At the Bedside: Adoptive cell therapy for melanoma—clinical development

Adoptive cell therapy for melanoma, particularly using TIL, consists of a complex and difficult set of procedures, although it has a strong preclinical background and justification and has been pursued clinically by one small group of investigators over the last 20 years. More recent developments and a better understanding of the molecular basis of the anti-tumor immune response have led to the conduct of clinical trials that use lymphoid depletion with chemotherapy and/or TBI to exploit the favorable immune milieu of homeostatic lymphoid reconstitution during transfer of effector T cells. Improved ways of propagating T cells ex vivo have also simplified and shortened the cell-growth process. Current TIL trials have now been expanded beyond the initial center where it was developed, reproducing excellent objective response rates of 40–50% in previously treated melanoma patients and more importantly, demonstrating that a significant proportion of patients will be alive and free of disease 3–5 years after treatment, raising the possibility that those patients may be cured of their disease. Newer methods for growing the infiltrating T cells using immune-checkpoint antibodies or other agents to condition the tumor before harvest and improved technology to simplify the complex and often cumbersome cell-growth process suggest that this technology may be able to be disseminated to a wide selection of cancer centers and may be a candidate for testing in a randomized Phase III trial to show definitively its benefit in patients with metastatic melanoma. In the accompanying review, the preclinical work that supports the idea of adoptive cell therapy with TIL and expands the concept in promising new ways will be explored. J. Leukoc. Biol. 95: 000–000; 2014. INITIAL DEMONSTRATION OF SUCCESSFUL ADOPTIVE CELL THERAPY: LAK CELLS WITH IL-2 The earliest adoptive cell therapy trials in the 1980s were conducted with LAK cells administered with high-dose IL-2 [1‐4]. LAK cells were autologous peripheral blood monocytes from a leukapheresis blood specimen that were incubated with IL-2 in media in large plastic plates and harvested after 72 h of activation to induce nonclass I-restricted lytic activity. The LAK trials resulted in significant response rates in patients with previously treated melanoma and established that IL-2 was a treatment modality for melanoma that could induce long-term survival in the modest proportion (15%) of patients who had CR and PR. The toxicity of the combination regimen was severe, predominantly as a result of the use of high-dose IL-2, resulting in a capillary leak syndrome that in some cases, was associated with noncardiogenic pulmonary edema, tachyarrhythmias, and renal failure. Initial trials in small numbers of patients showed response rates in melanoma for LAK therapy of 20%, with 23 responses of 106 patients treated in one study. A subsequent, randomized trial of LAK cells, plus high-dose IL-2 compared with high-dose IL-2 alone in 181 cancer patients who had failed all standard therapy, included 54 melanoma patients. The data showed a trend toward improved survival for patients with melanoma who received IL-2 plus LAK cells compared with those who received IL-2 alone (at 24 months, 32% vs. 15% OS with a two-sided P0.064). None of 26 patients with melanoma who received IL-2 alone was alive at 5 years of follow-up; five of 28 who received IL-2 plus LAK cells were alive, and three continued in CR beyond 5 years. These borderline data diminished enthusiasm for the use of LAK cells, as new murine preclinical data showed that antigen-specific T cells grown from tumors might be more therapeutically active.