Biology subjects

Almeida, R. C.

Publications and source records attributed to Almeida, R. C..

2 recordsLinked to original sources

bioRxiv2023

Mechanisms of Resistance to CAR-T cell Immunotherapy: Insights from a Mathematical Model

Chimeric Antigen Receptor (CAR)-T cell therapy long-term follow-up studies revealed non-durable remissions in a significant number of patients. Some of the mechanisms underlying these relapses include poor CAR T cell cytotoxicity or persistence, as well as antigen loss or lineage switching in tumor cells. In order to investigate how antigen-mediated resistance mechanisms affect therapy outcomes, we develop a mathematical model based on a set of integral-partial differential equations. Using a continuous variable to describe the level of antigen expression of tumor cells, we recapitulated important cellular mechanisms across patients with different therapeutic responses. Fitted with clinical data, the model successfully captured the dynamics of tumor and CAR-T cells for several hematological cancers. Furthermore, the role played by these mechanisms are explored with regard to different biological scenarios, such as pre-existing or acquired mutations, providing a deeper understanding of key factors underlying resistance to CAR-T cell immunotherapy. Statement of significanceOur study introduces the first mathematical model to characterize the influence of a continuous level of antigen expression on the interplay between Chimeric Antigen Receptor (CAR)-T cells and cancer cells. We examine various cellular mechanisms across different hematologic cancers, taking into account both antigen-positive and antigen-negative relapses. Our findings shed light on the role of antigen density in CAR-T cell therapies and provide a valuable framework to investigate resistance with potential to improve patients outcomes.

cancer biology↗

bioRxiv2019

Three-Compartment Model of CAR T-cell Immunotherapy

Immunotherapy has gained great momentum with chimeric antigen receptor T-cell (CAR T) therapy, in which patients T lymphocytes are genetically manipulated to recognize tumor-specific antigens to increase tumor elimination efficiency. Improved CAR T cell immunotherapy requires a better understanding of the interplay between CAR T cell doses and tumor burden, administration protocol, toxicity, resistance to immunotherapy, among other features. We developed a three-compartment mathematical model to describe tumor response to CAR T cell immunotherapy in immunodeficient mouse models. It encompasses interactions between tumor cells, effector and long-term memory CAR T cells such as tumor induced immunosuppression effects, conversion of memory T cells into effector T cells in the presence of tumor cells, and individual specificities considered as uncertainties in the parameters of the model. The model was able to represent two different immunotherapy scenarios with different CAR receptors and tumor targets reported in the literature. Further in silico studies considering different dosing quantities and tumor burden showed that the proposed model can represent the three possible therapy outcomes: tumor elimination, equilibrium, and escape. We found that therapy effectiveness may also depend on small variations in the parameter values, regarded as intrinsic individual specificities, as T cell proliferation capacity, as well as immunosuppressive tumor microenvironment factors. These issues may significantly reduce the chance of tumor elimination. In this way, the developed model provides potential use for assessing different CAR T cell protocols and associated efficacy without further in vivo experiments.

immunology↗