Um biomarcador de imunoterapia altamente sensível, sem a necessidade de sonda e não invasivo para a aptidão de células CAR-T

We tackle the challenge of enhancing efficacy and reducing costs in cell therapies, crucial for advancing medical treatment and broadening access to innovative healthcare solutions. The ultimate goal of this project is to develop a biomarker – eFIT – that enhances therapeutic efficacy, lowers costs, and is suitable for widespread clinical adoption. eFIT measures the fitness state of the cell and works as an early biomarker for cellular dysfunction. Our ambitious goal originated from the cross-fertilization between biochemistry and thermodynamics. We go beyond the traditional view of heat being just a measure of the metabolic activity or the amount of biomass of a living system. Embodiment of a CUTTING-EDGE VIEW of heat, the rate of energy dissipation per cell (eFIT) characterizes functionally integrated networks in cells with a single parameter, detecting early responses to challenges before loss of function (Bento et al., 2022). In addition, eFIT assay by MICROCALORIMETRY is PROBE-FREE and NON-INVASIVE, making eFIT well-suited for clinical implementation. As a proof of concept, we applied eFIT assay to CAR T immunotherapy. Clinical trials show that pre-procedure T CELL FITNESS is critical for CAR T therapy success (Locke et al., 2020) (Chen et al., 2021). CURRENT IMMUNOTHERAPY BIOMARKERS are: (1) either molecular markers that are sensitive to INDIVIDUAL PATHWAYS but miss the integrative nature of the cell (e.g. LAG-3 (Finney et al., 2019)); or (2) integrative biomarkers (e.g. IFN-gamma production) that are excellent markers of overall T cell function, but LACK SENSITIVITY as they detect changes only when cellular function is compromised (e.g. CAR T IFN-gamma production (FDA, 2017)). Our heat-based eFIT FITNESS BIOMARKER is both INTEGRATIVE and SENSITIVE constituting a significant advance over the current state of the art. Project milestones are focused in reducing the technological risk and obtaining key results that lay the ground for the next stage of the project. The two main aims are (Figure 1): 1. Validate eFIT as a predictive biomarker for CAR T therapy efficacy by identifying the most suitable T cells. 2. Construct a PROTOTYPE of a HIGH-THROUGHPUT eFIT reader that serves as the foundation for a medical device suitable for large-scale point-of-care deployment. Due to its UNIVERSAL character, eFIT can support any cell therapy because it is agnostic concerning the subsets of cell used, the modifications made (e.g. CAR T, CAR NK, TCR, TIL), the ALLOGENIC or AUTOLOGOUS source of cells, or the disease target (different cancer types, autoimmune diseases, prevention of GRAFT-VERSUS-HOST DISEASE or CYTOMEGALOVIRUS INFECTION after hematopoietic cell transplants). Finally, our rationale can be translated to STEM CELL THERAPY.