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

In vivo chimeric antigen receptor (CAR)-T cell therapy. ​

Literature Information ​

DOI10.1038/s41573-025-01291-5
PMID41028170
JournalNature reviews. Drug discovery
Impact Factor101.8
JCR QuartileQ1
Publication Year2025
Times Cited0
KeywordsChimeric Antigen Receptor, CAR-T Cell Therapy, In Vivo Engineering, Viral Vectors, Nanotechnology
Literature TypeJournal Article, Review
ISSN1474-1776
AuthorsAdrian Bot, Andrew Scharenberg, Kevin Friedman, Lin Guey, Robert Hofmeister, James I Andorko, Michael Klichinsky, Frank Neumann, Jagesh V Shah, Andrew J Swayer, Kyle Trudeau, Drew Weissman, Matthias T Stephan, Christian J Buchholz, Carl H June

TL;DR ​

This review discusses the innovative approach of in vivo CAR-T cell engineering, which aims to enhance the accessibility and efficacy of CAR-T cell therapies for hematological malignancies and potentially autoimmune diseases by eliminating the need for ex vivo processing. Recent technological advances in virology, RNA delivery, and nanotechnology have shown promising results in early clinical studies, suggesting a shift towards more scalable and effective treatment options.

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Chimeric Antigen Receptor · CAR-T Cell Therapy · In Vivo Engineering · Viral Vectors · Nanotechnology

Abstract ​

Chimeric antigen receptor (CAR)-T cell therapy has transformed the outcomes of patients with haematological malignancies, yet its use is limited by labour-intensive manufacturing, constrained production capacity and variable clinical performance. In vivo CAR-T cell engineering, in which CAR-T cells are generated directly inside the patient's body, seeks to overcome these challenges by eliminating the need for ex vivo cell processing and complex logistics, as well as improve clinical performance. Recent advances in virology, RNA medicines and nanotechnology have catalysed a radical overhaul of this approach, which uses targeted delivery systems such as lentiviral vectors and lipid nanoparticles to introduce CAR-encoding genetic material into endogenous T cells. Early clinical studies have shown efficient transduction, sustained CAR expression and initial signs of antitumour activity, establishing proof of concept. This Review explores the underlying technologies - including RNA delivered by lipid nanoparticles and engineered viral vectors - and discusses how they are being adapted to develop more broadly applicable, scalable, safe and effective CAR-T cell therapies. By removing the need for ex vivo manipulation and chemotherapeutic conditioning, this strategy could enable the wider application of CAR-T cell therapies not just to blood cancers but to autoimmune diseases for which ex vivo CAR-T cell therapies have shown strong promise, such as systemic lupus erythematosus.

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Primary Questions Addressed ​

  1. What are the specific advantages of in vivo CAR-T cell therapy compared to traditional ex vivo methods?
  2. How do recent advancements in virology and nanotechnology enhance the efficacy of in vivo CAR-T cell therapies?
  3. What challenges remain in the clinical implementation of in vivo CAR-T cell therapy for autoimmune diseases?
  4. How does the use of targeted delivery systems like lentiviral vectors and lipid nanoparticles affect the safety profile of CAR-T cell therapies?
  5. In what ways could in vivo CAR-T cell therapy be adapted for treating solid tumors, given its current focus on hematological malignancies?

Key Findings ​

Research Background and Objectives ​

Chimeric antigen receptor (CAR)-T cell therapy has significantly improved the prognosis for patients with hematological malignancies. However, its widespread adoption is hampered by challenges such as labor-intensive manufacturing, limited production capacity, and inconsistent clinical outcomes. This review aims to explore the potential of in vivo CAR-T cell engineering as a solution to these challenges, enhancing the feasibility and efficacy of CAR-T therapies.

Main Methods/Materials/Experimental Design ​

The review discusses the innovative approaches in in vivo CAR-T cell engineering, focusing on targeted delivery systems for CAR-encoding genetic material. Key technologies include:

  1. Lentiviral Vectors: These are used to deliver genetic material into T cells, allowing for stable CAR expression.
  2. Lipid Nanoparticles: These facilitate the delivery of RNA to T cells, enabling rapid and efficient CAR-T cell generation.

The following flowchart illustrates the technical route of in vivo CAR-T cell engineering:

Mermaid diagram

Key Results and Findings ​

  • Efficient Transduction: Early clinical studies indicate that both lentiviral vectors and lipid nanoparticles effectively transduce endogenous T cells.
  • Sustained CAR Expression: The introduction of CAR-encoding genetic material leads to prolonged CAR expression in T cells.
  • Initial Antitumor Activity: Preliminary results show promising antitumor responses, establishing proof of concept for in vivo CAR-T cell engineering.

Main Conclusions/Significance/Innovativeness ​

The review highlights that in vivo CAR-T cell engineering has the potential to:

  • Overcome the logistical challenges associated with ex vivo CAR-T cell manufacturing.
  • Expand the applicability of CAR-T therapies beyond hematological malignancies to autoimmune diseases, such as systemic lupus erythematosus, where ex vivo therapies have shown promise.
  • Enhance safety and scalability of CAR-T therapies by removing the need for ex vivo manipulation and chemotherapeutic conditioning.

Research Limitations and Future Directions ​

While the findings are promising, the review notes several limitations:

  • Clinical Validation: Further extensive clinical trials are necessary to confirm the efficacy and safety of in vivo CAR-T therapies across a broader patient population.
  • Long-term Outcomes: The durability of CAR expression and long-term antitumor activity remain to be fully assessed.
  • Broader Applications: Future research should explore the potential of in vivo CAR-T therapies for various cancer types and autoimmune conditions.

Future directions include optimizing delivery systems, refining the engineering process, and investigating combination therapies to enhance the effectiveness of in vivo CAR-T cell treatments.

References ​

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  10. Recent advances and current challenges in CAR-T cell therapy. - R Joy;K Phair;R O'Hara;D Brady - Biotechnology letters (2024)

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