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Curated Papers > High-Impact Authoritative Literature on CAR-T Therapy

Barriers to Chimeric Antigen Receptor T-Cell (CAR-T) Therapies in Clinical Practice. ​

Literature Information ​

DOI10.1007/s40290-022-00428-w
PMID35672571
JournalPharmaceutical medicine
Impact Factor4.5
JCR QuartileQ1
Publication Year2022
Times Cited47
KeywordsChimeric Antigen Receptor T-Cell, Cancer Treatment, Clinical Barriers, Immune Response, Manufacturing Limitations
Literature TypeJournal Article, Review
ISSN1178-2595
Pages163-171
Issue36(3)
AuthorsAjeet Gajra, Abigail Zalenski, Aishwarya Sannareddy, Yolaine Jeune-Smith, Kandice Kapinos, Ankit Kansagra

TL;DR ​

Chimeric antigen receptor T-cell (CAR-T) therapy has shown promising results in treating various hematologic malignancies by harnessing and engineering a patient's own T cells to target cancer cells. However, significant barriers such as complex logistics, manufacturing challenges, toxicity, and high costs hinder its widespread adoption, prompting discussions on potential solutions to improve accessibility to this transformative treatment.

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Chimeric Antigen Receptor T-Cell · Cancer Treatment · Clinical Barriers · Immune Response · Manufacturing Limitations

Abstract ​

Chimeric antigen receptor T-cell (CAR-T) therapy is a revolutionary cancer treatment modality where a patient's own T cells are collected and engineered ex vivo to express a chimeric antigen receptor (CAR). These reprogrammed CAR-T cells, when reinfused into the same patient, stimulate a T-cell mediated immune response against the antigen-expressing malignant cells leading to cell death. The initial results from pivotal clinical trials of CAR-T agents have been promising, leading to multiple approvals in various hematologic malignancies in the relapsed setting, including acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma, and, more recently, multiple myeloma. However, since the initial trials and US Food and Drug Administration approvals, there have been significant barriers to the widespread use of this therapy. The barriers to the use of CAR-T therapy include complex logistics, manufacturing limitations, toxicity concerns, and financial burden. This review discusses potential solutions to overcome these barriers in order to make this life-changing therapy widely accessible.

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Primary Questions Addressed ​

  1. What are the specific manufacturing limitations that currently hinder the scalability of CAR-T therapies?
  2. How do the toxicity concerns associated with CAR-T therapies compare to traditional cancer treatments?
  3. In what ways can healthcare systems address the financial burden of CAR-T therapies for patients?
  4. What role does patient selection play in overcoming barriers to the effective use of CAR-T therapies?
  5. How might advancements in technology improve the logistics involved in CAR-T therapy administration?

Key Findings ​

Research Background and Purpose ​

Chimeric Antigen Receptor T-cell (CAR-T) therapy represents a groundbreaking approach in cancer treatment, particularly for hematologic malignancies. Since its initial FDA approval in 2017, CAR-T therapy has shown promise in treating conditions such as relapsed/refractory acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). However, despite its success in clinical trials, the widespread adoption of CAR-T therapy is hindered by several barriers, including logistical complexities, safety concerns, and high costs. This review aims to explore these barriers and propose potential solutions to enhance the accessibility of CAR-T therapy.

Main Methods/Materials/Experimental Design ​

The review discusses various barriers to CAR-T therapy categorized into product-related, clinical outcome-related, and financial challenges. Key aspects include:

  1. Patient Eligibility: Evaluation of real-world evidence (RWE) regarding the efficacy of CAR-T therapy in broader patient populations.
  2. Treatment Delivery Models: Discussion on transitioning CAR-T therapy from inpatient to outpatient settings to improve accessibility.
  3. Manufacturing and Authorization: Examination of the lengthy manufacturing processes and slow prior authorization from insurance providers.
Mermaid diagram

Key Results and Findings ​

  • Efficacy and Safety: Initial trials indicated high efficacy, but the real-world application shows variability in patient outcomes, particularly regarding severe toxicities like cytokine release syndrome (CRS).
  • Relapse Rates: A significant portion of patients (30-60%) experience disease relapse post-CAR-T therapy, with challenges in managing both CD19+ and CD19- relapses.
  • Healthcare Utilization: Post-treatment healthcare utilization often remains high, especially for patients experiencing severe side effects, although costs tend to decrease after treatment compared to pre-treatment levels.

Main Conclusions/Significance/Innovation ​

The review emphasizes that while CAR-T therapy has transformative potential, addressing the outlined barriers is crucial for its mainstream adoption. Innovations in CAR-T design, such as allogeneic therapies and improved outpatient models, could enhance patient access and reduce costs. The review advocates for better communication between healthcare providers and CAR-T centers to streamline treatment delivery.

Research Limitations and Future Directions ​

  • Limitations: The review highlights the limited representation of diverse patient populations in clinical trials and the potential discrepancies between trial outcomes and real-world efficacy.
  • Future Directions: Future research should focus on:
    • Developing strategies to reduce manufacturing times and costs.
    • Exploring outpatient delivery models while ensuring safety protocols.
    • Investigating the long-term effects of CAR-T therapy on quality of life and overall healthcare costs.

Summary Table of Barriers and Solutions ​

BarrierDescriptionProposed Solutions
Patient EligibilityStrict trial criteria limit real-world accessExpand eligibility criteria based on RWE
Treatment DeliveryInpatient settings limit accessDevelop outpatient models and community clinics
ManufacturingLong vein-to-vein time delaysExplore allogeneic CAR-T and decentralized production
Prior AuthorizationSlow insurance processesStreamline prior authorization procedures

This comprehensive overview provides insights into the challenges facing CAR-T therapy and emphasizes the importance of continued innovation and collaboration to enhance patient access to this promising treatment modality.

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Literatures Citing This Work ​

  1. Construction of a cuproptosis-related lncRNA signature for predicting prognosis and immune landscape in osteosarcoma patients. - Shumin Ni;Jinjiong Hong;Weilong Li;Meng Ye;Jinyun Li - Cancer medicine (2023)
  2. Tackling Mantle Cell Lymphoma in Europe. - Denis Horgan;Jan Walewski;Igor Aurer;Carlo Visco;Eva Giné;Bogdan Fetica;Mats Jerkeman;Marta Kozaric;Maria Gomes da Silva;Martin Dreyling - Healthcare (Basel, Switzerland) (2022)
  3. Costs, effectiveness, and safety associated with Chimeric Antigen Receptor (CAR) T-cell therapy: Results from a comprehensive cancer center. - Sérgio Chacim;Teresa Monjardino;José Luís Cunha;Pedro Medeiros;Patrícia Redondo;Maria José Bento;José Mário Mariz - PloS one (2022)
  4. Innovation in BCMA CAR-T therapy: Building beyond the Model T. - Rahul Banerjee;Sarah S Lee;Andrew J Cowan - Frontiers in oncology (2022)
  5. International oncology drug approvals for multiregional or single-country clinical trials: A systematic review. - Min Zhang;Igho Onakpoya;Katrin Rupalla - Frontiers in medicine (2022)
  6. FDG-PET/CT in the Monitoring of Lymphoma Immunotherapy Response: Current Status and Future Prospects. - Akram Al-Ibraheem;Ahmed Saad Abdlkadir;Malik E Juweid;Kamal Al-Rabi;Mohammad Ma'koseh;Hikmat Abdel-Razeq;Asem Mansour - Cancers (2023)
  7. Recent advances in treatment of nodal and gastrointestinal follicular lymphoma. - Takuya Watanabe - World journal of gastroenterology (2023)
  8. How can Cytokine-induced killer cells overcome CAR-T cell limits. - Elisa Cappuzzello;Emilia Vigolo;Giulia D'Accardio;Giuseppe Astori;Antonio Rosato;Roberta Sommaggio - Frontiers in immunology (2023)
  9. Bringing CAR T cell therapy trials to underserved populations. - Hoda Badr;Rayne Rouce;Michael E Scheurer;Premal Lulla;Martha Mims;Pavan Reddy - Cancer cell (2023)
  10. Adoptive NK Cell Therapy - a Beacon of Hope in Multiple Myeloma Treatment. - Son Hai Vu;Ha Hong Pham;Thao Thi Phuong Pham;Thanh Thien Le;Manh-Cuong Vo;Sung-Hoon Jung;Je-Jung Lee;Xuan-Hung Nguyen - Frontiers in oncology (2023)

... (37 more literatures)

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