Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination
Menée in vitro, à l'aide d'un modèle murin et sur 11 patients atteints d'un lymphome non hodgkinien indolent à lymphocytes B, cette étude met en évidence l'intérêt d'un traitement combinant l'injection intratumorale de la protéine recombinante Flt3L, une radiothérapie et un agoniste du récepteur TLR3 pour induire la régression de la tumeur et augmenter l'efficacité des anti-PD1
Indolent non-Hodgkin’s lymphomas (iNHLs) are incurable with standard therapy and are poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently killed by primed T cells, in vivo priming of anti-lymphoma T cells has been elusive. Here, we demonstrate that lymphoma cells can directly prime T cells, but in vivo immunity still requires cross-presentation. To address this, we developed an in situ vaccine (ISV), combining Flt3L, radiotherapy, and a TLR3 agonist, which recruited, antigen-loaded and activated intratumoral, cross-presenting dendritic cells (DCs). ISV induced anti-tumor CD8+ T cell responses and systemic (abscopal) cancer remission in patients with advanced stage iNHL in an ongoing trial (NCT01976585). Non-responding patients developed a population of PD1+CD8+ T cells after ISV, and murine tumors became newly responsive to PD1 blockade, prompting a follow-up trial of the combined therapy. Our data substantiate that recruiting and activating intratumoral, cross-priming DCs is achievable and critical to anti-tumor T cell responses and PD1-blockade efficacy.