[HTML][HTML] Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain

M Singh, C Vianden, MJ Cantwell, Z Dai, Z Xiao… - Nature …, 2017 - nature.com
M Singh, C Vianden, MJ Cantwell, Z Dai, Z Xiao, M Sharma, H Khong, AR Jaiswal, F Faak…
Nature communications, 2017nature.com
CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to
prime tumor-specific CD8+ T cell responses. Here, we study the antitumor activity and
mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound
CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas
generates tumor-specific, CD8+ T cells that express PD-1 and suppress tumor growth.
Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity …
Abstract
CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8+ T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8+ T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8+ T cells, and an increased ratio of intratumoral CD8+ T cells to CD4+ Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain.
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