Adoptive cell therapy for the treatment of patients with metastatic melanoma
Introduction
Melanoma appears to be unique among human cancers because of its ability to induce significant numbers of lymphocytes with anti-tumor activity during the natural course of tumor growth [1]. Thus, tumor infiltrating lymphocytes (TIL) or peripheral lymphocytes repeatedly stimulated in vitro with autologous melanoma cells often demonstrate in vitro recognition of melanoma cells based on assays of lysis or cytokine secretion. The ability to isolate and characterize anti-tumor lymphocytes from patients with melanoma has thus enabled the identification and characterization of multiple melanoma associated antigens that can be the target of immunotherapy [2, 3]. The development of techniques to grow large numbers of anti-tumor lymphocytes has enabled the development of cell transfer therapies that are by far, the most effective treatment for patients with metastatic melanoma [4, 5•, 6].
Effective cancer immunotherapy is dependent on the presence of large numbers of anti-tumor lymphocytes with appropriate homing and effector functions that enable them to seek out and destroy cancer cells in vivo. Adoptive cell therapy (ACT) refers to an immunotherapy approach in which anti-tumor lymphocytes are identified and grown ex vivo and then infused into the cancer patient, often along with vaccines or growth factors that can augment the in vivo impact of the transferred cells [6]. Since ACT involves the administration of ex vivo cultured lymphocytes, very large numbers of anti-tumor lymphocytes can be generated and infused. The ability to test the activity of cells before infusion enables the identification of highly selected cells with high avidity for tumor antigens. Naturally occurring anti-tumor lymphocytes are often anergized or tolerized in vivo and thus the ability to culture these cells ex vivo away from suppressive influences that exist in vivo enables the administration of highly activated cells that exhibit multiple anti-tumor effector functions. Perhaps the most important factor responsible for the effectiveness of ACT is the ability to manipulate the host before cell transfer to provide an improved environment for the transferred cells. A variety of immunosuppressive influences can exist in the cancer patient including the presence of lymphocytes or myeloid cells with immunosuppressive activity. These suppressive factors may play a role in limiting the anti-tumor effectiveness of non-specific immune stimulants such as interleukin-2 (IL-2). Cancer vaccines are ineffective probably owing partly to the presence of these suppressive influences [7]. This ability to remove lymphoid and myeloid suppressor cells before immune stimulation is unique to ACT as a form of immunotherapy.
It should be emphasized that although melanoma is unique in its ability to naturally result in the generation of anti-tumor T cells in vivo, there does not appear to be any difference in the susceptibility of different cancer types to the anti-tumor activity of lymphocytes. Virtually all tumors are equally susceptible to lysis and are able to stimulate cytokine release from anti-tumor lymphocytes when tumor antigen is encountered. Thus principles that are being learned concerning the effectiveness of ACT in patients with melanoma can be of value in applying ACT therapy to patients with other cancer types using lymphocytes genetically engineered to manifest anti-tumor function [6, 8••].
Section snippets
Early clinical studies of ACT for melanoma
A crucial step in the development of effective ACT for the treatment of patients with melanoma was the demonstration in 1987 that lymphocytes infiltrating into metastatic melanoma deposits could be grown in interleukin-2 (IL-2) and exhibit major histocompatability complex (MHC) restricted recognition of both fresh and cultured melanoma cells [1]. Utilizing current techniques reactivity against melanoma can be detected in TIL from approximately 80% of melanoma patients [9, 10]. The first use of
ACT following lymphodepletion in patients with melanoma
Early animal models predicted that the effectiveness of cell transfer therapies could be improved by administering either total body irradiation or lymphodepleting chemotherapy before the cell transfer. The limited persistence of the transferred cells in our early human trials thus led us to explore the use of lymphodepletion in patients with metastatic melanoma before receiving ACT with TIL. A series of clinical trials have been performed in a total of 93 patients with metastatic melanoma
Mechanisms of action of ACT in humans
Extensive studies of the mechanisms of action of ACT in humans have been performed. On the basis of animal models it appears that the lymphopenic environment acts predominantly by eliminating T regulatory cells and by eliminating competition for homeostatic cytokines such as IL-7 and IL-15 that are vital for T cell survival [23, 24, 25•]. Other factors may be involved as well such as the impact of chemotherapy and whole body irradiation on increasing extravasation of bacteria from the
Improvements in ACT that are being studied
The 49–72% objective response rates in patients with metastatic melanoma indicate that ACT represents the best available treatment for patients with this disease [4, 5•, 6]. A summary of Surgery Branch, NCI immunotherapy efforts for the treatment of patients with metastatic melanoma is shown in Figure 4. Objective response rates to treatment vaccines are about 3%, IL-2 and anti CTLA-4 about 15%, and ACT has increased response rates to 72% with increasing lymphodepletion before cell transfer.
References and recommended reading
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