Nos résultats montrent que le traitement associant l’IFN-γ et le GGTI-298 stimule in vitro la capacité des cellules de mélanome à activer des effecteurs LTCD8+ cytotoxiques spécifiques. Dans notre modèle, les cellules tumorales expriment des tumeurs exprimant le
peptide MelanA-MART1 présenté par l’haplotype HLA-A0201 du CMH-I. Ces résultats paraissent intéressants pour le développement d’immunothérapies adoptives. Cependant il est primordial de pouvoir confirmer la spécificité et la fonctionnalité des lymphocytes activés avec des cellules tumorales traitées. Grâce à l’utilisation de souris immunodéficiences (Scid) et/ou de souris transgéniques exprimant HLA-A2 (Pajot et al., p3060) sur lesquelles nous implanterons des cellules du mélanome humain LB1319-MEL, (HLA-A0201+/MelanA- MART1+) nous testerons la capacité des différents effecteurs immuns obtenus après nos stimulations in vitro à contrôler la croissance tumorale. Cette expérience évalue, dans un modèle pré clinique l’efficacité en thérapie adoptive, des effecteurs immuns obtenus après stimulation avec les cellules de mélanome HLA compatibles prétraitées. Ces effecteurs immuns seront induits à partir de lymphocytes du sang périphérique de donneurs sains ou de patients porteurs de mélanomes (HLA-A0201+).
Notre travail a également permis de mettre en évidence l’efficacité de notre protocole de vaccination utilisant des cellules de mélanome murin traitées par l’association IFN/GGTI- 298. L’a confirmation du potentiel vaccinal, des cellules de mélanome murines prétraitées in vitro, sera réalisée par la mise en évidence de populations mémoires dans des souris immunisées. Dans le modèle humain des expériences de co-cultures de PBMC et de cellules de mélanome traitées, permettront la recherche de LT CD8+/CD28+/CD27+/CD62L-/CCR7- qui ont été décrites par Rosenberg et al (Powell et al., 2005) comme les effecteurs mémoires spécifiques des mélanomes et impliquées dans les effets cliniques.
Ces aspects du travail seront entrepris afin de préparer la phase translationnelle vers des partenaires cliniques. Ils seront réalisés en collaboration étroite avec les cliniciens de l’Institut Claudius Regaud responsables du traitement des patients atteints de mélanome, en vue de la mise en place de protocoles d’immunothérapie (Figure H).
Vaccination
Transfert Adoptif
Vaccination
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