Methods for treatment of cancers harboring an H3K27M mutation
Inventors
Monje-Deisseroth, Michelle • Majzner, Robbie • MacKall, Crystal • Mount, Christopher
Assignees
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Publication Number
US-12582675-B2
Publication Date
2026-03-24
Expiration Date
Abstract
The invention relates to immunotherapeutic treatment of cancer. In particular, the invention relates to methods of treating cancer carrying a histone H3 K27M (H3K27M) mutation (e.g., diffuse midline glioma with H3K27M mutation) using immunotherapeutic compositions comprising immune cells engineered to express GD2-specific chimeric antigen receptors.
Core Innovation
The invention provides an immunotherapeutic approach for cancers characterized by histone H3 K27M (H3K27M). It identifies ganglioside GD2 as broadly and highly overexpressed on H3K27M mutant gliomas relative to H3 WT high-grade gliomas, linking increased GD2 to upregulated ganglioside synthesis pathway genes. Based on this association, it uses immune cells genetically modified to express a GD2-specific chimeric antigen receptor (CAR) for treating such cancers, including diffuse midline glioma and diffuse intrinsic pontine glioma.
In the described approach, the GD2-specific CAR-expressing immune cells are used to achieve GD2-dependent killing and immune activation. The partial disclosure reports CAR-mediated GD2-dependent in vitro killing and cytokine generation, with reported immune markers including IFN-gamma and other measures of cell death and activation. The CAR is described using representative antigen-binding and signaling architectures, including a GD2-binding scFv and CAR structural components.
The disclosure further reports in vivo patient-derived orthotopic xenograft evidence for tumor clearance and survival benefit using GD2-CAR T cells in H3K27M settings. It describes potent tumor clearance, including clearance to background signal after a single IV dose, and includes observation of neuroinflammation/hydrocephalus-related toxicity in certain models. It also notes possible mitigation approaches centered on monitoring and/or combination with radiation or anticancer agents.
Claims Coverage
The partial claims provide coverage for two independent methods: (1) in vitro killing of cancer cells using GD2-specific CAR-expressing immune cells when the cancer cells have an H3K27M mutation, and (2) a patient-sample workflow that determines H3K27M and then contacts the cancer cells with GD2-specific CAR-expressing immune cells. The inventive features include H3K27M-defined cancer selection, GD2-specific CAR-expressing immune cells, and specific constraints on CAR components and outcomes such as killing and cytokine generation.
H3K27M-defined GD2 CAR-mediated in vitro killing
A method of killing cancer cells in vitro comprising contacting the cancer cells with an effective amount of immune cells genetically modified to express a chimeric antigen receptor (CAR) specific for ganglioside GD2 (GD2), wherein the cancer cells have a histone H3 K27M (H3K27M) mutation.
Patient sample H3K27M determination followed by GD2 CAR contacting
A method comprising obtaining a biological sample comprising cancer cells from a patient; determining presence of an H3K27M mutation within the cancer cells; and contacting the cancer cells with immune cells genetically modified to express a chimeric antigen receptor (CAR) specific for ganglioside GD2 (GD2).
Across the independent claims, the central inventive theme is selecting or validating cancers with an H3K27M mutation and contacting them with immune cells expressing a GD2-specific CAR to achieve the claimed contacting outcome. Dependent claim refinements in the partial set specify GD2-binding epitope/scFv details (including 14G2a), CAR domain and co-stimulatory selections, and contacting outcomes including killing and cytokine generation.
Stated Advantages
Potent tumor clearance, including clearance to background signal after a single IV dose, in patient-derived orthotopic xenograft models.
Survival benefit for GD2-CAR T cells in the described in vivo models.
CAR-mediated GD2-dependent in vitro killing and cytokine generation (including IFN-gamma).
Documented Applications
Immunotherapeutic treatment of cancers with histone H3 K27M (H3K27M), particularly diffuse intrinsic pontine glioma (DIPG) / diffuse midline glioma (DMG), using GD2-specific CAR-expressing immune cells.
In vitro killing of cancer cells by contacting GD2-specific CAR-expressing immune cells with cancer cells carrying an H3K27M mutation.
Patient sample workflow including obtaining a biological sample, determining H3K27M mutation presence, and contacting cancer cells with GD2-specific CAR-expressing immune cells.
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