Abstract
T cells engineered to express chimeric antigen receptors (CARs) combining an external antibody binding domain with the CD3ζ T cell receptor (TCR) signaling domain for triggering cell activation are being used for immunotherapeutic targeting of tumor cells in a non-HLA restricted manner. In this study we transduced T cells with a CD19-CAR construct containing a truncated CD34 gene (tCD34) marker and used these to target the B cell antigen CD19 on the surface of a Hodgkin’s lymphoma (HL) cell line (L591) both in vitro and in vivo. Levels of tCD34 expression in transduced peripheral blood mononuclear cells (PBMCs) ranged from 6% - 20% and this was increased to 82% after selection for transduced tCD34+ cells. In vitro cytotoxicity testing on a CD19+ HL cell line (L591) showed specific cell lysis initiated by the CD19-CAR transduced PBMCs. Importantly, CD19-CAR T cells prevented the growth of L591 HL tumor cells when co-injected subcutaneously (sc) in 6/6 severe combined immunodeficient (SCID) mice. There was no evidence of anti-tumor activity when CD19-CAR T cells were infused intravenously (iv) at the same time as L591 HL tumor cells were injected sc. However, 3/6 SCID mice showed tumor rejection within 83 days after iv infusion of CD19-CAR T cells 3 - 9 days after establishment of L591 HL tumors, while all control animals succumbed to tumors within 60 days. Interestingly, immuno-histochemical analysis of L591 HL tumors demonstrated that CD19-CAR T cells were detected not earlier than 11 days after infusion within the tumor mass. These results suggest that CD19 is a potentially attractive target for the immunotherapy of HL.
Highlights
Hodgkin’s lymphoma (HL) is the most common lymphoma in young people in industrialised countries, with around 1500 new cases diagnosed per year in the UK
In vitro cytotoxicity testing on a CD19+ HL cell line (L591) showed specific cell lysis initiated by the CD19-chimeric antigen receptors (CARs) transduced peripheral blood mononuclear cells (PBMCs)
The results demonstrate that activated PBMCs transduced with a retroviral vector to express a CAR specific for CD19 are capable of specific lysis of CD19+ ve HL target cells in an in vitro cytotoxicity assay and can mediate significant tumor regression in an in vivo model of HL
Summary
Hodgkin’s lymphoma (HL) is the most common lymphoma in young people in industrialised countries, with around 1500 new cases diagnosed per year in the UK. The remaining tumour bulk consists of a non-neoplastic infiltrate of leucocytes including lymphocytes and prominent eosinophils. Up to 50% of HL is associated with Epstein-Barr virus (EBV), a ubiquitous gamma-herpesvirus which persists for life in B lymphocytes of the host after primary infection [1]. In EBV-positive HL, HRS cells express a limited number of latent EB viral genes including the viral oncogene latent membrane protein (LMP)-1. HL is one of the most treatable adult cancers with over 80% of patients achieving complete remission following chemotherapy and/or radiotherapy. A proportion of patients have resistant primary disease and up to a third of those achieving remission later relapse.
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