Immunostimulatory gene therapy with chemotherapy remodels pancreatic tumors and induces immune signatures associated with prolonged survival
4 affiliations
- 1Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- 2Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
- 3Lokon Pharma AB, Uppsala, Sweden
- 4Department of Clinical Science, Intervention and Technology, Karolinska Hospital, Stockholm, Sweden
Abstract
Background: Immune desert/excluded tumors remain a major immunotherapeutic challenge. Herein, we aim to describe mechanistic insights of LOAd703, a novel tumor microenvironment gene engineering therapy targeting CD40 and 4–1BB, in patients with advanced solid cancer commonly associated with unresponsiveness to immunotherapy.
Methods: The study evaluated blood and biopsy samples from pancreatic (n=29), colorectal (n=5), biliary (n=3), and ovarian cancer (n=4), treated with LOAd703 in combination with chemotherapy in a Swedish phase I/II clinical trial (NCT032259899).
Results: Transcriptomic profiling of tumors before and after treatment initiation revealed induction of signatures known to predict immunotherapy responses and an enrichment for adaptive immune response pathways encompassing antigen-presentation and T-cell activation. In pancreatic cancer subanalysis, adaptive immune responses together with increased CD40 expression were associated with longer survival and CD40 appeared as a central node among upregulated immune biomarkers consistent with the mechanism of action of LOAd703. Treatment benefit was further associated with reduced expression of immunosuppressive and tumor-promoting factors both in tumors and peripheral blood. Systemically, treatment generated a Th1 profile in plasma, accompanied by an increase in effector/effector memory T cells and a reduction of regulatory T cells.
Conclusions: These findings support that intratumoral LOAd703 in combination with chemotherapy drives local and systemic immune remodeling in commonly immunotherapy-unresponsive tumors. Further, the treatment reprograms the tumor microenvironment to reduce tumor-promoting factors and immunosuppression.
One sentence summary: Targeting CD40 and 4–1BB with gene therapy in combination with chemotherapy induces immune responses associated with longer survival in pancreatic cancer.
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BibTeX
@article{wenthe2026immunostimulatory,
title = {{Immunostimulatory gene therapy with chemotherapy remodels pancreatic tumors and induces immune signatures associated with prolonged survival}},
author = {Jessica Wenthe and Hanna Grauers Wiktorin and Amanda Hahn and Sedigheh Naseri and Ahmed Calandigary and Luke White and Linda C Sandin and Clara Bernedal Nordström and Stephan Mielke and Tanja Lövgren and Gustav J Ullenhag and Angelica Loskog},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = oct,
doi = {10.1136/jitc-2026-016908},
url = {https://doi.org/10.1136/jitc-2026-016908},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immunostimulatory gene therapy with chemotherapy remodels pancreatic tumors and induces immune signatures associated with prolonged survival
AU - Jessica Wenthe
AU - Hanna Grauers Wiktorin
AU - Amanda Hahn
AU - Sedigheh Naseri
AU - Ahmed Calandigary
AU - Luke White
AU - Linda C Sandin
AU - Clara Bernedal Nordström
AU - Stephan Mielke
AU - Tanja Lövgren
AU - Gustav J Ullenhag
AU - Angelica Loskog
PY - 2026
DA - 2026/10/28
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-016908
UR - https://doi.org/10.1136/jitc-2026-016908
AB - Background: Immune desert/excluded tumors remain a major immunotherapeutic challenge. Herein, we aim to describe mechanistic insights of LOAd703, a novel tumor microenvironment gene engineering therapy targeting CD40 and 4–1BB, in patients with advanced solid cancer commonly associated with unresponsiveness to immunotherapy. Methods: The study evaluated blood and biopsy samples from pancreatic (n=29), colorectal (n=5), biliary (n=3), and ovarian cancer (n=4), treated with LOAd703 in combination with chemotherapy in a Swedish phase I/II clinical trial (NCT032259899). Results: Transcriptomic profiling of tumors before and after treatment initiation revealed induction of signatures known to predict immunotherapy responses and an enrichment for adaptive immune response pathways encompassing antigen-presentation and T-cell activation. In pancreatic cancer subanalysis, adaptive immune responses together with increased CD40 expression were associated with longer survival and CD40 appeared as a central node among upregulated immune biomarkers consistent with the mechanism of action of LOAd703. Treatment benefit was further associated with reduced expression of immunosuppressive and tumor-promoting factors both in tumors and peripheral blood. Systemically, treatment generated a Th1 profile in plasma, accompanied by an increase in effector/effector memory T cells and a reduction of regulatory T cells. Conclusions: These findings support that intratumoral LOAd703 in combination with chemotherapy drives local and systemic immune remodeling in commonly immunotherapy-unresponsive tumors. Further, the treatment reprograms the tumor microenvironment to reduce tumor-promoting factors and immunosuppression. One sentence summary: Targeting CD40 and 4–1BB with gene therapy in combination with chemotherapy induces immune responses associated with longer survival in pancreatic cancer.
SN - 2051-1426
ER -