or allogenic tumor cells, but also in fibroblasts or lymphocytes, and also in vivo, by direct injection of the vectors intratumoraly or subcutaneously. Other strategies are developed, as, for example, the successful transfer of the herpes simplex virus thymidine kinase gene in allogenic lymphocytes to control graft-versus-host disease (GVHD) after injection of these cells for immunotherapy of patients with leukemia, in order to induce a graft versus leukemia reaction (GVL). Some clinical and biological responses have been reported. These first results are very encouraging for a field which is only in its infancy. Never molecular basic and clinical researches have been so close. Major efforts have to be spent not only on basic research, but also in clinical research, with the development of high quality clinical trials. that because they have their own requirements, should not be designed as chemotherapeutic trials.