OR10

In vivo CAR T cell therapy against angioimmunoblastic T cell lymphoma

A Krug(1) A Saidane(1) C Martinello(1) F Fusil(2) A Michels(3) C J Buccholz(3,4) J E Ricci(1) E Verhoeyen(1,2)

1:C3M, Université Côte d’Azur, INSERM U1065, Nice, 06204, France; 2:CIRI – International Center for Infectiology Research, Université de Lyon; Inserm U1111; Université Claude Bernard Lyon 1; CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, Lyon, F-69007, France; 3:Molecular Biotechnology and Gene Therapy, Paul-Erlich-Institut, Langen, 63225, Germany; 4:Division of Medical Biotechnology, Paul-Erlich-Istitut, Langen, 63225, Germany

Angioimmunoblastic T cell lymphoma (AITL) represents a rare complex malignancy with no specific treatment available and a poor survival outcome. We have previously generated a unique preclinical mouse model for AITL by overexpressing glyceraldehyde-3-phosphate dehydrogenase (GAPDH) exclusively in T cells, resulting in a T cell lymphoma closely mimicking the clinical and pathological features of human AITL disease, with CD4⁺ follicular helper T cells being the drivers of the malignancy.

By lentiviral (LV) transduction, we generated CD8⁺ T cells expressing a chimeric antigen receptor (CAR) against the CD4 epitope present on the malignant T cells. To allow the vector’s exclusive entry into CD8⁺ T cells, the anti-CD4CAR LV has been pseudotyped with a CD8 receptor-targeted measles virus envelope (anti-CD4CAR CD8-LV).

Anti-CD4CAR CD8-LV transduced murine AITL biopsies resulted in CAR expression on CD8⁺ T cells and in their expansion, accompanied by an almost complete elimination of the neoplastic CD4⁺ T cells, as compared to the control transduced with GPF-encoding CD8-LV. We then evaluated the anti-CD4CAR CD8-LV functionality and specificity in vivo by direct injection into the bloodstream of our preclinical mAITL model. This resulted in the generation of functional anti-CD4CAR CD8⁺ effector T cells in vivo and in a significant reduction of the CD4⁺ neoplastic T cells from the tumor, which correlated with an increased survival of the AITL mice.

This study might offer a new therapeutic perspective for patients suffering from a CD4-driven T cell lymphoma, which could surmount the main problems of current ex vivo CAR T cell therapy.