Key Points
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Adoptive cell transfer (ACT) of tumour-specific T cells to a lymphodepleted host mediates objective clinical responses in a substantial percentage of patients with metastatic solid tumours.
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CD4+ forkhead box P3 (FOXP3)+ regulatory T (TReg) cells are interleukin-2 (IL-2)-dependent negative immunoregulators of immune responses to self- and non-self-antigens in vivo. They might suppress antitumour responses, contributing to the poor clinical responses in patients with cancer (especially those who receive immunotherapy in non-lymphodepleting settings).
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Homeostatic cytokines such as IL-7 and IL-15 increase CD8+ T-cell functions and are required for their maintenance and memory CD8+ T-cell generation. Competing immune cells, including T cells, B cells and natural killer (NK) cells, might function as sinks for these cytokines, attenuating antitumour responses in non-lymphodepleting settings.
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Lymphodepleting regimens including systemic chemotherapy and total body irradiation can have an impact on antigen-presenting cell (APC) function and numbers. Although these regimens might deplete the absolute number of APCs, they can also promote the functional maturation of these cells.
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Preclinical mouse models of ACT therapy have elucidated the phenotype and the functional characteristics of CD8+ T cells associated with superior antitumour treatment. These attributes include lymph-node homing capacity, cytokine secretion, responsiveness to homeostatic signals, replicative history and proliferative potential.
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In patients, T-cell engraftment after ACT is associated with expression of the co-stimulatory molecules CD28 and CD27 and IL-7 receptor α-chain and it might indicate a selective survival of less-differentiated T cells.
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Persistence of adoptively transferred T cells correlates with successful antitumour responses and is associated with T-cell proliferative capacity as a function of telomere length.
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T-cell receptor (TCR) transduction of naive T cells or haematopoietic stem cells can be used to generate de novo, less-differentiated, central-memory-like tumour-specific CD8+ T cells for ACT.
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More robust lymphodepleting preconditioning regimens might augment the survival and antitumour function of adoptively transferred T cells.
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Criteria used for selection of T cells for ACT, interferon-γ release and cytolytic function, might be expanded to include TCR affinity, phenotypic analyses, alternative cytokine production (such as IL-2) and the measurement of telomere length.
Abstract
Adoptive cell transfer after host preconditioning by lymphodepletion represents an important advance in cancer immunotherapy. Here, we describe how a lymphopaenic environment enables tumour-reactive T cells to destroy large burdens of metastatic tumour and how the state of differentiation of the adoptively transferred T cells can affect the outcome of treatment. We also discuss how the translation of these new findings might further improve the efficacy of adoptive cell transfer through the use of vaccines, haematopoietic-stem-cell transplantation, modified preconditioning regimens, and alternative methods for the generation and selection of the T cells to be transferred.
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Acknowledgements
This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. The authors would like to thank all the members of the translational immunology team at the NCI especially M. E. Dudley, J. C. Yang, P. F. Robbins, R. A. Morgan, R. M. Sherry, M. R. Parkhurst, J. R Wunderlich and S. L. Topalian.
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Glossary
- Common cytokine-receptor γ-chain
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(γc). A signalling subunit of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21.
- Standard oncological criteria
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Clinical criteria that determine whether or not a treatment for cancer is effective. The World Health Organization originally defined an objective clinical response as a 50% decrease in the sum of the products of perpendicular diameters of all lesions without an increase greater than 25% in any lesions or appearance of new lesions. Subsequent updated criteria are known as response evaluation criteria in solid tumours (RECIST). RECIST defines an objective clinical response as a 30% decrease in the sum of the longest diameters of target lesions, without an increase greater than 20% in any target lesions or appearance of new lesions.
- Tumour-infiltrating lymphocytes
-
(TILs). The heterogeneous population of T cells found in a tumour bed. These cells are characterized by a diversity of phenotypes, antigen specificities, avidities and functional characteristics. They can be activated and expanded ex vivo and re-infused into the tumour-bearing host.
- Non-myeloablative regimen
-
Treatment that induces a severe, but transient, leukopaenia without permanent damage to haematopoietic stem cells, thereby allowing spontaneous recovery of the haematological function of the host.
- Homeostatic proliferation
-
A process of activation and proliferation of leukocytes in the lymphopaenic 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.
- Pmel-1 mouse model of ACT
-
A mouse model of adoptive cell transfer (ACT) therapy for established B16 melanomas and autoimmunity against the melanocyte-associated differentiation antigen gp100. Treatment consists of adoptive transfer of gp100-specific CD8+ T cells derived from the T-cell receptor (TCR) transgenic mouse pmel-1 in combination with altered ligand vaccine and cytokines that signal through a receptor that contains the common cytokine-receptor γ-chain (γc).
- Cross-presentation
-
The process whereby antigen-presenting cells take up, process and present extracellular antigens, in association with MHC class I molecules, to CD8+ T cells.
- Toll-like receptor
-
A member of the family of evolutionarily conserved receptors that was first described in Drosophila melanogaster. These receptors mediate innate immunity and inflammatory responses that can subsequently modulate adaptive immunity in mammals.
- Trans-presentation
-
A process by which the interleukin-15 receptor α-chain (IL-15Rα) presents active IL15 in trans to opposing cells expressing a complex, with a low affinity for IL-15, that contains IL-15Rα and the common cytokine-receptor γ-chain (γc), thereby transducing a signal.
- Telomere
-
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.
- Telomerase
-
A ribonucleoprotein enzyme that uses its internal RNA component as a template to synthesize telomeric DNA directly onto the ends of chromosome arms.
- Phage display
-
A technique in which bacteriophages are engineered to express on their cell surface a fusion protein comprised of a foreign peptide or protein and their capsid proteins.
- Complementarity-determining region
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The hypervariable amino-acid sequences in T-cell-receptor variable regions that interact with complementary amino acids on the peptide–MHC complex.
- Myeloablative regimen
-
Treatment that causes severe bone-marrow suppression requiring administration of haematopoietic stem cells to reconstitute the haematological function of the host and to assure host survival.
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Gattinoni, L., Powell, D., Rosenberg, S. et al. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6, 383–393 (2006). https://doi.org/10.1038/nri1842
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DOI: https://doi.org/10.1038/nri1842
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