Curated Papers > Highly Cited Authoritative Literature on "CAR-T Therapy"

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.

Literature Information

DOI	10.1016/S0140-6736(14)61403-3
PMID	25319501
Journal	Lancet (London, England)
Publication Year	2015
Times Cited	1622
Keywords	CD19 chimeric antigen receptor, acute lymphoblastic leukaemia, T cell therapy
Literature Type	Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't
ISSN	0140-6736
Pages	517-528
Issue	385(9967)
Authors	Daniel W Lee, James N Kochenderfer, Maryalice Stetler-Stevenson, Yongzhi K Cui, Cindy Delbrook, Steven A Feldman, Terry J Fry, Rimas Orentas, Marianna Sabatino, Nirali N Shah, Seth M Steinberg, Dave Stroncek, Nick Tschernia, Constance Yuan, Hua Zhang, Ling Zhang, Steven A Rosenberg, Alan S Wayne, Crystal L Mackall

TL;DR

This phase 1 trial evaluated the feasibility and safety of CD19-CAR T cell therapy in children and young adults with refractory B-cell malignancies, finding that the maximum tolerated dose was 1×10^6 CAR T cells per kg and that all toxicities were reversible, with notable adverse events including cytokine release syndrome. These results demonstrate the potential of CD19-CAR T cell therapy as an effective treatment option for patients with resistant forms of acute lymphoblastic leukaemia, highlighting its promise in improving outcomes for this population.

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CD19 chimeric antigen receptor · acute lymphoblastic leukaemia · T cell therapy

Abstract

BACKGROUND Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells.

METHODS This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696.

FINDINGS Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients).

INTERPRETATION CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur.

FUNDING National Institutes of Health Intramural funds and St Baldrick's Foundation.

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Primary Questions Addressed

1. What are the long-term effects of CD19-CAR T cell therapy on children and young adults after treatment for acute lymphoblastic leukaemia?
2. How does the response rate of CD19-CAR T cells compare with other treatment options for refractory B-cell malignancies in pediatric patients?
3. What specific biological markers correlate with a successful response to CD19-CAR T cell therapy in this patient population?
4. Are there any strategies being explored to enhance the efficacy of CD19-CAR T cells in patients who do not respond to initial treatment?
5. What are the implications of cytokine release syndrome in the management of patients receiving CD19-CAR T cell therapy, and how can it be effectively mitigated?

Key Findings

Background and Objectives

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has demonstrated efficacy in treating various B-cell malignancies. However, this phase 1 dose-escalation trial aimed to systematically assess the feasibility, toxicity, maximum tolerated dose (MTD), response rates, and biological correlates of CD19-CAR T-cell therapy in children and young adults with refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma.

Main Methods/Materials/Experimental Design

The study design involved an open-label, phase 1, dose-escalation trial with the following key components:

• Participants: Children and young adults (aged 1–30 years) with relapsed or refractory CD19+ ALL or non-Hodgkin lymphoma.
• CAR T-cell Manufacturing: Autologous T cells were modified to express CD19-CAR using a clinical-grade retroviral vector. The manufacturing process took 11 days.
• Pre-Infusion Conditioning: Patients received fludarabine and cyclophosphamide to lymphodeplete before receiving the CAR T-cell infusion.
• Dose Escalation: The study utilized a standard 3 + 3 design to determine the MTD, starting with doses of 1 × 10⁶ and 3 × 10⁶ CAR T cells per kg.
• Response Assessment: Evaluated on day 28 post-infusion using criteria for complete response (CR), complete response with incomplete count recovery (CRi), stable disease (SD), and progressive disease (PD).

Key Results and Findings

• Patient Enrollment: 21 patients were enrolled from July 2012 to June 2014, with a 90% feasibility rate for generating the prescribed CAR T-cell dose.
• Toxicity: The maximum tolerated dose was determined to be 1 × 10⁶ CAR T cells per kg. Grade 4 cytokine release syndrome (CRS) occurred in 14% of patients, while other grade 3 adverse events included fever and hypokalaemia.
• Response Rates: The overall complete response rate was 66.7% (14/21), with 60% achieving MRD-negative status. Among patients with ALL, 70% achieved CR.
• Survival Outcomes: The median follow-up was 10 months, showing a 51.6% overall survival rate and a 78.8% leukemia-free survival rate in patients who achieved MRD-negative remission.

Main Conclusions/Significance/Innovation

CD19-CAR T-cell therapy is a feasible and effective treatment for refractory B-ALL in children and young adults, with a significant proportion achieving complete responses. The therapy demonstrated potent anti-leukemic activity, and the associated toxicities were reversible. This study provides critical data supporting CD19-CAR T cells as a viable bridge to hematopoietic stem cell transplantation (HSCT) for patients with chemoresistant disease.

Limitations and Future Directions

• Study Limitations: The small sample size limits the generalizability of findings. The study primarily focused on short-term outcomes, with long-term efficacy and safety still to be established.
• Future Directions: Future studies should explore the long-term persistence of CAR T cells, strategies to prevent CRS, and the efficacy of dual-targeting CARs to address antigen escape (e.g., CD19-negative relapses).

Summary Table of Key Findings

Parameter	Result
Number of Patients Enrolled	21
Feasibility Rate	90%
Maximum Tolerated Dose	1 × 10⁶ CAR T cells per kg
Complete Response Rate	66.7% (14/21)
MRD-Negative Complete Response Rate	60% (12/20 with B-ALL)
Overall Survival Rate	51.6% at median follow-up of 10 months
Leukemia-Free Survival Rate	78.8% for MRD-negative responders

This comprehensive evaluation underscores the potential of CD19-CAR T-cell therapy in treating refractory B-ALL and highlights the need for ongoing research to optimize treatment protocols and improve patient outcomes.

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Literatures Citing This Work

1. Immune-based therapies for childhood cancer. - Crystal L Mackall;Melinda S Merchant;Terry J Fry - Nature reviews. Clinical oncology (2014)
2. T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. - Cor H J Lamers;Sabine van Steenbergen-Langeveld;Mandy van Brakel;Corrien M Groot-van Ruijven;Pascal M M L van Elzakker;Brigitte van Krimpen;Stefan Sleijfer;Reno Debets - Human gene therapy methods (2014)
3. Challenges to chimeric antigen receptor (CAR)-T cell therapy for cancer. - Michael S Magee;Adam E Snook - Discovery medicine.. (2014)
4. Advances in T-cell therapy for ALL. - Stephan A Grupp - Best practice & research. Clinical haematology (2014)
5. Modern immunotherapy of adult B-lineage acute lymphoblastic leukemia with monoclonal antibodies and chimeric antigen receptor modified T cells. - Elena Maino;Anna Maria Scattolin;Piera Viero;Rosaria Sancetta;Anna Pascarella;Michele Vespignani;Renato Bassan - Mediterranean journal of hematology and infectious diseases (2015)
6. Designing chimeric antigen receptors to effectively and safely target tumors. - Michael C Jensen;Stanley R Riddell - Current opinion in immunology (2015)
7. Using gene therapy to manipulate the immune system in the fight against B-cell leukemias. - Diana C G Bouhassira;Joshua J Thompson;Marco L Davila - Expert opinion on biological therapy (2015)
8. Improving access to novel agents for childhood leukemia. - Weili Sun;Paul S Gaynon;Richard Sposto;Alan S Wayne - Cancer (2015)
9. Thymic expression of a T-cell receptor targeting a tumor-associated antigen coexpressed in the thymus induces T-ALL. - Yongzhi Cui;Masahiro Onozawa;Haven R Garber;Leigh Samsel;Ziyao Wang;J Philip McCoy;Sandra Burkett;Xiaolin Wu;Peter D Aplan;Crystal L Mackall - Blood (2015)
10. Chimeric antigen receptors and bispecific antibodies to retarget T cells in pediatric oncology. - Maya Suzuki;Kevin J Curran;Nai-Kong V Cheung - Pediatric blood & cancer (2015)

... (1612 more literatures)

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