Cutaneous T cell lymphoma (CTCL) is an indolent subset of T cell, non-Hodgkin’s lymphoma where cancerous T cells form cutaneous lesions in addition to comprising a circulating disease compartment. Mycosis fungoides (MF) and Sezary Syndrome (SS) are the most common CTCL disease subtypes, with SS considered to be an advanced variant.
In most instances, CTCL patients experience skin related symptoms without further complications. However, approximately 10% progress to later stage disease with serious complications. Bone marrow transplants, histone deacetylase (HDAC) inhibitors, phototherapy and chemotherapy are common therapeutic options. Although remission rates of approximately 30% are observed, they are not durable, highlighting the need for new treatment options. Immunotherapeutic approaches such as monoclonal antibodies, antibody-drug conjugates and chimeric antigen receptor (CAR) T cells have the potential to provide promising advances for the treatment of this disease. However, these approaches rely heavily on the ability to identify a tumour specific target that is, conversely, essentially absent on normal cells.
Herein, we propose Tumour Associated Glycoprotein 72 (TAG-72) as one such target. TAG-72 is a high molecular weight mucin-associated truncated O-glycan that has been established as a marker of pan adenocarcinomas but had not been explored in T cell lymphoma. Using flow cytometry, we analysed TAG-72 on CD3+ T cells from healthy donors (HD, n=15), SS (n=21), MF (n=18) and other CTCL patients that are not SS or MF (n=8); expression was significantly increased on patient samples compared to healthy donors (p<0.05). As a compartment of CTCL disease is skin associated, punch biopsies of lesion affected skin were obtained from 11 patients and assessed for TAG-72 expression by immunohistochemistry; 3 individuals presented with cutaneous infiltrating TAG-72 cells. These combined results provide support for use of TAG-72 as a target antigen in the treatment of CTCL. Accordingly, we produced anti-TAG-72 CAR-T cells and tested their ability to eliminate CTCL in vitro. Peripheral blood mononuclear cells (PBMCs) isolated from CTCL patients (n=36) were co-cultured with TAG72 specific CAR-T cells generated from healthy donors. Appropriate controls were maintained in parallel. Following 24h exposure, CD3+/TAG-72+ expressing CTCL cells were significantly reduced (p<0.0001) by the CAR-T cells, compared to the non-transduced control T cells. Analysis of T cell leukaemia patients (n=5) showed no expression of TAG-72 on their CD3+ cells.
Taken together, these are the first evidence to demonstrate TAG-72 as a potential target for the treatment of CTCL.