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Intratumoral immunostimulatory AdCD40L gene therapy in patients with advanced solid tumors

Abstract

AdCD40L is a replication-deficient virus carrying the gene for CD40 ligand which has previously been evaluated in patients with urothelial cancer and malignant melanoma. Herein, we present the results of repeated intratumoral injections of AdCD40L in seven patients with metastatic solid cancer. One patient who developed urothelial cancer derived from a renal transplant was treated with repeated injections of AdCD40L alone. The remaining patients suffered from cholangiocarcinoma, kidney, breast, rectal, or ovarian cancer and received AdCD40L repeatedly (4x) in combination with cyclophosphamide. The treatment was safe and generally well-tolerated. Two patients had clinical benefit of the treatment and one of them was accepted for re-treatment. Circulating proinflammatory cytokines were commonly increased after treatment, but save for TNFα, significances were not reached which could be due to the low number of patients. Similar to earlier findings in AdCD40L-treated melanoma patients, IL8 plasma levels were high in the present study. In conclusion, gene therapy by repeated intratumoral AdCD40L injections alone, or in combination with cyclophosphamide, is feasible and safe in patients with solid cancers. The potential of intratumoral CD40L gene transfer as treatment of cancer was illustrated by the clinical improvement in two out of seven patients.

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Fig. 1: Radiological evaluation of a lymph node metastasis in patient #1.
Fig. 2: Radiological evaluation of a metastasis in the urinary bladder in patient #1.
Fig. 3: Immunological response in a treated and an untreated metastasis in patient #1.
Fig. 4: Anti-adenovirus antibodies increase post-treatment.
Fig. 5: Immune marker analysis.

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Acknowledgements

We are grateful to all patients who participated in this study. We thank study nurses Agneta Lindahl and Åsa Johansson for their patient coordination and care, radiologists Christina Lundberg and Anders Nilsson for their participation in administering the intratumoral injections and Gabriella Paul Wetterberg at Uppsala University for sample preparation and experimental analyses.

Funding

This study was supported by grants to Dr. Ullenhag by the research foundation Stiftelsen Onkologiska Kliniken i Uppsala Forskningsfond and Lion’s Cancer Fund at Uppsala University Hospital and by grants to Dr. Tötterman and Dr. Loskog from the Swedish Cancer Society, Medical Faculty at Uppsala University and the Swedish State Support for Clinical Research and Lion’s Cancer Fund at Uppsala University Hospital. The study was also supported by grants to Håkan Ahlström from the Swedish Cancer Society and Lion’s Cancer Fund at Uppsala University Hospital.

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Correspondence to Gustav J. Ullenhag.

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Dr Loskog is the CEO and board member of Lokon Pharma AB. She also holds a research grant from Lokon Pharma AB. Dr Loskog is a scientific advisor and alternate board member of NEXTTOBE AB. She is the founder of Lynxalo AB and has a royalty agreement with Alligator Bioscience AB. Dr Totterman has a royalty agreement and is an advisor to Alligator Bioscience AB. Håkan Ahlström is one of the founders and employee of Antaros Medical AB, Bioventure Hub, Mölndal, Sweden. The remaining authors declare no financial conflict of interest.

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Irenaeus, S., Hellström, V., Wenthe, J. et al. Intratumoral immunostimulatory AdCD40L gene therapy in patients with advanced solid tumors. Cancer Gene Ther 28, 1188–1197 (2021). https://doi.org/10.1038/s41417-020-00271-8

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