Genetically modified IL-2 bone marrow-derived myeloid cells reprogram the glioma immunosuppressive tumormicroenvironment

Canella, A.; Nazzaro, M.; Rajendran, S.; Schmitt, C.; Haffey, A.; Nigita, G.; Thomas, D.; Wrightnour, H.; Fadda, P.; Mardis, E. R.; Cripe, T. P.; Rajappa, P.

doi:10.1101/2022.10.19.511786

bioRxiv · 10.1101/2022.10.19.511786

Genetically modified IL-2 bone marrow-derived myeloid cells reprogram the glioma immunosuppressive tumormicroenvironment

Canella, A.·Nazzaro, M.·Rajendran, S.·Schmitt, C.·Haffey, A.·Nigita, G.·Thomas, D.·Wrightnour, H.·Fadda, P.·Mardis, E. R.·Cripe, T. P.·Rajappa, P.

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Abstract

Gliomas are the most prevalent type of brain tumors and one of the leading causes of cancer-related death in the adolescent and young adult population (AYA). Two-thirds of glioma AYA patients are affected by low-grade gliomas (LGGs), but there are no specific treatments. Therefore, a percentage of LGG patients experience tumor relapse and malignant progression to high-grade glioma which leads to fatal outcomes. In part, malignant progression is potentiated by the immunosuppressive stromal component of the tumor microenvironment (TME) underscored by M2-macrophages and a paucity of cytotoxic T cells. As a result, first-line immunotherapies have failed to improve outcomes for patients with progressive high-grade gliomas. Here, we report the efficacy of an in vivo approach that demonstrates the potential for a novel cell-mediated innate immunotherapy designed to abrogate immunosuppressive mechanisms within the glioma TME and enhance the recruitment of activated effector T cells. A single dose of engineered bone marrow-derived myeloid cells that release Interleukin-2 (GEMys-IL2) was used systemically to treat mice with LGG tumors systemically. Our results demonstrate that GEMys-IL2 efficiently crossed the blood brain barrier (BBB), infiltrated the glioma microenvironment, and reprogrammed the infiltrating immune cell composition and transcriptome. In addition, GEMys-IL2 impaired tumor progression and extended survival in a LGG immunocompetent mouse model. In conclusion, we demonstrated that GEMys-IL2 have a therapeutic effect in vivo, thus supporting its potential application as a novel immunotherapy that warrants further investigation.

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Canella, A., Nazzaro, M., Rajendran, S., Schmitt, C., Haffey, A., Nigita, G., Thomas, D., Wrightnour, H., Fadda, P., Mardis, E. R., Cripe, T. P., Rajappa, P.. 2022-10-21. Genetically modified IL-2 bone marrow-derived myeloid cells reprogram the glioma immunosuppressive tumormicroenvironment. https://doi.org/10.1101/2022.10.19.511786

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