Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma

ABSTRACT To circumvent the toxicity caused by systemic injection of cytokines, cytokine cDNA genes encoding the human interleukin IL-2 cDNA (Ad-IL-2) and murine interferon IFN-_γ_ gene (Ad-

IFN-_γ_) were inserted into adenoviral vectors. These constructs were used for intratumoral gene therapy of murine renal adenocarcinoma Renca tumors. Treatment with three doses of Ad-IL-2 or

Ad- IFN-_γ_, given a day apart, was more effective than single-dose gene therapy. We found that tumor irradiation enhanced the therapeutic efficacy of Ad-IL-2 and Ad-IFN-_γ_ intratumoral

gene therapy. Tumor irradiation, administered 1 day prior to three doses of Ad-IL-2 treatment, was more effective than radiation or Ad-IL-2 alone, resulting in tumor growth arrest in all

mice, increased survival and a consistent increase in complete tumor regression response rate. Complete responders rejected Renca tumor challenge and demonstrated specific cytotoxic T-cell

activity, indicative of specific tumor immunity. The effect of radiation combined with three doses of Ad-IFN-_γ_ was less pronounced and did not lead to tumor immunity. Histological

observations showed that irradiation of the tumor prior to gene therapy increased tumor destruction and inflammatory infiltrates in the tumor nodules. These findings demonstrate that tumor

irradiation improves the efficacy of Ad-IL-2 gene therapy for induction of antitumor immune response. Access through your institution Buy or subscribe This is a preview of subscription

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GENE THERAPY IN PATIENTS WITH ADVANCED SOLID TUMORS Article 14 December 2020 BETA PRIME: A FIRST-IN-MAN PHASE 1 STUDY OF ADAPT-001, AN ARMED ONCOLYTIC ADENOVIRUS FOR SOLID TUMORS Article

Open access 25 December 2023 RECOMBINANT ONCOLYTIC ADENOVIRUS ARMED WITH CCL5, IL-12, AND IFN-Γ PROMOTES CAR-T INFILTRATION AND PROLIFERATION IN VIVO TO ERADICATE LOCAL AND DISTAL TUMORS

Article Open access 02 September 2023 REFERENCES * Greenlee RT, Murray T, Bolden S, et al. Cancer statistics, 2000. _CA Cancer J Clin._ 2000;50:7–33. Article  CAS  PubMed  Google Scholar  *

Mulders P, Figlin R, deKernion JB, et al. Renal cell carcinoma: recent progress and future directions. _Cancer Res._ 1997;57:5189–5195. CAS  PubMed  Google Scholar  * Chow WH, Gridley G,

McLaughlin JK, et al. Protein intake and risk of renal cell cancer. _J Natl Cancer Inst._ 1994;86:1131–1139. Article  CAS  PubMed  Google Scholar  * Haas GP, Hillman GG . Update on the role

of immunotherapy in the management of kidney cancer. _Cancer Control_. 1996;3:66–71. Article  Google Scholar  * Motzer RJ, Bander NH, Nanus DM . Renal-cell carcinoma. _New England J Med._

1996;335:865–875. Article  CAS  Google Scholar  * Kim S, Haas GP, Hillman GG . Development of immunotherapy for the treatment of malignacies refractory to conventional therapies. _Cytokines

Mol Ther._ 1996;2:13–19. CAS  PubMed  Google Scholar  * Hillman GG, Haas GP, Wahl WH, et al. Adoptive immunotherapy of cancer: biological response modifiers and cytotoxic cell therapy.

_Biotherapy_. 1992;5:119–129. Article  CAS  PubMed  Google Scholar  * Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction

with lymphokine-activated killer cells for the treatment of patients with advanced cancer. _J Natl Cancer Inst._ 1993;85:622–632. Article  CAS  PubMed  Google Scholar  * Dybal EJ, Maughan

RL, Sud S, et al. Synergy of radiation therapy and immunotherapy in murine renal cell carcinoma. _J Urol._ 1992;148:1331–1337. Article  CAS  PubMed  Google Scholar  * Younes E, Haas GP,

Dezso B, et al. Local tumor irradiation augments the response to IL-2 therapy in a murine renal adenocarcinoma. _Cell Immunol._ 1995;165:243–251. Article  CAS  PubMed  Google Scholar  *

Dezso B, Haas GP, Hamzavi F, et al. The mechanism of local tumor irradiation combined with interleukin 2 therapy in murine renal carcinoma: histological evaluation of pulmonary metastases.

_Clin Cancer Res._ 1996;2:1543–1552. CAS  PubMed  Google Scholar  * Hillman GG, Visscher D, Ali E, et al. Systemic treatment with interleukin-4 induces regression of pulmonary metastases in

a murine renal cell carcinoma model. _Cell Immunol._ 1995;160:257–263. Article  CAS  PubMed  Google Scholar  * Hillman GG, Visscher D, Hamzavi F, et al. Inhibition of murine renal carcinoma

pulmonary metastases by systemic administration of interferon gamma: mechanism of action and potential for combination with IL-4. _Clin Cancer Res._ 1997;3:1799–1806. CAS  PubMed  Google

Scholar  * Addison CL, Braciak T, Ralston R, et al. Intratumoral injection of an adenovirus expressing interleukin 2 induces regression and immunity in a murine breast cancer model. _Proc

Natl Acad Sci USA_. 1995;92:8522–8526. Article  CAS  PubMed  PubMed Central  Google Scholar  * Addison CL, Bramson JL, Hitt MM, et al. Intratumoral coinjection of adenoviral vectors

expressing IL-2 and IL-12 results in enhanced frequency of regression of injected and untreated distal tumors. _Gene Ther._ 1998;5:1400–1409. Article  CAS  PubMed  Google Scholar  * Cordier

L, Duffour MT, Sabourin JC, et al. Complete recovery of mice from a pre-established tumor by direct intratumoral delivery of an adenovirus vector harboring the murine IL-2 gene. _Gene Ther._

1995;2:16–21. CAS  PubMed  Google Scholar  * Huang H, Chen SH, Kosai K, et al. Gene therapy for hepatocellular carcinoma: long-term remission of primary and metastatic tumors in mice by

interleukin-2 gene therapy _in vitro_. _Gene Ther._ 1996;3:980–987. CAS  PubMed  Google Scholar  * Toloza EM, Hunt K, Swisher S, et al. _In vitro_ cancer gene therapy with a recombinant

interleukin-2 adenovirus vector. _Cancer Gene Ther._ 1996;3:11–17. CAS  PubMed  Google Scholar  * Saffran DC, Horton HM, Yankauckas MA, et al. Immunotherapy of established tumors in mice by

intratumoral injection of interleukin-2 plasmid DNA: induction of CD8+T-cell immunity. _Cancer Gene Ther._ 1998;5:321–330. CAS  PubMed  Google Scholar  * Slos P, De Meyer M, Leroy P, et al.

Immunotherapy of established tumors in mice by intratumoral injection of an adenovirus vector harboring the human IL-2 cDNA: induction of CD8(+) T-cell immunity and NK activity. _Cancer Gene

Ther._ 2001;8:321–332. Article  CAS  PubMed  Google Scholar  * Chartier C, Degryse E, Gantzer M, et al. Efficient generation of recombinant adenovirus vectors by homologous recombination in

Escherichia coli. _J Virol._ 1996;70:4805–4810. CAS  PubMed  PubMed Central  Google Scholar  * Chroboczek J, Bieber F, Jacrot B . The sequence of the genome of adenovirus type 5 and its

comparison with the genome of adenovirus type 2. _Virology_. 1992;186:280–285. Article  CAS  PubMed  Google Scholar  * Fallaux FJ, Bout A, van der Velde I, et al. New helper cells and

matched early region 1-deleted adenovirus vectors prevent generation of replication-competent adenoviruses. _Hum Gene Ther._ 1998;9:1909–1917. Article  CAS  PubMed  Google Scholar  * Lusky

M, Christ M, Rittner K, et al. _In vitro_ and _in vivo_ biology of recombinant adenovirus vectors with E1, E1/E2a, or E1/E4 deleted. _J Virol._ 1998;72:2022–2032. CAS  PubMed  PubMed Central

  Google Scholar  * Hillman GG, Maughan RL, Grignon DJ, et al. Neutron or photon irradiation for prostate tumors: enhancement of cytokine therapy in a metastatic tumor model. _Clin Cancer

Res._ 2001;7:136–144. CAS  PubMed  Google Scholar  * Zeng M, Cerniglia GJ, Eck SL, et al. High-efficiency stable gene transfer of adenovirus into mammalian cells using ionizing radiation.

_Hum Gene Ther._ 1997;8:1025–1032. Article  CAS  PubMed  Google Scholar  * Hillman GG, Maughan RL, Grignon DJ, et al. Responsiveness of experimental prostate carcinoma bone tumors to neutron

or photon radiation combined with cytokine therapy. _Int J Rad Onc Biol Phys._ 2003;56:1426–1437. Article  CAS  Google Scholar  * Bellone M, Iezzi G, Rovere P, et al. Processing of engulfed

apoptotic bodies yields T cell epitopes. _J Immunol._ 1997;159:5391–5399. CAS  PubMed  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Radiation Oncology, Barbara Ann Karmanos Cancer Institute at Wayne State University School of Medicine and Harper Hospital, Detroit, 48201, Michigan, USA Gilda G Hillman, Yu Wang, Jennifer L

Wright, Andrey Layer, Mark Yudelev & Jeffrey D Forman * Transgene SA, 11 Rue de Molsheim, Strasbourg, 67085, France Philippe Slos & Micael De Meyer * Department of Pathology,

Barbara Ann Karmanos Cancer Institute at Wayne State University School of Medicine and Harper Hospital, Detroit, 48201, Michigan, USA Mingxin Che Authors * Gilda G Hillman View author

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inPubMed Google Scholar * Jeffrey D Forman View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Gilda G Hillman.

ADDITIONAL INFORMATION _This work was supported by Transgene SA_ RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hillman, G., Slos, P., Wang, Y. _et al._

Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma. _Cancer Gene Ther_ 11, 61–72 (2004). https://doi.org/10.1038/sj.cgt.7700656 Download

citation * Received: 29 April 2003 * Published: 18 December 2003 * Issue Date: 01 January 2004 * DOI: https://doi.org/10.1038/sj.cgt.7700656 SHARE THIS ARTICLE Anyone you share the following

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SharedIt content-sharing initiative KEYWORDS * adenovirus * IL-2 * IFN-γ * radiation * renal carcinoma