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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References
Marabelle A, Tselikas L, de Baere T, Houot R. Intratumoral immunotherapy: using the tumor as the remedy. Ann Oncol: Off J Eur Soc Med Oncol. 2017;28(suppl_12):xii33–xii43.
Ullenhag G, Loskog ASI. AdCD40L—crossing the valley of death? Int Rev Immunol. 2012;31:289–98.
Loskog A, Maleka A, Mangsbo S, Svensson E, Lundberg C, Nilsson A, et al. Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients. Br J Cancer. 2016;114:872–80.
Lindqvist C, Sandin LC, Fransson M, Loskog A. Local AdCD40L gene therapy is effective for disseminated murine experimental cancer by breaking T-cell tolerance and inducing tumor cell growth inhibition. J Immunother (Hagerstown, Md: 1997). 2009;32:785–92.
Loskog A, Dzojic H, Vikman S, Ninalga C, Essand M, Korsgren O, et al. Adenovirus CD40 ligand gene therapy counteracts immune escape mechanisms in the tumor Microenvironment. J Immunol (Baltim, Md: 1950). 2004;172:7200–5.
Loskog AS, Fransson ME, Totterman TT. AdCD40L gene therapy counteracts T regulatory cells and cures aggressive tumors in an orthotopic bladder cancer model. Clin Cancer Res. 2005;11(24 Pt 1):8816–21.
Liljenfeldt L, Dieterich LC, Dimberg A, Mangsbo SM, Loskog ASI. CD40L gene therapy tilts the myeloid cell profile and promotes infiltration of activated T lymphocytes. Cancer Gene Ther. 2014;21:95–102.
Westberg S, Sadeghi A, Svensson E, Segall T, Dimopoulou M, Korsgren O, et al. Treatment efficacy and immune stimulation by AdCD40L gene therapy of spontaneous canine malignant melanoma. J Immunother (Hagerstown, Md: 1997). 2013;36:350–8.
Malmstrom PU, Loskog AS, Lindqvist CA, Mangsbo SM, Fransson M, Wanders A, et al. AdCD40L immunogene therapy for bladder carcinoma–the first phase I/IIa trial. Clin Cancer Res. 2010;16:3279–87.
Irenaeus S, Schiza A, Mangsbo SM, Wenthe J, Eriksson E, Krause J, et al. Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients. Oncotarget 2017;8:78573–87.
Schiza A, Wenthe J, Mangsbo S, Eriksson E, Nilsson A, Totterman TH, et al. Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients. J Transl Med. 2017;15:79.
He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B. A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA. 1998;95:2509–14.
Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, et al. Metronomic cyclophosphamide regimen selectively depletes CD4 + CD25 + regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol, immunotherapy: CII. 2007;56:641–8.
Hammers H. Immunotherapy in kidney cancer: the past, present, and future. Curr Opin Urol. 2016;26:543–7.
Boutsikou E, Domvri K, Hardavella G, Tsiouda D, Zarogoulidis K, Kontakiotis T. Tumour necrosis factor, interferon-gamma and interleukins as predictive markers of antiprogrammed cell-death protein-1 treatment in advanced non-small cell lung cancer: a pragmatic approach in clinical practice. Therapeutic Adv Med Oncol. 2018;10:1758835918768238.
Hartoonian C, Sepehrizadeh Z, Tabatabai Yazdi M, Jang YS, Langroudi L, Amir Kalvanagh P, et al. Enhancement of immune responses by co-delivery of CCL19/MIP-3beta chemokine plasmid with HCV core DNA/protein immunization. Hepat monthly. 2014;14:e14611.
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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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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DOI: https://doi.org/10.1038/s41417-020-00271-8
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