Next-generations of CAR-T Cell Therapy in Hematologic Malignancies

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment, particularly for hematologic malignancies. Despite remarkable success, current CAR-T therapies face considerable limitations including antigen escape, exhaustion, and the need for individualized manufacturing. Next-generation CAR-T therapies aim to address these limitations through innovative strategies:
Universal or allogeneic CAR-T cells, derived from healthy donors and gene-edited to prevent graft-versus-host disease (GVHD), offer an off-the-shelf alternative to patient-derived autologous products. Dual or tri-specific CAR designs target multiple antigens simultaneously, reducing the risk of tumor evasion. Additionally, advancements in synthetic biology enable controllable CAR-T constructs, enhancing safety and durability.
By integrating gene-editing tools such as CRISPR, optimizing signaling domains, and leveraging novel co-stimulatory molecules, next-generation CAR-T therapies hold the potential to improve efficacy, persistence, and applicability in both hematologic and solid tumors.

This Research Topic seeks to explore novel approaches in next-generation CAR-T cell therapy aimed at overcoming prominent therapeutic obstacles in hematologic malignancies. Specifically:
1) Improve Accessibility and Affordability – Current CAR T therapies are patient-specific, making them costly and time-consuming to manufacture. The goal is to develop universal (allogeneic) CAR-T cells from healthy donors, not necessarily T-cells, which can be mass-produced and readily available, reducing both costs and treatment delays.
2) Enhance Effectiveness – Tumors often evade CAR T therapy by losing the targeted antigen. Designing dual or tri-specific CARs that recognize multiple antigens can reduce the risk of tumor escape and improve long-term treatment success.
3) Increase Persistence and Durability – Many CAR-T cells lose function over time. Optimizing their metabolism, improving co-stimulatory domains, and using gene modifications can help them survive longer and maintain effectiveness.
4) Reduce Toxicity and Side Effects – CAR-T therapy can cause severe immune reactions like cytokine release syndrome (CRS). Developing tunable or switchable CAR-T cells could help control their activity and minimize risks.
5) Leverage Advanced Gene Editing – Techniques like CRISPR can fine-tune CAR-T cells for greater precision, safety, and adaptability, improving their overall therapeutic potential.

To gather further insights within the spectrum of next-generation CAR-T cell therapies in hematologic malignancies, we welcome articles addressing, but not limited to, the following themes:

- Innovations in CAR T-cell engineering (dual/triple-targeting, tunable CARs).

- Advances in allogeneic (off-the-shelf) CAR T-cell development (e.g., techniques using NKT cells, NK cells, gene-edited T-cells etc.).

- Strategies to enhance persistence and overcome T-cell exhaustion.

- Approaches to minimize toxicity (CRS, neurotoxicity, secondary malignancies, persistent cytopenias).


Topic Editor Andrea Aroldi received an Honorarium from Novartis.
Topic Editor Mirko Farina received Honoraria from Novaris, Gilead and Jazz Pharmaceuticals.
The other Topic Editors declare no competing interests with regard to the Research Topic subject.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• ... View all formats

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: CAR-T cells, CAR-T toxicity, alternative CAR-T products, off-the shelf CAR-T cells

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