2 weeks Ago
The development of CAR-T technology in recent years has been a major milestone in the fight against cancer. These sort of "living drugs"—T-cells modified to expand, recognize and attack cancer cells within the body—offer hope to many patients after relapse or failure of the standard treatment, especially in blood cancers. However, sustained complete remissions are only observed in less than 50% of the patients one year after infusion, leaving room for improvement.
A new study from the Josep Carreras Leukemia Research Institute identifies three key features of the CAR-T cells themselves that help predict the success of the therapy, regardless of the patient. The study, published in Cell Reports Medicine , is authored by Mercedes Guerrero and Aina Rill, and led by Pablo Menéndez, Clara Bueno and Elisabetta Mereu, with the collaboration of the Hospital Clínic de Barcleona and the Salamanca's Biomedical Research Institute (IBSAL), providing patients and critical clinical data. These institutions are part of the CIBERONC program and the Spanish Advanced Therapies Network (TERAV-ISCIII).
Using the latest technologies in single cell multiomics, the research team analyzed the effectiveness of an already in-use CAR-T product against B-cell acute lymphoblastic leukemia , varnimcabtagene autoleucel (varni-cel), correlating the effects to its biological features. They studied the product before being injected into the patients (infusion product) and during its expansion inside their blood stream, a process that takes around 4 weeks and results not only in the production of many more cells, but also in the differentiation of the original CAR-Ts into different types of immune T-cells, as would happen in a "native" immune system. Results show that T-cells incorporating the CAR construct (CARpositive) have a higher proliferation rate than those who did not.
Also, the CARpositive population has a higher proportion of CD4 + cells, compared to the CARnegatives, more prone to CD8 + type. In the infusion product, a threefold or higher amount of CD4 + cells over CD8 + cells was related to complete cancer remission (95% patients) and five-year event-free survival (43% patients). Also, still in the pre-infusion part of the CAR-T therapy, the research shows that it is possible to find signals of T-cell exhaustion already in the infusion product.
T-cell exhaustion results in low activity cells, and is related to early relapses, lower event-free survival and lower persistence of the CAR-T cells into the patient after treatment. Taken together, these results encourage a better-quality control of the infusion products, focusing on the CD4 vs. CD8 ratio and the presence of exhaustion signals.
Once the product has been infused into the patients, there are also signals predicting its future success. Researchers found that the expansion of the CAR-T cells in the next few weeks is critical. During this expansion, both CARpositive and CARnegative cells work together to establish a functional and diverse set of T-cells, especially the cytotoxic populations, able to directly kill cancer cells : the CD8 + and the gamma-delta cells, found to be the key elements of the therapeutic effect.
Indeed, in the most successful treatments, this latter type increased up to 200-fold and tracking its amount in the blood stream proved to be a reliable prognosis marker. The present research represents the analysis of a significant group of patients, offering a strong enough view on the diversity of CAR-T infusion products and its course during therapy. The screening of a larger group may add some nuisance to the findings and help identify other objective features of the CAR-T products, either before or after infusion, that can help increase its success, in terms of complete remission rates and long event-free survival, for the benefit of cancer patients.
More information: Mercedes Guerrero-Murillo et al, Integrative single-cell multi-omics of CD19-CARpos and CARneg T cells suggest drivers of immunotherapy response in B cell neoplasias, Cell Reports Medicine (2024). DOI: 10.1016/j.
xcrm.2024.101803.
