Project #13324
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#13324 : Defining the differential contributions of CD4+ and CD8+ anti-CD19 CAR T cells to tumor outcome, immune recruitment and toxicity
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Name of Applicant : Marine Cazaux
Date of application : 13-06-2019
Unit : Dynamics of Immune Responses
Location : Metchnikoff-4th floor-4012
Phone : 0698845478
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Project context and summary :

Gene-modified T cells expressing a chimeric antigen receptor (CAR) targeting the CD19 molecule have demonstrated promising clinical efficacy in the treatment of B cell malignancies. However, the frequent relapses and toxic adverse events such as cytokine release syndrome represent hurdles to the success of CAR T cell therapies. In most clinical settings, CAR T cells are generated from a mixture of autologous CD4+ and CD8+ T cells before being infused into patients. This inter-patient heterogeneity within the composition of CAR T cell products renders the large variety of response efficacy and toxicity difficult to interpret. Using a model of B cell aggressive lymphoma developing in the bone marrow, we investigate the differential contributions of CD4+ and CD8+ anti-CD19 CAR T cells to tumor outcome and changes in the tumor microenvironment. Our first in vivo imaging and flow cytometry results suggest that CD4+ CAR T cells have poor cytotoxic potential compared to CD8+ CAR T cell. On the other hand, CD4+ CAR T cells were largely responsible for the cytokine release syndrome and have a unique role in boosting the accumulation of NK cells at the tumor site. Using single cell RNAseq, we aim to identify the changes in the bone marrow tumor microenvironment induced by CD4+ and CD8+ CAR T cells, focusing on the recruitment of host specific immune cell populations and their activation status. Identifying specific contributions of the CD4+ and CD8+ CAR T cells to immune cell recruitment and tumor outcome would help designing optimal CAR T cell products, with important clinical implications.

Related team publications :
Cazaux, M. et al. (2019) Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity. Journal of Experimental Medicine DOI: 10.1084/jem.20182375
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Project Type : Short
Status : Awaiting Publication
Global Satisfaction for this application : Pretty Good (4/5)

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