Populations of T cells that are specific for tumour-associated antigens can be expanded to generate large numbers of cells and transferred into tumour-bearing hosts, a process known as adoptive cell transfer (ACT)-based immunotherapy.
T cells can be genetically engineered to express αβ T cell receptors (which recognize MHC-restricted peptide antigens) or chimeric antigen receptors, which are antibody-like structures capable of recognizing structures on the surface of tumour cells or tumour-associated cells.
Tumours are complex masses that comprise numerous cell types, including transformed cells as well as non-transformed stromal cells and immune cells (such as myeloid cells and various T cell subsets).
Transformed cells (tumour cells) express mutated genes and genes that are normally epigenetically repressed in most adult tissues, and these genes can trigger tumour masses to grow uncontrollably, resist death and invade tissues. The products of these genes can be targeted by immunotherapy.
ACT can be improved by destroying host elements that interfere with the function of tumour-specific T cells. This can be accomplished using lymphodepletion mediated by chemotherapy or total-body irradiation.
The differentiation state of tumour-specific T cells affects the efficacy of T cell-based immunotherapy. 'Younger', less-differentiated T cells are more effective than cells that have fully acquired effector functions.
DNA sequencing might be useful in the identification of targetable neo-antigens expressed by tumours.
New combinations of ACT-based immunotherapy with 'targeted therapies' offer promising new directions.
Immunotherapy based on the adoptive transfer of naturally occurring or gene-engineered T cells can mediate tumour regression in patients with metastatic cancer. Here, we discuss progress in the use of adoptively transferred T cells, focusing on how they can mediate tumour cell eradication. Recent advances include more accurate targeting of antigens expressed by tumours and the associated vasculature, and the successful use of gene engineering to re-target T cells before their transfer into the patient. We also describe how new research has helped to identify the particular T cell subsets that can most effectively promote tumour eradication.
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This work was supported by the Intramural Research Program of the Center for Cancer Research, US National Cancer Institute (NCI), National Institutes of Health. The authors would like to thank C. Klebanoff, L. Gattinoni, C. Hinrichs and P. Muranski for discussions about T cell differentiation, M. Bachinski for editorial help, E. Tran for critically reading the manuscript, and all the members of the translational immunology team at the NCI, especially J. C. Yang, P. F. Robbins, R. A. Morgan, R. M. Sherry, S. Feldman, M. Parkhurst, M. Hughes, G. Phan and U. Kammula.
The authors declare no competing financial interests.
- Tumour-infiltrating lymphocyte
(TIL). A member of the heterogeneous population of T cells found in a tumour. TILs are characterized by a diversity of phenotypes, antigen specificities, avidities and functional characteristics. TIL populations can be activated and expanded ex vivo and re-infused into the tumour-bearing host.
(IL-2). A T cell growth factor that is capable of triggering the expansion of both effector T cell and regulatory T cell populations. IL-2 is used to treat patients with melanoma and as a part of some ACT-based treatment regimes.
- Adoptive cell transfer
(ACT). The administration of tumour-specific lymphocytes (obtained from the patient (autologous) or from a donor (allogeneic)) following a lymphodepleting preparative regimen.
The use of total-body irradiation or cytotoxic drugs to deplete the lymphoid compartment in a patient.
- Myeloid-derived suppressor cells
(MDSCs). A group of immature CD11b+GR1+ cells (which include precursors of macrophages, granulocytes, dendritic cells and myeloid cells) that are produced in response to various tumour-derived cytokines. These cells have been shown to induce tolerance in tumour-associated CD8+ T cells.
The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules.
A process by which the immune system of a host may alter the gene expression of an emerging tumour, such that the most immunogenic epitopes are removed or 'edited', thereby facilitating tumour escape from immune recognition.
- Carcinoembryonic antigen
A protein found in fetal gastrointestinal tissue that can be upregulated in some gastrointestinal cancers and can serve as a marker of tumour burden.
- Objective clinical responses
The response evaluation criteria in solid tumours (RECIST) define an objective response as a 30% reduction in the sum of the longest diameters of measurable tumour lesions when comparing post-treatment with pretreatment values. The World Health Organization criteria define an objective response to be a 50% reduction in the sum of the products of perpendicular diameters of measurable lesions. In both sets of criteria, no new lesions can appear. Perhaps the most important clinical end point is benefit from a treatment based on increased survival time, although this can only be assessed using controlled patient cohorts.
- Driver mutations
A nonsense mutation in a gene that causes a cancer cell to have a survival and/or growth advantage.
- Cancer–testis antigens
(Also known as cancer germline antigens). A class of >100 proteins that are expressed by many human cancers but not by normal adult tissues except in the testes and fetal ovaries. These antigens include CTAG1, MAGEA3 and SSX1.
- Complementarity-determining regions
Short amino acid sequences found in the variable domains of antigen receptor proteins that recognize an antigen and therefore provide the receptor with its specificity for that particular antigen.
- Directed evolution
A cyclic sequence of steps (including modification, selection and amplification) that is used, typically in vitro, to enrich for proteins or nucleic acids that show properties that are desired by the researcher but that are not necessarily found in nature.
- Chimeric antigen receptors
(CARs). Antigen receptors that contain sequences from more than one source, such as an antibody molecule, a T cell receptor signalling chain, and an activating motif.
- Homeostatic proliferation
A process of activation and proliferation of leukocytes in the lymphopenic environment. T cell homeostatic proliferation is driven by T cell receptor interactions with self-peptide–MHC complexes and T cell responsiveness to cytokines such as interleukin-7 (IL-7), IL-15 and possibly IL-21.
- Recombination-activating genes
These genes (Rag1 and Rag2) are expressed by developing lymphocytes. Mice that are deficient in either RAG protein fail to produce B and T cells owing to a developmental block in the gene rearrangement that is required for antigen receptor expression.
- Allelic exclusion
A mechanism that ensures that a lymphocyte expresses antigen receptors of only a single specificity at its cell surface. This is an integral step in the clonal commitment of a lymphocyte lineage.
- Cytokine storm
A sudden surge in the circulating levels of pro-inflammatory cytokines, such as interleukin-1, interleukin-6, tumour necrosis factor and interferon-γ. Clinically, this can result in hypotension, acute renal failure, poor pulmonary function and even death.
- Central memory T cell
(TCM cell). An antigen-experienced CD8+ T cell that lacks immediate effector function but is able to mediate rapid recall responses. These cells also rapidly develop the phenotype and function of effector memory T cells after re-stimulation with antigen. TCM cells retain the migratory properties of naive T cells and therefore circulate through the secondary lymphoid organs.
- Effector memory T cell
(TEM cell). A terminally differentiated T cell that lacks lymph-node-homing receptors but expresses receptors that enable it to home to inflamed tissues. TEM cells can exert immediate effector functions without the need for further differentiation.
The segment at the end of chromosome arms, which consists of a series of repeated DNA sequences (TTAGGG in all vertebrates) that regulate chromosomal replication at each cell division.
Inter-individual genetic variation at the MHC locus. In a partially matched transplant, for example, some MHC molecules are shared by the donor and recipient, but in addition the donor has some MHC molecules that the recipient does not.
- TH2 cells
(T helper 2 cells). A subset of CD4+ T cells that has an important role in humoral immunity and in allergic responses. TH2 cells express the transcription factors GATA3 and STAT6 and produce cytokines such as interleukin-4 (IL-4), IL-5, IL-9 and IL-13, which regulate IgE synthesis, eosinophil proliferation, mast cell proliferation and airway hyperresponsiveness, respectively. A TH2 cell pattern of cytokine expression is observed in allergic inflammation and in parasitic infections, conditions that are both associated with IgE production and eosinophilia.
- TH1 cells
(T helper 1 cells). A subset of CD4+ T cells that expresses the transcription factor T-bet and is associated with cell-mediated immunity. TH1 cells provide help for cytotoxic T cell responses by secreting high concentrations of interleukin-2, tumour necrosis factor and interferon-γ. They may also promote immunopathology in certain autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis.
- TH17 cells
(T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in antibacterial and antifungal immunity and may also have a role in autoimmune diseases. Their generation involves IL-23 and IL-21, as well as the transcription factors RORγt and STAT3.
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Restifo, N., Dudley, M. & Rosenberg, S. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12, 269–281 (2012). https://doi.org/10.1038/nri3191
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