Biology subjects

Barros, L. R. C.

Publications and source records attributed to Barros, L. R. C..

4 recordsLinked to original sources

bioRxiv2024

Healthy B cells: allies or adversaries of CAR-T cell immunotherapy?

Chimeric antigen receptor (CAR)-T cell immunotherapy has achieved significant success against various haematological cancers, including B-cell malignancies. Its efficacy against B-cell cancers is influenced by the presence of healthy B-cells expressing the target antigen, and B-cell aplasia (BCA) serves as an indicator of successful therapy outcome. However, the precise influence of healthy B-cells on the in vivo dynamics of CAR-T cells and their ultimate impact on therapy outcomes remain unclear. Here, we propose a mathematical model to describe CAR-T cell immunotherapy in B-cell cancer patients. Our model successfully captured the interactions between different CAR-T cell phenotypes, tumour cells, and healthy B cells in patients who achieved a complete response. Using these cases, we constructed virtual scenarios to investigate how variations in baseline tumour and healthy B-cell populations, along with patient-specific factors related to CAR-T cell expansion and B-cell influx from the bone marrow, affect treatment outcomes. Our results suggest that the onset and duration of BCA is a patient-specific feature that depends primarily on the continuous influx of newly generated B cells, their proliferative capacity, and the expansion and cytotoxicity of CAR-T cells. Statement of significanceThis study presents a significant advancement in understanding the dynamics of CAR-T cell immunotherapy in B-cell malignancies by introducing a mathematical model that captures the complex interactions between CAR-T cells, tumour cells, and healthy B cells. The model provides crucial insights into how patient-specific factors, such as baseline tumour burden, B-cell populations, and CAR-T cell expansion, influence treatment outcomes, including the onset and duration of B-cell aplasia (BCA), a key marker of therapeutic success. Healthy B cells can act as allies, adversaries, or have a neutral effect on the therapy, depending on the tumour burden. These findings highlight the importance of personalised approaches in CAR-T cell immunotherapy, offering potential pathways to optimise treatment strategies for improved efficacy and patient outcomes.

cancer biology↗

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↗

bioRxiv2019

DEVELOPMENT OF CAR-T CELL THERAPY FOR B-ALL USING A POINT-OF-CARE APPROACH

Recently approved by the FDA and European Medicines Agency, CAR-T cell therapy is a new treatment option for B-cell malignancies. Currently, CAR-T cells are manufactured in centralized facilities and face bottlenecks like complex scaling up, high costs and logistic operations. These difficulties are mainly related to the use of viral vectors and the requirement to expand CAR-T cells to reach the therapeutic dose. In this paper, by using Sleeping Beauty-mediated genetic modification delivered by electroporation, we show that CAR-T cells can be generated and used without the need for ex vivo activation and expansion, consistent with a point-of-care (POC) approach. Our results show that minimally manipulated CAR-T cells are effective in vivo against RS4;11 leukemia cells engrafted in NSG mice even when inoculated after only 4 hours of gene transfer. In an effort to better characterize the infused CAR-T cells, we show that 19BBz T lymphocytes infused after 24h of electroporation (where CAR expression is already detectable) can improve the overall survival and reduce tumor burden in organs of mice engrafted with RS4;11 or Nalm-6 B cell leukemia. A side-by-side comparison of POC approach with a conventional 8-day expansion protocol using Transact beads demonstrated that both approaches have equivalent antitumor activity in vivo. Our data suggests that POC approach is a viable alternative for the generation and use of CAR-T cells, overcoming the limitations of current manufacturing protocols. Its use has the potential to expand CAR immunotherapy to a higher number of patients, especially in the context of low-income countries.

immunology↗