Chimeric antigen receptor (CAR) T-cells have recently shown remarkable success in the treatment of hematologic cancers. There have been attempts made to explore CAR T cells against diffuse intrinsic pontine glioma (DIPG) or diffuse midline glioma (DMG), one of the most common and deadliest primary brain cancer in pediatric population where no effective treatment is available. However, CAR T cells for gliomas face challenges including intratumoral heterogeneity, dynamic expression of target receptors, and the inability of T cells to traffic to tumors to mediate desired antitumor effects. In contrast to the lack of T cells, many solid tumors, especially gliomas, are abundant in immune-suppress...

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Chimeric antigen receptor (CAR) T-cells have recently shown remarkable success in the treatment of hematologic cancers. There have been attempts made to explore CAR T cells against diffuse intrinsic pontine glioma (DIPG) or diffuse midline glioma (DMG), one of the most common and deadliest primary brain cancer in pediatric population where no effective treatment is available. However, CAR T cells for gliomas face challenges including intratumoral heterogeneity, dynamic expression of target receptors, and the inability of T cells to traffic to tumors to mediate desired antitumor effects. In contrast to the lack of T cells, many solid tumors, especially gliomas, are abundant in immune-suppressive myeloid cells such as macrophages. Therefore, converting these immune suppressive cells into tumoricidal phenotype represents a promising strategy for cell-based therapy and potentially could overcome many of the limitations of CAR T cells. Here, we propose an innovative strategy to produce CAR macrophages in vivo as a new cell therapy against DMG. This will be the first study to evaluate the feasibility of producing CAR macrophages in vivo using an mRNA platform and to assess the antitumor efficacy of CAR macrophages for DMG immunotherapy. We will test the effectiveness of in vivo generated CAR macrophages targeting disialoganglioside GD2, a receptor that is universally enriched on the tumor surface of DMG. If successful, our proposed research will overcome a major technical hurdle that has limited cell therapy and potentially revolutionize its treatment for high-grade gliomas and other cancers. Furthermore, it would pave the way for increased adoption of mRNA therapeutics for treating cancer and other human diseases.

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