Scientists have found features in CAR-T therapies that may help predict their effectiveness in patients.
The Spanish research team studied a CAR-T therapy in use against B-cell acute lymphoblastic leukaemia, varnimcabtagene autoleucel. They studied the treatment before infusion and then its progress in the blood stream of five patients, over a period of four weeks.
The first finding was that T-cells that were successfully transduced (CAR-positive) proliferated at a greater rate than CAR-negative cells. A key feature of CAR-positive cells was a high proportion of CD4+ cells compared to CD8+ cells. Higher CD4:CD8 ratios were associated with treatment success; when CD4+ cells were three times more numerous than CD8+ cells within the infusion product, this was associated with complete cancer remission and five-year event-free survival.
A third finding was that laboratory examination could reveal early signs of T cell exhaustion in the infusion product, independent of CAR expression, indicating a reduced chance of success.
The researchers call for improved quality control of CAR-T with attention paid to the ratio of CD4 and CD8 cells and to signals of exhaustion.
After infusion, the researchers found CAR-positive and CAR-negative cells working together to establish a “functional and diverse” set of T cells. At this stage CD8+ and gamma-delta cytotoxic T cells were associated with successful therapy.
The research was undertaken at the Josep Carreras Leukaemia Research Institute, Barcelona, Spain, and reported in the journal Cell Reports Medicine.
The researcher state: “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 nuance 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.”
Source:
Guerrero-Murillo M, Rill-Hinarejos A, Trincado JL, Bataller A, Ortiz-Maldonado V, Benítez-Ribas D, Español-Rego M, González-Navarro EA, Martínez-Cibrián N, Marchese D, Martín-Martín L, Martín García-Sancho A, Rives S, Heyn H, Juan M, Urbano-Ispizúa Á, Delgado J, Orfao A, Mereu E, Bueno C, Menendez P. (2024) “Integrative single-cell multi-omics of CD19-CARpos and CARneg T cells suggest drivers of immunotherapy response in B cell neoplasias.” Cell Reports Medicine, 28 October 2024, doi: 10.1016/j.xcrm.2024.101803.
Link: https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00550-0
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