GC-04. Development of the in vivo model of therapy for prostate cancer and assessment of antitumor activity of oncolytic viruses combined with CAR T-cell immunotherapy
Anton N. Chikaev1, Sergey V. Kulemzin1, Olga Yu. Volkova1, Tatyana N. Belovezhets1, Anastasiya V. Semenova2, Sergey S. Zainutdinov2, Antonina A. Grazhdantseva2, Galina V. Kochneva2
1 Institute of Molecular and Cellular Biology SB RAS, Novosibirsk, Russia
2 State Research Center of Virology and Biotechnology “Vector”, Novosibirsk, Russia
Dr. Anton N. Chikaev, phone: +7 (913) 938-52-93, e-mail: email@example.com
Despite common views that the early-stage prostate cancer is usually well treatable with surgery and hormonal therapy, the disorder remains risky, due to a tendency to develop into the chemo- and castration-resistant metastatic forms. Thus, development and testing of effective therapy for prostate cancer are urgent tasks of modern oncology. Hence, we proposed a combination therapy for prostate cancer based on the two powerful anticancer platforms: CAR-T and oncolytic virotherapy. The first component is T cells expressing chimeric antigen receptor which specifically directed towards the main prostate cancer antigen PSMA (aPSMA-CAR-T). Together with aPSMA-CAR-T, it is proposed to use a recombinant vaccinia virus strain L-IVP (VV-GMCSF-CXCL11) which have been modified to express GM-CSF and CXCL11 cytokines. This should result in efficient lysis of PC3/PSMA prostate cancer cells, as well as boost the tumor homing activity and cytotoxicity of the host immune cells and adoptively transferred aPSMA-CAR-T. This project aims to develop an in vivo model of therapy for prostate cancer and to explore the antitumor potential of aPSMA-CAR-T and VV-GMCSF-CXCL11 platforms separately or in combination.
Materials and methods
We used NOD/Scid mice for human prostate cancer xenograft model. The mice were subcutaneously injected with 2*10^6 PSMA-expressing PC3 cells (PSMA-PC3) and divided into 5 groups. At the 16th day after tumor administration mice from the 1st group received intratumoral injections of VV-GMCSF-CXCL11 at a dose of 10^7 PFU/mouse. Each mouse from the 2nd group was intravenously treated with 2*10^7 human aPSMA-CAR-T cells at the 18th and 23rd day after PSMA-PC3 engraftment. Third group received both virus and CAR-T: mice were intratumorally treated with 10^7 PFU/mouse of VV-GMCSF-CXCL11 at the day 16 followed by the two intravenous injections of 2*10^7 aPSMA-CAR-T at the 18th and 23rd days. Negative control groups were intratumorally injected with saline or intravenously treated with untransduced human T-cells.
We have shown that the single dose of oncolytic VV-GMCSF-CXCL11 virus inhibit tumor growth up to 90% at the 15th day after treatment, whereas mice that received aPSMA CAR-T only or virus with aPSMA CAR-T didn’t control tumors. The probable reason was insufficient immunodeficiency of NOD/Scid mice, since even at the 7th day after second injection no human CAR-T cells were already presented in mice blood. Such rapid elimination of CAR-T may be due to the “host versus graft” reaction. Thus, we repeated the experiments using more immunocompromised NSG mouse model. We showed that CAR-T cells were able to persist and proliferate in NSG mice and, in contrast to NOD/Scid model, the highest antitumor activity was observed in aPSMA-CAR-T only group. However, mice that received combined therapy or virus only were not able to control tumors, which may be due to the spread of viral infection over the bodies of severely immunodeficient NSG mice. High concentration of viral particles in the blood of animals was confirmed by qPCR. The NSG model could be optimized by lowering the dose of VV-GMCSF-CXCL11.
Overall, it seems that both NOD/Scid and NSG-based mice models are not optimal translational models of combination therapy for prostate cancer. Apparently, it is necessary to use an immunocompetent mouse model with syngeneically transplanted PSMA+ tumors, as well as mouse CAR-T cells as a therapy.
This work was supported by the RFBR grant mk18-29-09044.
Oncolytic virus, CAR-T, prostate cancer, PSMA.