- This study used a novel CRISPR screen to systematically identify potential pathways for resistance to chimeric antigen receptor (CAR) T-cell killing in solid tumors
- Loss of genes in the interferon-gamma signaling pathway resulted in resistance to CAR T-cell therapy in multiple glioblastoma cell lines and pancreatic, ovarian and lung cancer cell lines, but not in hematologic malignancies
- After exposure to CAR T cells, glioblastoma cells lacking interferon-gamma receptor 1 showed lower upregulation of adhesion molecule ICAM-1, and this deficit reduced the duration and avidity of CAR T-cell binding to glioblastoma cells
- These findings suggest the design of CAR T-cell therapy should vary with different tumor histologies and should optimize T cell–tumor cell adhesion
Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of leukemia, lymphoma, and multiple myeloma, but it has had limited success in glioblastoma and other solid tumors.
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Scientists at Massachusetts General Hospital speculated that in addition to the suppressive microenvironment of solid tumors, certain cell-intrinsic mechanisms might make solid tumor cells more resistant to CAR T-cell killing.
Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Mass General Cancer Center, Rebecca C. Larson, PhD, a graduate student in the Harvard Immunology Program, and colleagues recently reported affirmative results. In Nature, they explain that loss of genes in the interferon-gamma receptor signaling pathway (IFNGR1, JAK1 or JAK2) is a major resistance mechanism to CAR T-cell therapy.
A Novel CRISPR Screen
The researchers developed a genome-wide CRISPR knockout screen in glioblastoma. They applied selective pressure with a CAR to each cell in the screen, then sequenced the remaining alive cells to see which knockouts conferred resistance.
Loss of genes in the interferon-gamma signaling pathway resulted in resistance to CAR T-cell therapy in:
- Multiple glioblastoma cell lines, including several derived from patients
- In vivo mouse models with IFNyR1, JAK1, or JAK2 knocked out
- Pancreatic, ovarian, and lung cancer cell lines in vitro and in vivo
Conversely, the interferon-gamma pathway did not affect the sensitivity of leukemia, lymphoma, or multiple myeloma to CAR T-cell therapy.
Glioblastoma cells lacking interferon-gamma receptor 1 showed lower upregulation of the adhesion molecule ICAM-1 after exposure to CAR T-cells. That reduced the propensity of the T cells to bind to glioblastoma cells and the duration of binding.
A Potential New Therapeutic Approach
The differences between hematologic and solid tumors in susceptibility to CAR T-cells implies treatment design should vary for different tumor histologies. These findings also suggest CAR T-cell designs or drug combinations should optimize T cell–tumor cell adhesion.
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