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.
Adoptive immunotherapy — the isolation of antigen-specific cells, their ex vivo expansion and activation, and subsequent autologous administration — is a promising approach to inducing antitumour immune responses. The molecular identification of tumour antigens and the ability to monitor the persistence and transport of transferred cells has provided new insights into the mechanisms of tumour immunotherapy. Recent studies have shown the effectiveness of cell-transfer therapies for the treatment of patients with selected metastatic cancers. These studies provide a blueprint for the wider application of adoptive-cell-transfer therapy, and emphasize the requirement for in vivo persistence of the cells for therapeutic efficacy.
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- CYTOTOXIC T LYMPHOCYTES
(CTLs). T lymphocytes that exert a cytolytic function following engagement by their T-cell antigen receptor on target cells. CTLs express the co-receptor CD8 and recognize antigenic peptides (or CTL epitopes) that are presented by HLA-class-I molecules.
- MHC-CLASS-I MOLECULES
Highly polymorphic glycoproteins that are expressed by every nucleated cell of vertebrates, and that are encoded by the gene cluster 'major histocompatibility complex' (MHC). The human MHC molecules are termed HLA (human leukocyte antigen) molecules. MHC-class-I molecules mainly present peptides from intracellular proteins to cytotoxic T cells.
- HLA-RESTRICTED ANTIGENS
T-cell receptors recognize antigen peptides on the surface of antigen-presenting cells in the context of an HLA molecule. Each HLA allele can bind only a fraction of the potential peptide pool, and this 'restricts' the peptide repertoire. So, the HLA-restricted antigenic peptides provide a unique immunological 'signature' that allows immune discrimination of tumour cells, but not normal cells.
- MHC-CLASS-II MOLECULES
Peptide receptors, similar to class-I molecules in structure and function, but expressed by a small set of professional antigen-presenting immune cells. They mainly present peptides from extracellular proteins to T-helper cells.
- CD4+ T CELLS
T cells bearing the CD4 surface glycoprotein, which recognizes MHC-class-II molecules. These cells provide helper function to CD8+ T cells through the release of cytokines and the activation of professional antigen-presenting cells.
- CD8+ T CELLS
T cells bearing the CD8 cell-surface glycoprotein, which recognizes MHC-class-I molecules on target cells. CD8+ T cells are usually cytotoxic T cells.
- ANERGIC T CELLS
T cells that are unable to undergo proliferation, secretion of inflammatory cytokines or other functions in response to antigens.
- SYNGENEIC TUMOURS
Tumours derived from mice with an identical genetic background; specifically, the same inbred line.
- GRAFT-VERSUS-HOST DISEASE
A toxic reaction that is mediated by donor-derived T lymphocytes within the graft towards the recipient's organs. The attack is usually directed toward the skin, gut, liver and haematopoietic cells.
Optimal stimulation of T-cell proliferation requires two signals. Signal one is transduced through T-cell-antigen receptors. Signal two is generically referred to as co-stimulation; several receptors on T cells have been reported to mediate co-stimulation, including CD28.
- LYMPHOKINE-ACTIVATED KILLER CELLS
(LAKs). Lymphocytes that have been cultured in high concentrations of cytokines (including interleukin 2). They show characteristic functional and phenotypic properties, such as in vitro lysis of tumour cells, in the absence of MHC restriction.
A multimeric component of the T-cell-receptor signalling apparatus. Direct activation of T cells by antibody cross-linking of CD3 complexes on the cell surface bypasses the requirement for T-cell receptor engagement of HLA-restricted antigens.
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Dudley, M., Rosenberg, S. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 3, 666–675 (2003). https://doi.org/10.1038/nrc1167
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