Project description:Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing immunogenic cell death features and which upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment with BO-112 of subcutaneous tumors derived from MC38, 4 T1 and B16-F10 leads to remarkable local disease control dependent on type-1 interferon and gamma-interferon. Some degree of control of non-injected tumor lesions following BO-112 intratumoral treatment was found in mice bearing bilateral B16-OVA melanomas, an activity which was enhanced with co-treatment with systemic anti-CD137 and anti-PD-L1 mAbs. More abundant CD8+ T lymphocytes were found in B16-OVA tumor-draining lymph nodes and in the tumor microenvironment following intratumoral BO-112 treatment, with enhanced numbers of tumor antigen-specific cytotoxic T lymphocytes. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Inspired by these data, intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098).
Project description:Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. Intratumoral administration is conceivably safer than systemic delivery and allows concentrate proinflammatory adjuvanticity in the tumor microenvironment and tumor-draining lymphoid tissue. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing immunogenic cell death features and that upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment of subcutaneous tumors derived from MC38, 4T1 and B16F10 with BO-112 leads to remarkable local disease control mediated by CD8+ T lymphocytes, as concluded from selective depletion experiments. Some degree of control of non-injected tumor lesions upon BO-112 intratumoral treatment was found in mice bearing bilateral B16OVA melanomas, that was enhanced when co-treated with systemic anti-CD137 and anti-PD-L1 immunomodulatory mAbs. More abundant CD8+ T lymphocytes were found in tumor-draining lymph nodes and in the tumor microenvironment following intratumoral treatment with BO-112. Enhanced numbers of tumor-specific CTLs recognizing melanosomal antigens and ovalbumin were readily detected among them. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098) and our results in mice suggest prominent anti-tumor local control through its proimmune effects. Intratumoral administration of BO-112, a nanoplexed form of PolyI:C, triggers an efficacious antitumor response in different tumor models as a consequence of proimmflamatory activity and its direct effects in tumor cells. BO-112 local administration induces direct tumor cell death by apoptosis, showing signs of immunogenic cell death, and a strong release of IFNα/β and other proinflammatory mediators. As a result, a tumor-specific CD8+ immune response is mounted or augmented to the point of controlling tumor progression both in the locally injected lesion and to some extent on distantly implanted tumor nodules
