CAR-T therapy has revolutionised the treatment of certain haematological cancers, such as acute lymphoblastic leukaemia and B-cell lymphoma. However, recent advances have allowed its application to be expanded to solid tumours and autoimmune diseases, ushering in a new era in personalised immunotherapy.
CAR-T in solid tumours: overcoming barriers
Unlike haematological cancers, solid tumours present additional challenges for CAR-T therapy. These include antigenic heterogeneity, immunosuppression of the tumour microenvironment and the difficulty of infiltration of CAR-T cells into the tumour. To overcome these barriers, strategies have been developed such as:
-New target antigens. identification of solid tumour-specific antigens, such as HER2, GD2 and EGFRVIII.
-CAR design modifications. Development of second- and third-generation CARs with multiple co-stimulators to improve lymphocyte persistence and efficacy.
-Use of cytokine receptor-modified T cells. Increased resistance to tumour immunosuppression through the expression of receptors that favour CAR-T lymphocyte proliferation and activation.
-Combination therapies: Synergy with immune checkpoint inhibitors and other targeted therapies to enhance the anti-tumour response.
These advances have allowed CAR-T therapies for solid tumours to begin to demonstrate efficacy in preclinical studies and early clinical trials.
Biomarkers predictive of CAR-T response
CAR-T therapy is not equally effective in all patients, so the identification of predictive biomarkers of response is key to its personalisation. Some of the biomarkers under investigation include
-Tumour antigen expression. A high level of target antigen expression (such as CD19 or BCMA) correlates with a better therapeutic response.
-Patient immune profile. The proportion of regulatory T lymphocytes (Tregs) and the functionality of CAR-T cells prior to treatment can predict the success of therapy.
-Genetic and epigenetic factors. Variants in genes related to immune activation may influence the efficacy of CAR-T therapy.
The use of these predictive biomarkers will allow for better patient selection and optimisation of treatment strategies, improving the efficacy of CAR-T therapy.
Reducing Adverse Effects in CAR-T Therapy
Despite its efficacy, CAR-T therapy can induce serious adverse effects, such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity (ICANS). To mitigate these risks, strategies have been developed such as:
Use of IL-6 inhibitors (Tocilizumab): drugs such as tocilizumab have demonstrated efficacy in the management of moderate to severe CRS.
Modulation of CAR design: Incorporation of “safety switches” in CAR-T lymphocytes that allow their elimination in case of severe adverse reactions.
Stepwise administration: Fractionated dosing strategies to reduce toxicity without compromising efficacy.
Researchers are evaluating experimental therapies with anakinra and other immunomodulators to block IL-1 and other inflammatory mediators, preventing neurotoxicity. They continue refining these approaches to maximize the safety and tolerability of CAR-T therapy, broadening its clinical application to a greater number of patients.
Conclusions
CAR-T therapy is rapidly evolving beyond its initial application in hematological malignancies. Its potential in solid tumors and autoimmune diseases represents a significant advance in personalized medicine. Optimization of predictive biomarkers and strategies to minimize adverse effects will be key to its wider implementation. As research progresses, CAR-T could establish itself as one of the most promising therapies of the 21st century, transforming the treatment of complex diseases with unprecedented precision.