Intratumoral injection of Ad-ISF35 (Chimeric CD154) breaks tolerance and induces lymphoma tumor regression.
Ad-ISF35, an adenovirus vector encoding a membrane-bound engineered CD154 chimeric protein (ISF35), induces complete A20 lymphoma tumor regression in mice after intratumoral direct injection (IDI). Ad-ISF35 induced durable local and systemic antitumor responses associated with a rapid tumor infiltration of macrophages and neutrophils as well as increased levels of proinflammatory cytokines in the tumor microenvironment. Ad-ISF35 IDI transduced preferentially fibroblasts and macrophages present in the tumor microenvironment, and ISF35 protein expression was observed in only 0.25% of cells present in the tumor. Moreover, Ad-ISF35 IDI induced upregulation of CD40 in tumor and immune regulatory cells, including those that did not express ISF35, suggesting the presence of a strong bystander effect. These responses resulted in the generation of IFN-γ-secreting cytotoxic lymphocytes and the production of specific cytotoxic antibodies against lymphoma cells. Overall, cellular immune therapy based on ISF35 induced phenotypic changes in the tumor cells and tumor microenvironment that were associated with a break in tumor immune tolerance and a curative antitumor effect in this lymphoma mouse model. Our data highlight the potential activity that modulation of costimulatory signaling has in cancer therapy.
1 Moores Cancer Center, University of California-San Diego , La Jolla, CA 92093-0820.
Mauricio
M
Urquiza
Johanna
J
Melo-Cardenas
Robier
R
Aguillon
Thomas J
TJ
Kipps
Januario E
JE
Castro
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D023201:CD40 Ligand / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D007108:Immune Tolerance; D056724:Immunity, Humoral; D018836:Inflammation Mediators / Q000378:metabolism; D015552:Injections, Intralesional; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000276:immunology / Q000473:pathology; D020556:Neutrophil Infiltration; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000276:immunology; D019076:Transgenes; D047368:Tumor Burden; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D018836:Inflammation Mediators; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand