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

Manisha Singh, Christina Vianden, Mark J. Cantwell, Zhimin Dai, Zhilan Xiao, Meenu Sharma, Hiep Khong, Ashvin R. Jaiswal, Faisal Faak, Yared Hailemichael, L. M. E. Janssen, Uddalak Bharadwaj, Michael A. Curran, Adi Diab, Roland L. Bassett, David J. Tweardy, Patrick Hwu and Willem W. Overwijk ()
Additional contact information
Manisha Singh: The University of Texas MD Anderson Cancer Center
Christina Vianden: The University of Texas MD Anderson Cancer Center
Mark J. Cantwell: Memgen
Zhimin Dai: The University of Texas MD Anderson Cancer Center
Zhilan Xiao: The University of Texas MD Anderson Cancer Center
Meenu Sharma: The University of Texas MD Anderson Cancer Center
Hiep Khong: The University of Texas MD Anderson Cancer Center
Ashvin R. Jaiswal: The University of Texas MD Anderson Cancer Center
Faisal Faak: The University of Texas MD Anderson Cancer Center
Yared Hailemichael: The University of Texas MD Anderson Cancer Center
L. M. E. Janssen: The University of Texas MD Anderson Cancer Center
Uddalak Bharadwaj: The University of Texas MD Anderson Cancer Center
Michael A. Curran: The University of Texas MD Anderson Cancer Center
Adi Diab: The University of Texas MD Anderson Cancer Center
Roland L. Bassett: The University of Texas MD Anderson Cancer Center
David J. Tweardy: The University of Texas MD Anderson Cancer Center
Patrick Hwu: The University of Texas MD Anderson Cancer Center
Willem W. Overwijk: The University of Texas MD Anderson Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-017-01572-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01572-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-017-01572-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().