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Curated Papers > Recent high-impact research on "CAR-T therapy" (IF≥30, last 5 years)

Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma. ​

Literature Information ​

DOI10.1038/s41591-022-01959-0
PMID36097221
JournalNature medicine
Impact Factor50.0
JCR QuartileQ1
Publication Year2022
Times Cited122
KeywordsCAR-T cell therapy, large B cell lymphoma, single-cell transcriptome sequencing, memory-like CD8 clones, regulatory CAR-T cells
Literature TypeJournal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
ISSN1078-8956
Pages1848-1859
Issue28(9)
AuthorsNicholas J Haradhvala, Mark B Leick, Katie Maurer, Satyen H Gohil, Rebecca C Larson, Ning Yao, Kathleen M E Gallagher, Katelin Katsis, Matthew J Frigault, Jackson Southard, Shuqiang Li, Michael C Kann, Harrison Silva, Max Jan, Kahn Rhrissorrakrai, Filippo Utro, Chaya Levovitz, Raquel A Jacobs, Kara Slowik, Brian P Danysh, Kenneth J Livak, Laxmi Parida, Judith Ferry, Caron Jacobson, Catherine J Wu, Gad Getz, Marcela V Maus

TL;DR ​

This study explores the mechanisms behind the varying responses to CD19-targeting CAR-T cell therapies in patients with large B cell lymphoma by analyzing single-cell transcriptomes from treated individuals. It reveals that memory-like CD8 T cell expansion correlates with better outcomes in one CAR-T product, while an increase in regulatory CAR-T cells in nonresponders can suppress effective responses and contribute to relapses, highlighting the importance of understanding these dynamics for improving CAR-T therapy efficacy.

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CAR-T cell therapy · large B cell lymphoma · single-cell transcriptome sequencing · memory-like CD8 clones · regulatory CAR-T cells

Abstract ​

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain new insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pretreatment and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with large B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells among nonresponders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-T regulatory cells to drive relapse.

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Primary Questions Addressed ​

  1. What are the specific molecular mechanisms that differentiate the responses to axi-cel and tisa-cel in CAR-T therapy?
  2. How do the distinct populations of CAR-T regulatory cells influence the long-term outcomes of patients undergoing CAR-T therapy?
  3. What role does the tumor microenvironment play in the efficacy of CAR-T therapies for refractory B cell lymphoma?
  4. How can the findings from single-cell transcriptome sequencing inform the development of next-generation CAR-T therapies?
  5. What strategies can be employed to overcome the identified failure mechanisms in CAR-T therapy for refractory large B cell lymphoma?

Key Findings ​

Research Background and Objectives ​

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for hematologic malignancies, particularly large B cell lymphomas. While around 50% of patients with refractory large B cell lymphoma achieve durable responses with CD19-targeting CAR-T therapies, the mechanisms underlying treatment failures remain poorly understood. This study aims to elucidate the cellular and molecular dynamics associated with clinical responses to two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel).

Main Methods/Materials/Experimental Design ​

The study employed single-cell transcriptome sequencing to analyze 105 samples from peripheral blood mononuclear cells (PBMCs) collected before and after treatment, as well as infusion products from 32 patients. The primary objective was to characterize the immune cell populations and their functional states associated with the different CAR-T therapies.

Technical Route ​

Mermaid diagram

Key Results and Findings ​

  • Proliferative Memory-like CD8 Clones: Tisa-cel responders exhibited a significant expansion of memory-like CD8 T cell clones, indicating a robust and sustained immune response.
  • Heterogeneous Populations in Axi-cel Responders: Patients treated with axi-cel showed more diverse T cell populations, which could indicate a less coordinated response.
  • Regulatory T Cells: Elevated levels of CAR-T regulatory cells were identified in nonresponders to axi-cel. These regulatory cells were shown to suppress the expansion of conventional CAR-T cells and were linked to late relapses in an in vivo model.

Main Conclusions/Significance/Innovation ​

The study highlights the temporal dynamics and distinct molecular characteristics of CAR-T cell responses to different therapies. It reveals that even minor increases in CAR-T regulatory cells can significantly impact treatment outcomes, leading to relapses. This research provides valuable insights into the immune landscape associated with CAR-T therapy and underscores the need for personalized approaches in treatment strategies.

Research Limitations and Future Directions ​

  • Limitations: The study's sample size, while providing valuable insights, may not capture the full diversity of patient responses. The focus on PBMCs might overlook critical interactions occurring within the tumor microenvironment.
  • Future Directions: Further studies should explore the tumor microenvironment's role in CAR-T efficacy and investigate strategies to modulate CAR-T regulatory cells to enhance treatment responses. Additionally, longitudinal studies could provide insights into the durability of responses over time.
AspectAxi-celTisa-cel
T cell PopulationMore heterogeneousExpansion of memory-like CD8 clones
Regulatory T CellsElevated in nonrespondersNot prominently observed
Response DynamicsLess coordinatedRobust and sustained
Clinical ImplicationsPotential for late relapsesMore durable responses observed

This structured summary captures the essence of the study, providing a clear overview of its background, methodology, findings, and implications for future research in CAR-T therapy.

References ​

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Literatures Citing This Work ​

  1. Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas. - Brian J Sworder;David M Kurtz;Stefan K Alig;Matthew J Frank;Navika Shukla;Andrea Garofalo;Charles W Macaulay;Mohammad Shahrokh Esfahani;Mari N Olsen;James Hamilton;Hitomi Hosoya;Mark Hamilton;Jay Y Spiegel;John H Baird;Takeshi Sugio;Mia Carleton;Alexander F M Craig;Sheren F Younes;Bita Sahaf;Natasha D Sheybani;Joseph G Schroers-Martin;Chih Long Liu;Jean S Oak;Michael C Jin;Sara Beygi;Andreas Hüttmann;Christine Hanoun;Ulrich Dührsen;Jason R Westin;Michael S Khodadoust;Yasodha Natkunam;Robbie G Majzner;Crystal L Mackall;Maximilian Diehn;David B Miklos;Ash A Alizadeh - Cancer cell (2023)
  2. Advancing CAR T cell therapy through the use of multidimensional omics data. - Jingwen Yang;Yamei Chen;Ying Jing;Michael R Green;Leng Han - Nature reviews. Clinical oncology (2023)
  3. Long-term response to autologous anti-CD19 chimeric antigen receptor T cells in relapsed or refractory B cell acute lymphoblastic leukemia: a systematic review and meta-analysis. - Magdi Elsallab;Moataz Ellithi;Susanne Hempel;Hisham Abdel-Azim;Mohamed Abou-El-Enein - Cancer gene therapy (2023)
  4. Multiomics STEP up in correlative analysis of response to CAR T cells. - Mark B Leick;Marcela V Maus - Nature reviews. Clinical oncology (2023)
  5. CAR immune cells: design principles, resistance and the next generation. - Louai Labanieh;Crystal L Mackall - Nature (2023)
  6. Chimeric Antigen Receptor T-Cell Therapy and Hematopoiesis. - Bryanna Reinhardt;Patrick Lee;Joshua P Sasine - Cells (2023)
  7. Non-viral TRAC-knocked-in CD19KICAR-T and gp350KICAR-T cells tested against Burkitt lymphomas with type 1 or 2 EBV infection: In vivo cellular dynamics and potency. - Tobias Braun;Alina Pruene;Milita Darguzyte;Alexander F Vom Stein;Phuong-Hien Nguyen;Dimitrios L Wagner;Jonas Kath;Alicia Roig-Merino;Michael Heuser;Lucas L Riehm;Andreas Schneider;Sabine Awerkiew;Steven R Talbot;André Bleich;Constanca Figueiredo;Martin Bornhäuser;Renata Stripecke - Frontiers in immunology (2023)
  8. Dynamics and specificities of T cells in cancer immunotherapy. - Giacomo Oliveira;Catherine J Wu - Nature reviews. Cancer (2023)
  9. Mechanisms of Resistance and Treatment of Relapse after CAR T-cell Therapy for Large B-cell Lymphoma and Multiple Myeloma. - Kai Rejeski;Michael D Jain;Eric L Smith - Transplantation and cellular therapy (2023)
  10. Editorial: Screening and verification of new targets for CAR-T immunotherapy in cancer. - Yang Su;Chen Yuan;Ming Shi - Frontiers in immunology (2023)

... (112 more literatures)

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