Christina Vianden

Hiep Khong

Manisha Singh

Mark Cantwell

Willem Overwijk

Zhimin Dai

Journal for ImmunoTherapy of Cancer

Springer - Publisher Connector

POSTER PRESENTATION Open Access
Induction of potent systemic anti-melanoma
immunity through intratumoral CD40 activation
and checkpoint blockade
Manisha Singh1*, Zhimin Dai1, Hiep Khong1, Christina Vianden1, Mark Cantwell2, Willem Overwijk1
From 30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)
National Harbor, MD, USA. 4-8 November 2015
Purpose
Agonistic CD40 antibodies generate strong tumor speci-
fic CD8 T cell response and anti-tumor activity; however
systemic anti-CD40 therapy has been associated with
cytokine release syndrome and liver toxicity. We studied
the anti-melanoma activity and mechanism of action of a
recombinant adenovirus expressing a stabilized version
of CD40L (rAd.CD40L) by local intratumoral delivery
approach to treat metastatic melanoma.
Experimental design
Mice bearing established B16 melanomas were treated
intratumorally with rAd.CD40L (ISF35) or rAd5 control
virus and received anti-PD1 plus anti-CTLA-4 systemi-
cally. Anti-tumor effects of mono or combination thera-
pies were determined by mice survival and tumor growth
measurement. The mechanistic contribution of immune
cells to this therapy was determined by using antibody
blockades. Immune cell infiltrates in tumor and expres-
sion of negative regulators on these cells were analyzed
by flow cytometry.
Results
Intratumoral administration of rAd.CD40L generated
systemic anti-tumor immunity mediated by CD8 T cells
and suppressed both injected and distant uninjected
wild-type B16.F10 melanomas. However, tumors did not
completely regress after therapy. Analysis of tumor-infil-
trating leukocytes revealed that almost 100% of tumor-
infiltrating CD8 T cells in the rAd.CD40L-treated group
had up-regulation of the T cell inhibitory molecule PD-1.
Combined treatment with rAd.CD40L plus anti-PD1 was
highly synergistic and induced higher number of mela-
noma specific CD8 T cells systemically. Concomitant
CTLA-4 blockade further improved the efficacy of treat-
ment and led to complete regression of melanoma in
about 50% of mice and generated memory CD8 T cells
response.
Conclusion
Immunotherapy based on intratumoral CD40 activation
is potentiated by PD-1 and CTLA-4 blockade and this
combination generates functional and long-lasting anti-
tumor CD8 T cell immunity that systemically suppresses
melanoma metastases. These results suggest combination
of rAd.CD40L with checkpoint blockade inhibitors may
offer a promising immunotherapeutic option of meta-
static melanoma that does not respond to checkpoint
blockage monotherapy.
Authors’ details
1University of Texas - MD Anderson Cancer Center, Houston, TX, USA.
2Memgen, LLC, San Diego, CA, USA.
Published: 4 November 2015
doi:10.1186/2051-1426-3-S2-P313
Cite this article as: Singh et al.: Induction of potent systemic anti-
melanoma immunity through intratumoral CD40 activation and
checkpoint blockade. Journal for ImmunoTherapy of Cancer 2015
3(Suppl 2):P313.
1University of Texas - MD Anderson Cancer Center, Houston, TX, USA
Full list of author information is available at the end of the article
Singh et al. Journal for ImmunoTherapy of Cancer 2015, 3(Suppl 2):P313
http://www.immunotherapyofcancer.org/content/3/S2/P313
© 2015 Singh et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://
creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/
zero/1.0/) applies to the data made available in this article, unless otherwise stated.


Induction of potent systemic anti-melanoma immunity through intratumoral CD40 activation and checkpoint blockade

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Induction of potent systemic anti-melanoma immunity through intratumoral CD40 activation and checkpoint blockade

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