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Enhanced Interferon Signaling May Improve CAR T-cell Immunotherapy for Solid Tumors

Key findings

  • 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.

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.

Transcriptional Profiling

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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David M. Langenau, PhD, Marcela V. Maus, MD, PhD, and colleagues created a new line of transparent zebrafish that allow single-cell imaging of tumor cell killing during immunotherapy with CAR T-cells, bispecific T-cell engagers and antibody–peptide epitope conjugates in a wide range of cancers.