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Uncoupling T-cell expansion from effector differentiation in cell-based immunotherapy |
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| Authors: | Joseph G. Crompton Madhusudhanan Sukumar Nicholas P. Restifo |
| Affiliation: | 1. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK;2. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;3. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Correspondence to: Nicholas P. Restifo National Cancer Institute, National Institutes of Health Mark O. Hatfield Clinical Research Center Room 3-5672, 10 Center Drive Bethesda, MD 20892-1502, USA Tel.: +1 301 496 4904 Fax: +1 301 451 6949 e-mail: restifo@nih.gov |
| Abstract: | Adoptive cellular immunotherapy (ACT) is a potentially curative therapy for patients with advanced cancer. Eradication of tumor in mouse models and humans correlates with both a high dose of adoptively transferred cells and cells with a minimally differentiated phenotype that maintain replicative capacity and multipotency. We speculate that response to ACT not only requires transfer of cells with immediate cytolytic effector function to kill the bulk of fast-growing tumor but also transfer of tumor-specific cells that maintain an ability for self-renewal and the capacity to produce a continual supply of cytolytic effector progeny until all malignant cells are eliminated. Current in vitro methods to expand cells to sufficient numbers and still maintain a minimally differentiated phenotype are hindered by the biological coupling of clonal expansion and effector differentiation. Therefore, a better understanding of the physiologic mechanism that couples cell expansion and differentiation in CD8+ T cells may improve the efficacy of ACT. |
| Keywords: | adoptive cell transfer T-cell based-therapy effector differentiation replicative senescence CD8+ T cells adoptive cellular immunotherapy |