In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5567-5567
Abstract:
STING (Stimulator of Interferon Genes) is an important mediator of innate and adaptive immunity that responds to invading cytosolic bacterial and viral pathogens, and double stranded DNA from transformed cells. Activation of the cGAS-STING pathway leads to pleiotropic cytokine (IFN-α, IFN-β, TNF-α, IL-6) production, maturation and activation of macrophages, and MHC class II expressing dendritic cells (DCs) with generation of CD8+ T cells. JNJ-67544412 (JNJ-4412) is a cyclic dinucleotide (CDN) developed as a STING agonist. JNJ-4412 binds both mouse and human STING and is more potent binding all the major human STING alleles than most other STING CDN agonists. JNJ-4412 phosphorylate STING and IRF3 and induces high levels of IFNβ and other cytokines in M1 and M2 macrophages, dendritic cells, and monocytes. In syngeneic mouse tumor studies, JNJ-4412 was dosed intratumorally (i.t.) on a q3d x 3 or qweekly schedule resulting in significant tumor regression, complete cures and long-lasting antitumor immunity. Body weight loss ( & lt;20%) was observed but was transient and recoverable and could be mitigated by utilizing a qweekly schedule with no loss of activity. Proinflammatory cytokines such as IFN-α, IFN-β, IP-10, TNF-α, IL-6 and MCP-1 were detected in tumor and plasma after dosing. Combination studies with anti-PD-1 resulted in enhanced dose-dependent efficacy in treated tumors. In bilateral tumor studies, JNJ-4412 inhibited growth of contralateral un-injected tumors. Pharmacodynamic (PD) and mechanism of action (MOA) studies revealed increased number of CD8+ T cells in the treated tumors; increased apoptosis (cleaved caspase 3); loss of vascularization; decreased tumor cell proliferation and pronounced hemorrhagic necrosis in tumors. Rechallenge of cured mice demonstrated long-lasting antitumor immunity. Thus, in vivo administration of JNJ-4412 potently activates the STING pathway resulting in inflammatory cytokine induction, activation of dendritic cells, proliferation of CD8+ T cells, increased apoptosis and curative antitumor efficacy with immunologic memory. Citation Format: Melissa Smith, Diana Chin, Szeman Chan, Sally Mahady, Liam Campion, Caitlin Morgan, Shefali Patel, Gerald Chu, Anna Hughes, Gilles Bignan, Pete Connolly, Stuart Emanuel, Kathryn Packman, Leopoldo L. Luistro. In vivo administration of the STING agonist, JNJ-67544412, leads to complete regression of established murine subcutaneous tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Su ppl):Abstract nr 5567.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2020-5567
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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