Curated Papers > High-impact authoritative literature on "CAR-T therapy"

CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients.

Literature Information

PMID	27111235
Journal	The Journal of clinical investigation
Impact Factor	13.6
JCR Quartile	Q1
Publication Year	2016
Times Cited	1162
Keywords	CD19 CAR-T cells, acute lymphoblastic leukemia, cytotoxicity, immunotherapy, biomarkers
Literature Type	Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
ISSN	0021-9738
Pages	2123-38
Issue	126(6)
Authors	Cameron J Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Theodore A Gooley, Sindhu Cherian, Michael Hudecek, Daniel Sommermeyer, Katherine Melville, Barbara Pender, Tanya M Budiarto, Emily Robinson, Natalia N Steevens, Colette Chaney, Lorinda Soma, Xueyan Chen, Cecilia Yeung, Brent Wood, Daniel Li, Jianhong Cao, Shelly Heimfeld, Michael C Jensen, Stanley R Riddell, David G Maloney

TL;DR

This study evaluated CD19-specific CAR-T cells manufactured from defined CD4+ and CD8+ T cell subsets in adults with B cell acute lymphoblastic leukemia, achieving a high remission rate of 93%. The findings revealed factors influencing CAR-T cell toxicity and efficacy, such as the importance of CAR-T cell dosing and lymphodepletion strategies, which can enhance patient safety and improve disease-free survival.

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CD19 CAR-T cells · acute lymphoblastic leukemia · cytotoxicity · immunotherapy · biomarkers

Abstract

BACKGROUND T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR-T cell products were prepared from unselected T cells.

METHODS We conducted a clinical trial to evaluate CD19 CAR-T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy.

RESULTS The defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission, as determined by flow cytometry. We established that high CAR-T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity. Moreover, we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. Risk-stratified CAR-T cell dosing based on BM disease burden decreased toxicity. CD8+ T cell-mediated anti-CAR transgene product immune responses developed after CAR-T cell infusion in some patients, limited CAR-T cell persistence, and increased relapse risk. Addition of fludarabine to the lymphodepletion regimen improved CAR-T cell persistence and disease-free survival.

CONCLUSION Immunotherapy with a CAR-T cell product of defined composition enabled identification of factors that correlated with CAR-T cell expansion, persistence, and toxicity and facilitated design of lymphodepletion and CAR-T cell dosing strategies that mitigated toxicity and improved disease-free survival.

TRIAL REGISTRATION ClinicalTrials.gov NCT01865617.

FUNDING R01-CA136551; Life Science Development Fund; Juno Therapeutics; Bezos Family Foundation.

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Primary Questions Addressed

1. What are the specific mechanisms by which the defined CD4+:CD8+ composition of CAR-T cells enhances therapeutic efficacy in adult B cell ALL patients?
2. How does the presence of serum biomarkers correlate with the risk of severe cytokine release syndrome and neurotoxicity in CAR-T cell therapy?
3. In what ways can the findings regarding CD8+ T cell-mediated immune responses inform future CAR-T cell product designs to improve patient outcomes?
4. What additional strategies could be explored to further mitigate the toxicity associated with high CAR-T cell doses in patients with varying tumor burdens?
5. How might the incorporation of fludarabine into lymphodepletion regimens affect the long-term persistence of CAR-T cells and overall patient survival rates?

Key Findings

Background and Objective

Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating B cell malignancies, particularly in the context of CD19-specific CAR-T cells. However, previous studies faced challenges in identifying the factors influencing the efficacy and toxicity of these T cells due to the phenotypic heterogeneity of the CAR-T cell products derived from unselected T cells. This study aimed to evaluate the safety and efficacy of CD19 CAR-T cells manufactured from well-defined CD4+ and CD8+ T cell subsets, administered in a specific composition to patients with B cell acute lymphoblastic leukemia (ALL) following lymphodepletion chemotherapy.

Main Methods/Materials/Experimental Design

The clinical trial involved the following key steps:

1. Patient Selection: Adults diagnosed with B cell acute lymphoblastic leukemia were selected.
2. Lymphodepletion: Patients underwent a lymphodepletion regimen prior to CAR-T cell infusion.
3. CAR-T Cell Manufacturing: CD19 CAR-T cells were produced from defined CD4+ and CD8+ T cell subsets, ensuring a controlled CD4+:CD8+ ratio.
4. Infusion and Monitoring: Patients received the CAR-T cell product, followed by close monitoring for response and adverse events.

The experimental design can be visualized as follows:

Key Results and Findings

• Efficacy: 93% of patients (27 out of 29) achieved bone marrow remission, as confirmed by flow cytometry.
• Toxicity: High doses of CAR-T cells and tumor burden were associated with increased risks of severe cytokine release syndrome (CRS) and neurotoxicity.
• Biomarkers: Serum biomarkers were identified that could help stratify patients for early intervention strategies.
• Risk-Adjusted Dosing: Implementing risk-stratified CAR-T cell dosing based on bone marrow disease burden successfully reduced toxicity.
• Immune Response: Some patients developed CD8+ T cell-mediated immune responses against the CAR transgene product, which correlated with limited CAR-T cell persistence and an increased risk of relapse.
• Lymphodepletion Enhancement: The addition of fludarabine to the lymphodepletion regimen enhanced CAR-T cell persistence and improved disease-free survival rates.

Main Conclusions/Significance/Innovation

The study concluded that a CAR-T cell product with a defined composition allowed for the identification of critical factors influencing CAR-T cell expansion, persistence, and associated toxicities. The findings facilitated the design of tailored lymphodepletion and CAR-T cell dosing strategies, which not only mitigated toxicity but also enhanced disease-free survival. This research highlights the importance of understanding the cellular composition of CAR-T products and its implications for patient outcomes.

Research Limitations and Future Directions

• Limitations: The study's findings are based on a relatively small patient cohort, which may limit the generalizability of the results. Additionally, the long-term effects of the defined CAR-T cell composition on relapse rates and overall survival require further investigation.
• Future Directions: Future studies should focus on larger, multicenter trials to validate the findings. Additionally, exploring the mechanisms behind CD8+ T cell-mediated immune responses against CAR-T cells and developing strategies to enhance CAR-T cell persistence and effectiveness could be beneficial. Further investigation into the identified serum biomarkers may also improve patient stratification and management in CAR-T cell therapies.

References

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Literatures Citing This Work

1. Toxicities of chimeric antigen receptor T cells: recognition and management. - Jennifer N Brudno;James N Kochenderfer - Blood (2016)
2. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. - Marianna Sabatino;Jinhui Hu;Michele Sommariva;Sanjivan Gautam;Vicki Fellowes;James D Hocker;Sean Dougherty;Haiying Qin;Christopher A Klebanoff;Terry J Fry;Ronald E Gress;James N Kochenderfer;David F Stroncek;Yun Ji;Luca Gattinoni - Blood (2016)
3. Forecasting Cytokine Storms with New Predictive Biomarkers. - Rayne H Rouce;Helen E Heslop - Cancer discovery (2016)
4. Human Vaccines & Immunotherapeutics: News. - Human vaccines & immunotherapeutics (2016)
5. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. - Christoph T Ellebrecht;Vijay G Bhoj;Arben Nace;Eun Jung Choi;Xuming Mao;Michael Jeffrey Cho;Giovanni Di Zenzo;Antonio Lanzavecchia;John T Seykora;George Cotsarelis;Michael C Milone;Aimee S Payne - Science (New York, N.Y.) (2016)
6. Immunotherapy for opportunistic infections: Current status and future perspectives. - Shigeo Fuji;Jürgen Löffler;Hermann Einsele;Markus Kapp - Virulence (2016)
7. Prospects for chimeric antigen receptor (CAR) γδ T cells: A potential game changer for adoptive T cell cancer immunotherapy. - Hamid Reza Mirzaei;Hamed Mirzaei;Sang Yun Lee;Jamshid Hadjati;Brian G Till - Cancer letters (2016)
8. Chimeric Antigen Receptor T cells for B Cell Neoplasms: Choose the Right CAR for You. - Marco Ruella;Carl H June - Current hematologic malignancy reports (2016)
9. Enhanced CAR T-cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors. - R Monjezi;C Miskey;T Gogishvili;M Schleef;M Schmeer;H Einsele;Z Ivics;M Hudecek - Leukemia (2017)
10. Does it make sense to target one tumor cell chemotactic factor or its receptor when several chemotactic axes are involved in metastasis of the same cancer? - Mariusz Z Ratajczak;Malwina Suszynska;Magda Kucia - Clinical and translational medicine (2016)

... (1152 more literatures)

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