CD19-targeted CAR-T cells have transformed the management of acute lymphoblastic leukaemia (ALL), especially in refractory or relapsed paediatric and young adult patients. Accumulated clinical experience has demonstrated complete remissions in over 80% of cases, but persistent relapses, toxicity and production logistics remain significant challenges.
This article discusses the latest advances and emerging strategies that are shaping the evolution of CAR-T therapies in ALL.
Antigen escape: beyond CD19
Escape through loss or modulation of the CD19 antigen remains the most common cause of relapse after CAR-T therapy. To address this, current research is focusing on:
- Biespecific CAR-T (CD19/CD22, CD19/CD20): recent clinical trials show a significant reduction in relapses due to tumour escape and better control of minimal residual disease.
- T-cell engager-secreting CAR-T: these allow endogenous T lymphocytes to be recruited against B cells that express other antigens, prolonging immune pressure.
- Epigenetic editing and reprogramming of tumour lymphocytes: experimental strategies to prevent phenotypic plasticity and CD19 loss.
These approaches are demonstrating that the combination of multiple targets and synergistic mechanisms may be key to overcoming resistance.
Persistence and functional improvement
The durability of the response remains a critical factor. Among the most promising strategies are:
- Fourth-generation CAR-T (‘armoured’): cells that secrete cytokines such as IL-18 or IL-15, promoting sustained expansion and activation of surrounding immune cells.
- Memory phenotype optimisation: the selection of naïve or central memory T cells improves persistence and reduces chronic T cell dysfunction.
- Metabolic reprogramming: cellular modifications that enable more efficient metabolism, improving CAR-T survival in adverse microenvironments.
The goal is to achieve a prolonged response without increasing toxicity, maintaining efficacy even in complex tumour environments.
Toxicity and safety strategies
Cytokine release syndrome (CRS) and associated neurotoxicity (ICANS) remain significant clinical challenges. Current approaches include:
- CAR-T with suicide or switchable switches: these allow cell activity to be stopped in the event of severe toxicity.
- Switchable CAR-T: real-time controllable activation systems, optimising safety and efficacy.
- In vivo therapies: use of lipid nanoparticles (LNPs) that allow CAR-T to be generated directly in the patient, avoiding lymphodepletion and reducing production times.
These strategies promise to improve tolerance without compromising antitumour activity.
Expansion of indications and accessibility
The potential of CD19 CAR-T cells goes beyond ALL:
- Autoimmune diseases: preliminary studies in systemic lupus erythematosus and multiple sclerosis show that CAR-T cells can ‘reset’ the immune system.
- Allogeneic (‘off-the-shelf’) CAR-T: these enable standardised treatments, reduce costs and production time, and facilitate global access to advanced therapies.
- Integration with immunomodulators: combination with checkpoint inhibitors or tumour microenvironment modulators can improve efficacy and reduce escape.
These advances could redefine the therapeutic strategy in haematology and autoimmunity, transforming CAR-T from a last-line resource to a more accessible and versatile treatment.
Challenges and future prospects
Despite the clinical impact, challenges remain to be resolved:
- Antigenic escape mechanisms and clonality of ALL.
- Optimisation of persistence and T memory without increasing toxicity.
- Scalability and logistics: faster, safer and more economical production for widespread use.
- Combination with other therapies: integrating CAR-T with immune modulators or specific targeted treatments.
Researchers are developing safer, longer-lasting, and more universal therapies, bringing cell immunotherapy closer to all patients with refractory or high-risk ALL.