TY - JOUR

T1 - Development of experimental mouse xenograft models of human tumors for preclinical in vivo studies of product for cellular immunotherapy

AU - Lopatnikova, Julia A.

AU - Shevchenko, Julia A.

AU - Filippova, Julia G.

AU - Fisher, Marina S.

AU - Obleukhova, Irina A.

AU - Zavjalov, Evgenii L.

AU - Solovjeva, Olga I.

AU - Razumov, Ivan A.

AU - Akahori, Yasushi

AU - Shiku, Hiroshi

AU - Sennikov, Sergey V.

N1 - The present study was supported by the Russian Science Foundation grant no. 21-65-00004, URL: https:// rscf.ru/project/21-65-00004/. Публикация для корректировки.

PY - 2023

Y1 - 2023

N2 - Introduction. In connection with the active development of new directions in cellular immunotherapy, the question of approaches for conducting preclinical studies on safety and efficacy is acute. The most optimal for solving this problem is the use of tumor xenografts to simulate tumor growth in the body while maintaining homeostasis, metabolism and possible mechanisms of tolerance to a therapeutic agent. The effectiveness of this approach to the analysis of the effectiveness of cell preparations led to the need to standardize methodological approaches to the selection of human tumor cell lines and lines of immunodeficient mice. The purpose of the study was to evaluate the effectiveness of xenograft formation in two strains of immunodeficient mice in order to obtain optimal models for preclinical studies of preparations of modified human cells. Material and methods. To test the models we used mice of the NRG (NOD.Cg-Rag1tm1Mom Il2rgtm1Wjl/SzJ) and SCID lines and human tumor cell lines SW620 (human colon adenocarcinoma), U-87MG (human epithelial brain tumor), SK-MEL-37 (melanoma), NW-MEL-38 (melanoma) and S6 (melanoma). Experimental animals were injected subcutaneously into the region of the right shoulder blade with 100 μl of tumor cell suspension at doses of 1, 3 and 5 mln/mouse, followed by measurement of the size of the tumor node. Results. The effectiveness of the formation of xenografts of various human cell lines in mice with immunodeficiency was evaluated. It has been shown that the NRG mice, compared to the SCID mice, has a higher ability to engraft tumor cell lines. And the cell lines themselves differ in the levels of expression of tumor-associated proteins and form a xenograft with different efficiency. The most optimal was the use of NRG mice and the SK-MEL-37 cell line, with a high level of expression of the GD2, NY-ESO-1 and MAGE-A4 antigens. An experiment on the treatment of solid tumors obtained after transplantation of human tumor cell lines into animals using anti-GD2-CAR-T cells showed effectiveness in reducing the size of the tumor node with intratumoral administration of modified human cells. Conclusion. The results obtained confirm the efficiency of using xenografts in evaluating the effectiveness of the antitumor immune response of modified cell preparations in vivo.

AB - Introduction. In connection with the active development of new directions in cellular immunotherapy, the question of approaches for conducting preclinical studies on safety and efficacy is acute. The most optimal for solving this problem is the use of tumor xenografts to simulate tumor growth in the body while maintaining homeostasis, metabolism and possible mechanisms of tolerance to a therapeutic agent. The effectiveness of this approach to the analysis of the effectiveness of cell preparations led to the need to standardize methodological approaches to the selection of human tumor cell lines and lines of immunodeficient mice. The purpose of the study was to evaluate the effectiveness of xenograft formation in two strains of immunodeficient mice in order to obtain optimal models for preclinical studies of preparations of modified human cells. Material and methods. To test the models we used mice of the NRG (NOD.Cg-Rag1tm1Mom Il2rgtm1Wjl/SzJ) and SCID lines and human tumor cell lines SW620 (human colon adenocarcinoma), U-87MG (human epithelial brain tumor), SK-MEL-37 (melanoma), NW-MEL-38 (melanoma) and S6 (melanoma). Experimental animals were injected subcutaneously into the region of the right shoulder blade with 100 μl of tumor cell suspension at doses of 1, 3 and 5 mln/mouse, followed by measurement of the size of the tumor node. Results. The effectiveness of the formation of xenografts of various human cell lines in mice with immunodeficiency was evaluated. It has been shown that the NRG mice, compared to the SCID mice, has a higher ability to engraft tumor cell lines. And the cell lines themselves differ in the levels of expression of tumor-associated proteins and form a xenograft with different efficiency. The most optimal was the use of NRG mice and the SK-MEL-37 cell line, with a high level of expression of the GD2, NY-ESO-1 and MAGE-A4 antigens. An experiment on the treatment of solid tumors obtained after transplantation of human tumor cell lines into animals using anti-GD2-CAR-T cells showed effectiveness in reducing the size of the tumor node with intratumoral administration of modified human cells. Conclusion. The results obtained confirm the efficiency of using xenografts in evaluating the effectiveness of the antitumor immune response of modified cell preparations in vivo.

KW - genetically modified T-lymphocytes

KW - lines of immunodeficient mice

KW - tumor

KW - tumor cell lines

KW - tumor xenografts

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85180562223&origin=inward&txGid=ec32ddf9f3b19ad080542b850da28b15

UR - https://www.mendeley.com/catalogue/2b6713a2-ae6a-3bfb-8574-5e8dc3dfc5d2/

U2 - 10.33029/0206-4952-2023-44-6-709-720

DO - 10.33029/0206-4952-2023-44-6-709-720

M3 - Article

VL - 44

SP - 709

EP - 720

JO - Immunologiya

JF - Immunologiya

SN - 0206-4952

IS - 6

ER -