Project description:The clinical success of chimeric antigen receptor (CAR) T-cell therapy for CD19+ B-cell malignancies may come at the expense of acute and chronic morbidities. Some patients suffer from significant, acute toxicities and those with persistent CAR T-cells require immunoglobulin therapy due to CAR-induced B-cell aplasia. Life-threatening effects include cytokine release syndrome, the exact etiology of which is unclear. To elucidate the underlying mechanisms of CAR-induced toxicities, we developed a mouse model in which human CD19 (hCD19)-specific mouse CAR T-cells were adoptively transferred into mice whose normal B-cells express a hCD19 transgene at hemizygous levels. In contrast to homozygous mice, hemizygous mice have higher B cell frequencies, providing a greater target antigen load to drive CAR-T cell activation. Hemizygous mice given a lethal dose of hCD19 transgene-expressing lymphoma cells and treated with CAR-T cells had undetectable levels of tumor. However, recipients experienced acute B-cell aplasia, morbidities and mortality in an antigen- and dose-dependent manner. IL-6, INF-g, and inflammatory pathway transcripts were enriched in affected tissues. As in patients, antibody-mediated neutralization of IL-6 blunted toxicity. This new model will prove useful in testing strategies designed to improve CD19-specific CAR T-cell therapy by reducing acute toxicities and reversing B-cell aplasia.
Project description:The clinical success of chimeric antigen receptor (CAR) T-cell therapy for CD19+ B-cell malignancies may come at the expense of acute and chronic morbidities. Some patients suffer from significant, acute toxicities and those with persistent CAR T-cells require immunoglobulin therapy due to CAR-induced B-cell aplasia. Life-threatening effects include cytokine release syndrome, the exact etiology of which is unclear. To elucidate the underlying mechanisms of CAR-induced toxicities, we developed a mouse model in which human CD19 (hCD19)-specific mouse CAR T-cells were adoptively transferred into mice whose normal B-cells express a hCD19 transgene at hemizygous levels. In contrast to homozygous mice, hemizygous mice have higher B cell frequencies, providing a greater target antigen load to drive CAR-T cell activation. Hemizygous mice given a lethal dose of hCD19 transgene-expressing lymphoma cells and treated with CAR-T cells had undetectable levels of tumor. However, recipients experienced acute B-cell aplasia, morbidities and mortality in an antigen- and dose-dependent manner. IL-6, INF-g, and inflammatory pathway transcripts were enriched in affected tissues. As in patients, antibody-mediated neutralization of IL-6 blunted toxicity. This new model will prove useful in testing strategies designed to improve CD19-specific CAR T-cell therapy by reducing acute toxicities and reversing B-cell aplasia.
