The Tumor Microenvironment and Inflammation Influence toxicity in patients with Large B Cell Lymphoma Treated with Axicabtagene Ciloleucel [RNA-Seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE153437 | GEO | 2020/07/27
REPOSITORIES: GEO
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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.
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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.
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Project description:2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that produces myriad toxicities across various experimental models. In rodents alone, there is huge divergence in the toxicological response across species, between strains within a species and even between sexes within a strain. This difference in sensitivities between sexes has been characterized in multiple rodent models, however with contrasting results: the severity of toxicity is greater in female rats than in males while male mice and guinea pigs are more sensitive to the effects of TCDD than females. While the presence of estrogens or androgens has a known impact on response, the specific transcriptional events that cause this difference remain unclear. We sought to characterize the transcriptional environment of male and female C57BL/6 mice treated with 500 M-NM-<g/kg TCDD and followed across a time-course. This dose was chosen as it is greater than the LD50 for male mice yet produces minimal effects in females. Additionally, evaluation along a time-course allows for the detection of specific changes that occur throughout the development of phenotypic toxicities. The transcriptional profile across the time-course was highly divergent between the sexes. Female TCDD-treated mice demonstrated a large number of altered transcripts as early as 6 hours following treatment, suggesting a large primary response, possibly indicative of the activation of numerous defense mechanisms. Conversely, male animals showed the greatest TCDD-mediated response 144 hours following exposure, potentially implicating significant secondary responses for the increased appearance of TCDD toxicities. Nr1i3 is statistically significantly altered at all time-points in the sensitive male animals. This mRNA encodes a transcription factor (constitutive androstane receptor; CAR) involved in the regulation of xenobiotic metabolism, as well as lipid metabolism, cell cycle and apoptosis. In particular, increased levels of CAR may result in induction of the anti-apoptotic gene Gadd45b and carboxylesterase Ces1d, both of which we identify as transcriptionally altered and may be responsible for phenotypic hepatic abnormalities, such as steatohepatitis and tumor formation. Further evaluation across studies of mice and rats into the role of Nr1i3 and associated genes are crucial to enhance our understanding of various TCDD-induced toxicities. Adult male and female C57BL/6 mice were treated by gavage with either 500 ug/kg TCDD in corn oil or corn oil vehicle alone. Animals were euthanized at either 6, 24, 72 or 144 hours after treatment and tissues were harvested. RNA was isolated from hepatic tissue and the transcriptome for each animal assayed on an individual microarray. Please note that 7 samples (out of total 65 samples) were identified as outliers and therefore the data were processed without the outliers as well. The normalized data without outliers were provided in the 'normalized_data_without_outliers.txt' file.
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