Novel Approach to Predict and Optimize CAR-T Cell Therapy

The development of CAR-T cell therapy marks a major breakthrough in cancer treatment. These “living drugs” are T-cells genetically engineered to spread through the body, identify, and destroy cancer cells. They offer new hope to many patients, especially those with recurring blood cancers who haven’t responded to traditional therapies.

However, despite these advances, fewer than 50% of patients achieve sustained full remission one year after treatment, underscoring the need for further optimization.

A recent study by the Josep Carreras Leukemia Research Institute has identified three key characteristics of CAR-T cells that help predict treatment success, regardless of the patient. Authored by Mercedes Guerrero and Aina Rill and published in Cell Reports Medicine, the study was led by Pablo Menéndez, Clara Bueno, and Elisabetta Mereu.

It involved collaboration with the Hospital Clínic de Barcelona and Salamanca's Biomedical Research Institute (IBSAL), both part of Spain's Advanced Therapies Network (TERAV-ISCIII) and the CIBERONC initiative.

Using advanced single-cell multiomics, the researchers analyzed varnimcabtagene autoleucel (varni-cel), an approved CAR-T therapy, assessing its effectiveness against B-cell acute lymphoblastic leukemia.

They examined the CAR-T cells both before infusion and as they expanded in patients' bloodstreams over four weeks, a period during which the cells differentiate into various T-cell subtypes, mimicking a natural immune response.

Key findings include:

- Enhanced Proliferation of CAR-Positive T-Cells: CAR-positive T-cells (those modified with the CAR construct) proliferate faster than CAR-negative cells, with a higher proportion of CD4+ helper T-cells compared to the predominantly CD8+ CAR-negative cells.
- CD4/CD8 Ratio and Remission Correlation: Complete remission and five-year event-free survival were linked to an infusion product with at least three times as many CD4+ cells as CD8+ cells.
- T-Cell Exhaustion Signals: Indicators of T-cell exhaustion in the infusion product were associated with early relapses, reduced CAR-T persistence, and lower event-free survival rates. 

These insights underscore the importance of rigorous quality control in infusion products, specifically monitoring the CD4/CD8 ratio and exhaustion signals, to improve treatment outcomes.

Post-infusion, the growth of CAR-T cells over three weeks plays a critical role. Both CAR-positive and CAR-negative cells contribute to a diverse and functional T-cell population, with cytotoxic CD8+ and gamma-delta T-cells showing particular importance for directly attacking cancer cells. The latter population increased by up to 200-fold in the most successful treatments, making it a reliable indicator of therapeutic efficacy.

This study, involving a substantial patient cohort, provides a comprehensive view of the diversity within CAR-T products and their progression during treatment. Screening larger patient groups could refine these findings and identify additional markers for CAR-T efficacy, ultimately enhancing long-term remission rates and event-free survival for cancer patients.