Efficacy-enhanced anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study
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ABSTRACT:
PROVIDER: PRJNA791547 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17307204_1.fastq.gz | Fastqsanger.gz | |||
| SRR17307204_2.fastq.gz | Fastqsanger.gz | |||
| SRR17307205_1.fastq.gz | Fastqsanger.gz | |||
| SRR17307205_2.fastq.gz | Fastqsanger.gz | |||
| SRR17307206_1.fastq.gz | Fastqsanger.gz |
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Project description:Chimeric antigen receptor-T (CAR-T) therapy remains to be investigated in T-cell malignancies. CD7 is an ideal target for T-cell malignancies but is also expressed on normal T cells, which may cause CAR-T cell fratricide. Donor-derived anti-CD7 CAR-T cells using endoplasmic reticulum retention have shown efficacy in patients with T-cell acute lymphoblastic leukemia (ALL). Here we launched a phase I trial to explore differences between autologous and allogeneic anti-CD7 CAR-T therapies in T-cell ALL and lymphoma. Ten patients were treated and 5 received autologous CAR-T therapies. No dose-limiting toxicity or neurotoxicity was observed. Grade 1-2 cytokine release syndrome occurred in 7 patients, and grade 3 in 1 patient. Grade 1-2 graft-versus-host diseases were observed in 2 patients. Seven patients had bone marrow infiltration, and 100% of them achieved complete remission with negative minimal residual disease within one month. Two-fifths of patients achieved extramedullary or extranodular remission. The median follow-up was 6 (range, 2.7- 14) months and bridging transplantation was not administrated. Patients treated with allogeneic CAR-T cells had higher remission rate, less recurrence and more durable CAR-T survival than those receiving autologous products. Allogeneic CAR-T cells appeared to be a better option for patients with T-cell malignancies.
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Project description:Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T-cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. In this study, we performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlation between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers. Microarray gene expression analysis was performed on hematological malignancies of different origins and their healthy hematopoietic counterparts as well as on healthy non-hematopoietic cell types from organs that are often targeted in Graft-versus-Host Disease (166 samples in total). Various non-hematopoietic cell types were cultured in the presence of IFN-γ or T-cell culture supernatant to allow gene expression analysis under inflammatory conditions. Malignant and healthy hematopoietic cells were isolated by flow cytometry based on expression of specific surface markers and healthy non-hematopoietic cell types were isolated or cultured from tissue biopsies or surgically removed specimen. Various non-hematopoietic cell types were in vitro cultured for 4 days in the presence of IFN-γ or T-cell culture supernatant to mimic inflammation. The dataset allows comparison of gene expression between hematological malignancies and healthy non-hematopoietic cell types to estimate efficacy and toxicity of immunotherapeutic targets for hematological malignancies. Total RNA was isolated from (malignant) hematopoietic cells isolated by flow cytometry based on expression of specific surface markers and from healthy non-hematopoietic cell types isolated or cultured from tissue biopsies or surgically removed specimen. From various non-hematopoietic cell types, total RNA was also isolated after 4 days of in vitro culture in the presence of IFN-γ or T-cell culture supernatant.
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