IL-7 and IL-15 allow the generation of suicide gene–modified alloreactive self-renewing central memory human T lymphocytes

Kaneko, Shin; Mastaglio, Sara; Bondanza, Attilio; Ponzoni, Maurilio; Sanvito, Francesca; Aldrighetti, Luca; Radrizzani, Marina; Seta-Catamancio, Simona La; Provasi, Elena; Mondino, Anna; Nagasawa, Toshiro; Fleischhauer, Katharina; Russo, Vincenzo; Traversari, Catia; Ciceri, Fabio; Bordignon, Claudio; Bonini, Chiara

doi:10.1182/blood-2008-05-156059

Cited by 147 publications

(125 citation statements)

References 52 publications

(69 reference statements)

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“…We speculate that IL-7-expanded cells following ACT by migrating to T-dLN and to the tumour might provide help to CD8 1 T cells and other immune effectors and by that favor tumour rejection. Thus, together with the finding that IL-7 and IL-15 drives the in vitro generation of selfrenewing central memory human T lymphocytes [54], our data support the use of IL-7 for the identification and the expansion of clinically relevant T-cell subsets. …”

supporting

confidence: 78%

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells

Caserta

Alessi²,

Basso³

et al. 2010

Eur J Immunol

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It is well established that tumours hinder both natural and vaccine-induced tumourspecific CD4 1 T-cell responses. Adoptive T-cell therapy has the potential to circumvent functional tolerance and enhance anti-tumour protective responses. While protocols suitable for the expansion of cytotoxic CD8 1 T cells are currently available, data on tumour-specific CD4 1 T cells remain scarce. We report here that CD4 1 T cells sensitized to tumour-associated Ag in vivo, proliferate in vitro in response to IL-7 without the need for exogenous Ag stimulation and accumulate several folds while preserving a memory-like phenotype. Both cell proliferation and survival accounts for the outgrowth of tumoursensitized T cells among other memory and naive lymphocytes following exposure to IL-7. Also IL-2, previously used to expand anti-tumour CTL, promotes tumour-specific CD4 1 T-cell accumulation. However, IL-7 is superior to IL-2 at preserving lymphocyte viability, in vitro and in vivo, maintaining those properties, that are required by helper CD4 1 T cells to confer therapeutic efficacy upon transplantation in tumour-bearing hosts. Together our data support a unique role for IL-7 in retrieving memory-like CD4 1 T cells suitable for adoptive T-cell therapy.Key words: Adoptive T-cell therapy . Cytokines . T helper cells . Tumour immunology Supporting Information available online IntroductionAdoptive cell therapy (ACT) with tumour-specific CD8 1 T lymphocytes has become one of the most promising approaches in cancer therapy. Rosenberg et al. first demonstrated the possibility to expand tumour-specific cytotoxic CD8 1 lymphocytes (CTL) from tumour lesions in high doses of IL-2 [1]. These authors later showed that the state of lymphocyte differentiation, induced in the presence of common g-chain receptor cytokines, is critical for therapeutic efficacy [2,3]. In spite of the recognized importance of Ag-specific CD4 1 T cells in both adaptive and innate immune responses, their identification remains elusive, and their in vitro amplification is hindered by the absence of reliable protocols able to support cell proliferation in the absence of terminal differentiation. While, Ag tumours elicit natural tumour-specific CD4 1 T-cell responses [4][5][6][7][8][9][10], functional tolerance is eventually observed through the induction of T-cell anergy [11,12], T-cell depletion [13] or the limitation of the memory repertoire [10,14,15]. This is possibly due to Ag persistence, and continual TCR signaling, as in the case of chronic 470viral infections [16][17][18]. In addition, regulatory CD4 1 T cells have been frequently found in the case of tumours, often among the tumour-infiltrating lymphocytes, thereby persuading the general interest towards CD8 1 CTL. Thus, CD4 1 T cells have not been widely exploited in ACT as well as the properties (i.e. homing potential, functionality, and survival) that CD4 1 T cells might require for successful applications in ACT are much less known than in the case for CD8 1 CTL.A large, still not definitive, amount of ...

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supporting

confidence: 78%

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells

Caserta

Alessi²,

Basso³

et al. 2010

Eur J Immunol

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“…16 Moreover, altered expression of both the membrane and soluble form potentially provides a survival advantage, as membranebound IL-7Ra signaling prevents activation induced cell death. 18 Reactive astrocytes in MS white matter brain lesions produce IL-7, 19 suggesting that the potential increased IL-7 responsiveness of CD8 T cells leads to enhanced cytotoxic responses in the brain, potentially inducing tissue damage. Moreover, this locally produced IL-7 in the brain may contribute to local expansion of these T cells.…”

Section: Resultsmentioning

confidence: 99%

Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

et al. 2012

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Polymorphisms (single-nucleotide polymorphism (SNP)) in the interleukin-7 receptor-a (IL-7Ra)/IL-7 pathway are associated with an increased risk to develop multiple sclerosis (MS). The rs6897932 SNP in the IL-7Ra leads to increased soluble IL-7Ra production. Given the functional interaction between sIL-7Ra, membrane-bound IL-7Ra and IL-7, we assessed IL-7, mIL-7Ra and sIL-7Ra levels in MS patients and healthy controls (HCs). One-hundred and twenty eight MS patients had significantly lower sIL-7Ra levels compared with 73 HCs. The levels of sIL-7Ra increased dose-dependent upon rs6897932 [C] risk allele carriership in both HCs and MS. Next, we hypothesized that lower sIL-7Ra could result in a higher mIL-7Ra to soluble IL-7Ra ratio. Indeed, 52 MS patients had significantly increased mIL-7Ra to sIL-7Ra ratio for both CD4 and CD8 T cells compared with 44 HCs. Given the supposed role of IL-7 in autoimmunity, we determined whether sIL-7Ra influences IL-7 levels. IL-7 levels were significantly decreased in 40 MS patients compared with 40 HCs. In conclusion, MS patients had lower free IL-7 and a higher membrane to soluble IL-7Ra ratio. The soluble IL-7Ra levels correlate with the rs6897932 [C] risk allele carriership. The skew at the IL-7 and IL-7Ra level may influence responsiveness of IL-7Ra þ cells.

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“…Activation with CD3/CD28 beads 42 and culture with IL-7/IL-15, 46 instead of activation with OKT3 and IL-2, allow genetically modifying T cells with enhanced persistence and superior antileukemia activity in vivo. 43 More recently, we have found that these properties are caused by the preferential transduction of putative stem memory T cells.…”

Section: Discussionmentioning

confidence: 99%