Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

Wang, Xiuli; Berger, Carolina; Wong, ChingLam W.; Forman, Stephen J.; Riddell, Stanley R.; Jensen, Michael C.

doi:10.1182/blood-2010-10-310599

Cited by 147 publications

(175 citation statements)

References 30 publications

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“…5,6,33 In support of this, clinical experience with adoptive transfer using bulk PBMC derived effector T cells for the treatment of CLL and ALL have suggested that some of the gene-engineered cells detected longterm in patients exhibit characteristics of T CM . [1][2][3][4] Although it is impossible to track the precursors of the persisting cells in those trials, these results indicate that the efficacy of adoptively transferred T cells might be augmented by specifically engineering the T cell subset that exhibits the intrinsic capacity to persist in vivo.…”

Section: Discussionmentioning

confidence: 93%

“…We have demonstrated in a non-human primate model and human T cell NOD/Scid IL2RgC null (NSG) mouse model that CD8 C effector T cells derived from macaque CD62L C CD95 C or CD62L C CD45RO C central memory T cells (T CM ), respectively, have the capacity to persist following adoptive transfer and re-populate functional memory niches. 5,6 Consistently, Busch et al demonstrated the self-renewal capacity and multipotency of single T CM in serial transfer design, indicating the stemness of T CM . 7,8 Here, we compared the relative engraftment performance of human CD8…”

Section: Introductionmentioning

confidence: 92%

“…three times a week to provide a systemic supply of human IL-15 in vivo, as previously described. 5 Human T cell engraftment was determined by flow cytometric analysis of harvested tissues based on staining with antibodies specific for human CD45 and CD8…”

Section: Xenograft Modelmentioning

confidence: 99%

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Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer

et al. 2015

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CD62LC precursors enriched for na€ ıve and stem cell memory precursors (T N/SCM ) with that of T CM . We found that cytotoxic T cells (CTLs) derived from T CM transcribed higher levels of CD28, FOS, INFg, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of g-chain cytokines compared to CTLs derived from T N/SCM . Higher frequencies of CTLs derived from T CM retained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/Scid IL-2RgC null mice, CD8 C T CM derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8C T CM derived CD19CAR C CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8 C T N/SCM derived counterparts. These studies support the use of T CM enriched cell products for adoptive therapy of cancer.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 92%

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Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer

et al. 2015

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“…T CM are thought to have long-lived behavior and show superior engraftment capacities compared with other memory T cell subsets in first preclinical trials (8)(9)(10)(11). Although some in vitro data suggest a loss of T CM phenotype during expansion (3,12), we recently demonstrated that partial inhibition of the IL-2R signal-ing pathway supports expansion of T CM without loss of CD62L/ CCR7 (11).…”

Section: Cd45ramentioning

confidence: 84%

Peripheral Blood–Derived Virus-Specific Memory Stem T Cells Mature to Functional Effector Memory Subsets with Self-Renewal Potency

Schmueck-Henneresse

Sharaf

Vogt

et al. 2015

The Journal of Immunology

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Memory T cells expressing stem cell–like properties have been described recently. The capacity of self-renewal and differentiation into various memory/effector subsets make them attractive for adoptive T cell therapy to combat severe virus infections and tumors. The very few reports on human memory stem T cells (TSCM) are restricted to analyses on polyclonal T cells, but extensive data on Ag-specific TSCM are missing. This might be due to their very low frequency limiting their enrichment and characterization. In this article, we provide functional and phenotypic data on human viral-specific TSCM, defined as CD8+CD45RA+CCR7+CD127+CD95+. Whereas <1% of total T cells express the TSCM phenotype, human CMV–specific TSCM can be detected at frequencies similar to those seen in other subsets, resulting in ∼1/10,000 human CMV–specific TSCM. A new virus-specific expansion protocol of sort-purified TSCM reveals both upregulation of various T cell subset markers and preservation of their stem cell phenotype in a significant proportion, indicating both self-renewal and differentiation potency of virus-specific T cells sharing their TCR repertoire. Furthermore, we describe a simplified culture protocol that allows fast expansion of virus-specific TSCM starting from a mixed naive T/TSCM pool of PBLs. Due to the clinical-grade compatibility, this might be the basis for novel cell therapeutic options in life-threatening courses of viral and tumor disease.

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“…Recent work from a number of groups has highlighted the relationship between cellular phenotype and in vivo T-cell expansion/persistence. [17][18][19][20][21][22] Indeed, Sommermeyer et al reported on the superior antitumor effects achieved when tumor-bearing mice were treated with a mix of central memory-derived CD8 C and naive-derived CD4 C CAR.CD19 T cells. 23 These findings were subsequently clinically validated by Turtle et al who reported achieving bone marrow remissions in 27 of 29 B-ALL patients who received lymphodepleting chemotherapy followed by infusions of CD4 C and CD8 C CAR.CD19 mixed at a defined ratio.…”

Section: Discussionmentioning

confidence: 99%

Fine-tuning the CAR spacer improves T-cell potency

et al. 2016

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The adoptive transfer of genetically engineered T cells expressing chimeric antigen receptors (CARs) has emerged as a transformative cancer therapy with curative potential, precipitating a wave of preclinical and clinical studies in academic centers and the private sector. Indeed, significant effort has been devoted to improving clinical benefit by incorporating accessory genes/CAR endodomains designed to enhance cellular migration, promote in vivo expansion/persistence or enhance safety by genetic programming to enable the recognition of a tumor signature. However, our efforts centered on exploring whether CAR Tcell potency could be enhanced by modifying pre-existing CAR components. We now demonstrate how molecular refinements to the CAR spacer can impact multiple biological processes including tonic signaling, cell aging, tumor localization, and antigen recognition, culminating in superior in vivo antitumor activity.

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Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

Cited by 147 publications

References 30 publications

Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer

Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer

Peripheral Blood–Derived Virus-Specific Memory Stem T Cells Mature to Functional Effector Memory Subsets with Self-Renewal Potency

Fine-tuning the CAR spacer improves T-cell potency

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Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

Cited by 147 publications

References 30 publications

Comparison of naïve and central memory derived CD8+effector cell engraftment fitness and function following adoptive transfer

Comparison of naïve and central memory derived CD8+effector cell engraftment fitness and function following adoptive transfer

Peripheral Blood–Derived Virus-Specific Memory Stem T Cells Mature to Functional Effector Memory Subsets with Self-Renewal Potency

Fine-tuning the CAR spacer improves T-cell potency

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Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer

Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer