Oncolytic therapy with recombinant vaccinia viruses targeting the interleukin-15 pathway elicits a synergistic response

Yasmin Shakiba; Pavel O Vorobyev; Gaukhar M Yusubalieva; Dmitry V Kochetkov; Ksenia V Zajtseva; Marat P Valikhov; Vladimir A Kalsin; Fedor G Zabozlaev; Alevtina S Semkina; Alexander V Troitskiy; Vladimir P Baklaushev; Peter M Chumakov; Anastasia V Lipatova

doi:10.1016/j.omto.2023.05.002

Oncolytic therapy with recombinant vaccinia viruses targeting the interleukin-15 pathway elicits a synergistic response

Mol Ther Oncolytics. 2023 May 13:29:158-168. doi: 10.1016/j.omto.2023.05.002. eCollection 2023 Jun 15.

Authors

Yasmin Shakiba^{1

2}, Pavel O Vorobyev¹, Gaukhar M Yusubalieva^{1

3

4}, Dmitry V Kochetkov¹, Ksenia V Zajtseva¹, Marat P Valikhov^{5

6}, Vladimir A Kalsin^{1

3}, Fedor G Zabozlaev³, Alevtina S Semkina^{5

6}, Alexander V Troitskiy³, Vladimir P Baklaushev^{1

3

4}, Peter M Chumakov¹, Anastasia V Lipatova¹

Affiliations

¹ Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
² Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia.
³ Federal Research and Clinical Center for Specialized Types of Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russian Federation.
⁴ Federal Center of Brain Research and Neurotechnologies, FMBA of Russia, 117513 Moscow, Russian Federation.
⁵ Department of Neurobiology, Serbsky Federal Medical Research Centre of Psychiatry and Narcology of the Ministry of Health of the Russian Federation, 119034 Moscow, Russia.
⁶ Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University 117997 Moscow, Russia.

Abstract

We developed recombinant variants of oncolytic vaccinia virus LIVP strain expressing interleukin-15 (IL-15) or its receptor subunit alpha (IL-15Rα) to stimulate IL-15-dependent immune cells. We evaluated their oncolytic activity either alone or in combination with each other in vitro and in vivo using the murine CT26 colon carcinoma and 4T1 breast carcinoma models. We demonstrated that the admixture of these recombinant variants could promote the generation of the IL-15/IL-15Rα complex. In vitro studies indicated that 4T1 breast cancer cells were more susceptible to the developed recombinant viruses. In vivo studies showed significant survival benefits and tumor regression in 4T1 breast cancer syngeneic mice that received a combination of LIVP-IL15-RFP with LIVP-IL15Ra-RFP. Histological analysis showed recruited lymphocytes at the tumor region, while no harmful effects to the liver or spleen of the animals were detected. Evaluating tumor-infiltrated lymphocytes represented profound activation of cytotoxic T cells and macrophages in mice receiving combination therapy. Thus, our experiments showed superior oncolytic effectiveness of simultaneous injection of LIVP-IL15-RFP and LIVP-IL15Ra-RFP in breast cancer-bearing mice. The combined therapy by these recombinant variants represents a potent and versatile approach for developing new immunotherapies for breast cancer.

Keywords: IL-15/IL-15Rα complex; LIVP; breast adenocarcinoma; colon carcinoma; interleukin-15; interleukin-15 receptor alpha; oncolytic virus; vaccinia virus.