BACTÉRIES IMMUNOSTIMULATRICES MODIFIÉES EN VUE DE COLONISER DES TUMEURS, DES CELLULES IMMUNITAIRES RÉSIDANT DANS UNE TUMEUR ET LE MICROENVIRONNEMENT TUMORAL
THANOS, Christopher, D.,GLICKMAN, Laura, Hix,SKOBLE, Justin,IANNELLO, Alexandre, Charles Michel,KEHOE, Haixing
申请号：
USUS2020/020240
公开号：
WO2020/176809A1
申请日:
2020.02.27
申请国别(地区):
US
年份:
2020
代理人:
摘要：
Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin" and/or pagP'. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine and/or purine auxotrophs. The bacteria optionally are one or more of asct, purl' and msbB'. The immunostimulatory bacteria, such as Salmonella species, are modified to encode proteins that induce type I interferon (IFN) expression, or that are variants thereof that have increased activity to induce type I IFN expression, or that are variants thereof that result in constitutive expression of type I IFN. The bacteria can encode a modified Stimulator of Interferon Genes (STING) protein from a non-human species, that has lower NF-κΒ signaling activity, and, optionally, higher type I IFN pathway signaling activity, compared to human STING. The bacteria preferentially infect immune cells in the tumor microenvironment, or tumor-resident immune cells, and/or induce less cell death in immune cells than in other cells. Also provided are methods of inhibiting the growth or reducing the volume of a solid tumor by administering the immunostimulatory bacteria.L'invention concerne des bactéries immunostimulatrices d'administration qui présentent une colonisation améliorée des tumeurs, du microenvironnement tumoral et/ou des cellules immunitaires résidant dans une tumeur, et une activité anti-tumorale améliorée. Les bactéries immunostimulatrices sont modifiées par délétion de gènes codant pour les flagelles ou par modification des gènes de sorte que les
