IL-12-armed oncolytic HSV-2 enhances CAR T cell efficacy against pancreatic cancer in xenografted models.
Chimeric antigen receptor (CAR) T cells show limited efficacy in solid tumors. Oncolytic viruses (OVs), especially those expressing immunomodulatory cytokines like interleukin-12 (IL-12), potentiate to synergize with CAR-T therapy.
We integrated an IL-12-expressing oncolytic herpes simplex virus type 2 (oHSV-2-IL-12) with mesothelin-targeting SS1-ICOSBBZ-CAR-T to treat Capan-2 pancreatic cancer cells xenografts in B-NDG immunodeficient mice.
SS1-ICOSBBZ-CAR-T alone exhibited partial anti-tumor activity, but could not eradicate established tumors. Intra-tumoral oHSV-2-IL-12 administration potently enhanced CAR-T efficacy, achieving complete and durable tumor elimination even at reduced CAR-T doses. After the initial tumors were fully eliminated by combination therapy, mice were re-challenged by inoculating mesothelin-negative and mesothelin-positive tumor cell lines on the left and right flanks, respectively. In the combination treatment group, mesothelin-positive tumors failed to form new tumors within two weeks after re-challenge, whereas mesothelin-negative tumors grew normally. These findings indicate that oHSV-2-IL-12 combined with CAR-T therapy confers durable, antigen-specific protection against tumor re-challenge. Mechanistically, oHSV-2-IL-12 promoted CAR-T proliferation and persistence in peripheral blood and spleen. IL-12 expression also augmented the direct oncolytic effect of oHSV-2 in immunodeficient hosts.
This synergistic approach achieves durable potent tumor clearance with reduced CAR-T doses, offering a transformative strategy against pancreatic cancer and other challenging solid malignancies.
We integrated an IL-12-expressing oncolytic herpes simplex virus type 2 (oHSV-2-IL-12) with mesothelin-targeting SS1-ICOSBBZ-CAR-T to treat Capan-2 pancreatic cancer cells xenografts in B-NDG immunodeficient mice.
SS1-ICOSBBZ-CAR-T alone exhibited partial anti-tumor activity, but could not eradicate established tumors. Intra-tumoral oHSV-2-IL-12 administration potently enhanced CAR-T efficacy, achieving complete and durable tumor elimination even at reduced CAR-T doses. After the initial tumors were fully eliminated by combination therapy, mice were re-challenged by inoculating mesothelin-negative and mesothelin-positive tumor cell lines on the left and right flanks, respectively. In the combination treatment group, mesothelin-positive tumors failed to form new tumors within two weeks after re-challenge, whereas mesothelin-negative tumors grew normally. These findings indicate that oHSV-2-IL-12 combined with CAR-T therapy confers durable, antigen-specific protection against tumor re-challenge. Mechanistically, oHSV-2-IL-12 promoted CAR-T proliferation and persistence in peripheral blood and spleen. IL-12 expression also augmented the direct oncolytic effect of oHSV-2 in immunodeficient hosts.
This synergistic approach achieves durable potent tumor clearance with reduced CAR-T doses, offering a transformative strategy against pancreatic cancer and other challenging solid malignancies.
Authors
Xu Xu, Wu Wu, Liu Liu, Zhou Zhou, Liang Liang, Li Li, Wang Wang, Liu Liu, Cai Cai, Tang Tang, Tu Tu, Hu Hu, Liu Liu, Meng Meng
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