Adoptive-cell-transfer therapy for the treatment of patients with cancer

Abstract

Adoptive-cell-transfer (ACT) therapy for patients with cancer relies on the ex vivo generation of highly active, tumour-specific lymphocytes, and their administration in large numbers to the autologous host. Preclinical models have identified characteristics of lymphocyte cultures that are required for successful ACT therapy. The most important characteristic is the presence of high affinity, tumour-antigen-specific CD8⁺ T cells. There is generally a direct correlation between treatment efficacy and the number of transferred, tumour-specific cells. Preclinical models have also identified ways to manipulate the host immune environment that increase ACT therapeutic efficacy. These include immunosuppression before cell administration and concurrent interleukin 2 administration with the transferred T cells. ACT therapy directed at viral antigens has been effective for elimination of Epstein–Barr virus (EBV)-induced post-transplant lymphoproliferative disease. EBV-specific lymphocyte cultures suitable for ACT therapy were generated by repetitive in vitro stimulation using EBV-transformed lymphoblastoid lines. Lymphocyte cultures that were selected for reactivity against melanoma antigens, including melanocyte-differentiation antigens, mediated cancer regression in some patients with metastatic melanoma. Melanoma-reactive cultures that were suitable for ACT therapy were generated from tumour-infiltrating lymphocytes that were rapidly expanded with anti-CD3 antibody. The generation of tumour-antigen-specific lymphocyte cultures is evolving rapidly, spurred on by the identification of tumour antigens and the T-cell receptors that recognize them. Further improvements to ACT therapy will depend on a deeper understanding of basic immunological processes, including the role of CD4⁺ T cells in the antitumour inflammatory response, the ability of lymphocytes to persist in vivo and travel to tumours, and the mechanisms of ACT augmentation by previous host immunosuppression.