TILling head and neck cancer for cell therapy

Abstract

In this issue of Cytotherapy , Junker et al. (1) describe their pre-clinical results of generating tumor-infi ltrating lymphocytes (TIL) from biopsies of head and neck squamous cell carcinoma (HNSCC). HNSCC remains a signifi cant clinical challenge because current treatment strategies are associated with signifi cant side-effects, and patients with advanced-stage disease have limited thera peutic options (2,3). Thus new approaches are necessary to improve outcomes and reduce treatment-related complications for HNSCC patients. Cell therapies have the potential to meet this challenge, best highlighted by the success of cell therapy for another head and neck cancer, nasopharyngeal carcinoma, which is associated with Epstein – Barr virus (EBV) (4 – 6). While subsets of HNSCC are positive for human papilloma virus (HPV) and strategies to generate HPV-specifi c T cells are being explored actively, a signifi cant number of HNSCC are HPV negative (7). Generating cell products for this group of HNSCC remains a challenge as only a few tumorassociated antigens have been described. Isolation and expansion of TIL is one strategy to overcome this problem. TIL have been used successfully as cell therapy for melanoma and, while initial studies were disappointing, combining TIL with high-dose chemotherapy and radiation has produced remarkable clinical responses (8,9). In addition, TIL have been used in the laboratory to identify melanoma antigens, and clone α β T-cell receptors (TCR) for clinical studies (10,11). Generating cytolytic TIL from cancers other than melanoma has been challenging (12). The article by Junker et al. (1) now demonstrates that the expansion of signifi cant numbers of TIL for clinical studies from HNSCC biopsies is feasible. They have adapted a two-step approach developed for melanoma (13), in which lymphocytes are initially expanded in highdose interleukin (IL)-2 and then expanded further with irradiated, allogeneic peripheral blood mononuclear cells in the presence of OKT3 and high-dose IL-2. Within 14 – 18 days this expansion protocol resulted in a mean 2370-fold expansion of TIL in 12 out of 15 biopsy samples. TIL contained CD4as well as CD8-positive T cells and TCR clonotype mapping revealed the presence of clonally expanded T cells suggestive of HNSCC-specifi c T cells. The authors were able to show that expanded TIL recognized autologous tumors for three out of four patients, as judged by interferon (IFN)γ ELISPOT assays. TIL of one of the patients recognized several allogeneic tumor cell lines in a major histocompatibility complex (MHC) class I-restricted fashion and T-cell clones generated from TIL from another patient had MHC class I-restricted cytolytic activity. These fi ndings suggested that TIL recognize tumor-associated antigens, and initial analyses revealed TIL-specifi city against NYESO-1, hTert, and cyclin B1. While the study from Junker et al. (1) is of practical significance, because it should pave the way for a phase I clinical trial of TIL transfer post-non-myeloablative conditioning in patients with HNSCC, it will also facilitate the future deve lopment of HNSCC-targeted cell therapies. The isolated T-cell clones present an invaluable tool to identify further tumor antigens expressed in HNSCC. In this regard the authors ’ fi nding that TIL recognize allogeneic tumor cell lines in a MHC class I-restricted manner indicate that HNSCC, like other cancers, express shared tumorassociated antigens. If successful, α β TCR derived from these clones could then be used to modify T cells genetically similar to α β TCR-based T-cell therapy pioneered for melanoma (10,11). Cytotherapy, 2011; 13: 772–773