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The journey of CAR-T therapy in hematological malignancies.
Literature Information
| DOI | 10.1186/s12943-022-01663-0 |
|---|---|
| PMID | 36209106 |
| Journal | Molecular cancer |
| Impact Factor | 33.9 |
| JCR Quartile | Q1 |
| Publication Year | 2022 |
| Times Cited | 93 |
| Keywords | CAR-T cell therapy, Combinatorial therapy, Drug product, Hematological malignancies, Targeted therapy |
| Literature Type | Journal Article, Review |
| ISSN | 1476-4598 |
| Pages | 194 |
| Issue | 21(1) |
| Authors | Junru Lu, Guan Jiang |
TL;DR
This review discusses the transformative impact of chimeric antigen receptor T (CAR-T) cell therapy on hematological malignancies, highlighting the development and success of various CAR-T products like Kymriah and Yescarta in achieving durable remissions in patients. It also addresses the challenges of relapse and resistance, emphasizing the need for novel strategies and technical advancements, such as nanobodies and CRISPR-Cas9, to enhance the efficacy and potential of CAR-T immunotherapy.
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CAR-T cell therapy · Combinatorial therapy · Drug product · Hematological malignancies · Targeted therapy
Abstract
Chimeric antigen receptor T (CAR-T) cells therapy has revolutionized the treatment paradigms for hematological malignancies, with multi-line therapy-refractory patients achieving durable complete remissions (CR) and relatively high objective response rate (ORR). So far, many CAR-T products, such as Kymriah, Yescarta and Tecartus, have been developed and got the unprecedented results. However, some patients may relapse afterwards, driving intense investigations into promoting the development of novel strategies to overcome resistance and mechanisms of relapse. Notable technical progress, such as nanobodies and CRISPR-Case9, has also taken place to ensure CAR-T cell therapy fully satisfies its medical potential. In this review, we outline the basic principles for the development and manufacturing processes of CAR-T cell therapy, summarize the similarities and differences in efficacy of different products as well as their corresponding clinical results, and discuss CAR-T immunotherapy combined with other clinical effects of drug therapy.
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Primary Questions Addressed
- What are the most significant challenges currently faced in the development of CAR-T therapies for hematological malignancies?
- How do the efficacy and safety profiles of different CAR-T products compare in treating various types of hematological malignancies?
- What novel strategies are being explored to prevent relapse in patients treated with CAR-T therapy?
- In what ways could advancements in technologies like nanobodies and CRISPR-Cas9 enhance the effectiveness of CAR-T cell therapy?
- How does the combination of CAR-T therapy with other drug therapies influence treatment outcomes in patients with hematological malignancies?
Key Findings
Background and Purpose
Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a groundbreaking treatment for hematological malignancies, leading to durable remissions in patients who are refractory to multiple therapies. Despite the success of CAR-T products like Kymriah, Yescarta, and Tecartus, issues such as patient relapse and treatment resistance necessitate ongoing research to enhance therapeutic efficacy and safety. This review discusses the principles, development, and clinical outcomes of CAR-T therapy, alongside innovative strategies to overcome limitations.
Main Methods/Materials/Experimental Design
The development of CAR-T therapy involves several key stages, including the engineering of T cells, CAR construction, and clinical application. The following flowchart outlines the process:
- Patient Leukapheresis: Blood is collected from the patient, and leukocytes are separated.
- T Cell Activation: T cells are activated using anti-CD3 and anti-CD28 antibodies, often supplemented with IL-2.
- Gene Modification: The CAR gene is introduced into T cells using viral vectors or electroporation.
- T Cell Expansion: Expanded T cells are cultured for sufficient numbers.
- Quality Control: Ensuring the safety and efficacy of the modified T cells.
- Infusion into Patient: The engineered T cells are infused back into the patient.
- Monitoring: Patients are monitored for therapeutic response and adverse effects.
Key Results and Findings
- CAR-T therapy has shown significant efficacy in treating various hematological malignancies, with response rates varying by product and indication.
- Kymriah has an objective response rate (ORR) of 52% in relapsed/refractory large B-cell lymphoma, while Yescarta reported an ORR of 83%.
- Common adverse events include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), with rates differing among products.
- Novel strategies such as combining CAR-T with checkpoint inhibitors (e.g., pembrolizumab) and utilizing CRISPR technology for gene editing are under investigation to enhance efficacy and mitigate resistance.
Main Conclusions/Significance/Innovation
CAR-T therapy represents a transformative approach in the treatment of hematological cancers, providing new hope for patients with refractory diseases. Innovations in CAR design, such as incorporating multiple antigen targeting and genetic editing, aim to improve therapeutic outcomes and reduce adverse effects. However, the high costs and complex manufacturing processes remain significant challenges.
Research Limitations and Future Directions
- Limitations: The review highlights the high incidence of adverse effects and the need for individualized therapy due to the complexities of CAR-T production.
- Future Directions: Continued research is needed to refine CAR-T designs, enhance manufacturing efficiency, and explore combination therapies with other immunomodulatory agents. The potential of CRISPR technology for safer and more effective CAR-T therapies warrants further exploration in clinical trials.
Summary Table of CAR-T Products
| Product | Indication | ORR (%) | CR (%) | Major AEs |
|---|---|---|---|---|
| Kymriah | B-ALL, R/R LBCL | 52 | 40 | CRS, ICANS |
| Yescarta | R/R LBCL | 83 | 58 | CRS, ICANS |
| Tecartus | R/R MCL | 93 | 67 | ICANS |
| Breyanzi | R/R LBCL | 73 | 53 | CRS, ICANS |
| Abecma | R/R MM | 73 | 33 | CRS, ICANS |
This structured summary captures the essential aspects of CAR-T therapy as reviewed by Lu and Jiang, providing a clear overview of its significance in modern oncology.
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Literatures Citing This Work
- Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors. - Qiuqiang Chen;Lingeng Lu;Wenxue Ma - Cancers (2022)
- Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphoma: A systematic literature review. - Stephen Jolles;Sergio Giralt;Tessa Kerre;Hillard M Lazarus;S Shahzad Mustafa;Roberto Ria;Donald C Vinh - Frontiers in oncology (2023)
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