Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors

Wongthida, Phonphimon, Schuelke, Matthew R., Driscoll, Christopher B., Kottke, Timothy, Thompson, Jill M, Tonne, Jason, Stone, Cathy, Huff, Amanda L., Wetmore, Cynthia, Davies, James A. ORCID: https://orcid.org/0000-0003-3569-4500, Parker, Alan L. ORCID: https://orcid.org/0000-0002-9302-1761, Evgin, Laura and Vile, Richard G. 2020. Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors. Neuro-Oncology 22 (12) , pp. 1757-1770. 10.1093/neuonc/noaa126

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Abstract

Diffuse Midline Glioma, formerly Diffuse Intrinsic Pontine Glioma (DIPG), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated 1) whether direct delivery of adenovirus expressing CD40L (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and, 2) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem. Methods Syngeneic gliomas in the brainstems of immune competent mice were treated with Ad-CD40L and survival, toxicity and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-Δ24-CD40L, was tested in human patient-derived Diffuse Midline Gliomas and immunocompetent models. Results Expression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intra-tumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-seq analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with IL-6, IL-1β and TNF-α. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-Δ24-CD40L, the backbone of which has already entered clinical trials for Diffuse Midline Glioma. Direct intra-tumoral injection of rAd-Δ24-CD40L, with systemic blockade of IL-6 and IL-1β, generated significant numbers of cures with readily manageable toxicity. Conclusions Virus-mediated delivery of CD40L has the potential to be effective in treating Diffuse Midline Gliomas without obligatory neuroinflammation-associated toxicity.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/)
Publisher:	Oxford University Press (OUP): Policy B
ISSN:	1522-8517
Date of First Compliant Deposit:	28 May 2020
Date of Acceptance:	13 May 2020
Last Modified:	02 May 2023 16:03
URI:	https://orca.cardiff.ac.uk/id/eprint/131954

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