Adoptive T-Cell Therapy of Melanoma Using Designer T-Cell Receptors

Abstract

Introduction: Robbins and colleagues reported in the February issue of the Journal of Clinical Oncology the antitumor activity of T cells genetically engineered to recognize a unique tumor antigen in patients with advanced, refractory sarcoma and metastatic melanoma [1]. This report is the most recent of a series of trials investigating the activity of a regimen consisting of antigen-specific T lymphocytes plus high-dose interleukin-2 (HD-IL2) for patients with advanced melanoma refractory to high-dose IL-2. The authors’ group at the National Cancer Institute Surgery Branch has contributed extensively to the literature in this field, and a prior report by Dudley et al. [2] in the same journal details the results of three sequential trials of tumor-infiltrating lymphocytes followed by HD-IL2, showing improved response rates up to 70% with the addition of lympho-depleting chemotherapy and 1200 cGy of total body irradiation, which is also profoundly myelosuppressive. The latter regimen is comparable in intensity to the fully myeloablative conditioning regimens used to prepare recipients with hematologic malignancy for allogeneic hematopoietic cell transplant [3]. The rationale for intense conditioning prior to the infusion of cytotoxic T cells is based on the concept that the homeostatic cytokines IL-7 and IL-15 become available in increased concentrations in the setting of profound lymphopenia and contribute to lymphoid reconstitution that enriches the percentage of antigen-specific clones, which are further maintained by the post-infusion administration of HD-IL2 [4]. In this study, the authors also pioneered the use of the cancer-testis antigen NY-Eso-1, which is found on a variety of solid tumors but is otherwise limited in adult tissues to the testis, which is also protected from systemic exposure by a physiologic “blood-testis barrier.” The absence of expression of this antigen in any normal adult tissue renders it ideal for use in cancer patients, where it is desirable to avoid immunologic cross-reaction with normal tissues expressing the tumor antigen or immunologically crossreactive proteins as well as to overcome or “break” immunologic tolerance which is more likely when a tumor antigen is also expressed on normal adult tissues (for example, the melanocyte differentiation antigens MART-1/ Melan-A, gp-100, and tyrosinase).