Principles of adoptive T cell cancer therapy

June, Carl H.

doi:10.1172/jci31446

Cited by 226 publications

(169 citation statements)

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“…2 Early clinical studies have demonstrated a 50-70% clinical response in patients. [3][4][5] However, the optimal protocols for expansion of T cells, especially antigenspecific CD8 C T cells, remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

et al. 2016

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Optimal expansion protocols for adoptive human T-cell therapy often include interleukin (IL)-15; however, the mechanism by which IL-15 improves the in vivo antitumor effect of T cells remains to be elucidated. Using human T cells generated from HLA-A2+ donors against novel T-cell epitopes derived from the human U266 myeloma cell line Ig light chain V-region (idiotype) as a model, we found that T cells cultured with IL-15 provided superior resistance to tumor growth in vivo, compared with IL-2, after adoptive transfer into immunodeficient hosts. This effect of IL-15 was associated with delayed/reversed senescence in tumor antigen-specific memory CD8 C T cells mediated through downregulation of P21 WAF1 , P16 INK4a , and P53 expression. Compared to IL-2, IL-15 stimulation dramatically activated JAK3-STAT5 signaling and inhibited the expression of DNA damage genes. Thus, our study elucidates a new mechanism for IL-15 in the regulation of STAT signaling pathways and CD8 C T-cell senescence.

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Section: Introductionmentioning

confidence: 99%

IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

et al. 2016

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“…Adoptive transfer of antigen-specific CD8 T cells into hosts represents a promising approach to treat tumors and viral infections [1][2][3][4]. To generate sufficient numbers of T cells for this therapy, T cells have to be stimulated and expanded in vitro.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

2008

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We determined the efficacy of in vitro expanded P14 TCR transgenic CD8 T cells to mediate tumor cell elimination and to protect against viral infection in mice. Contrary to previous studies, an adoptive transfer model without lymphodepletion, vaccination or cytokine treatment was used. Antigen-activated P14 T cells cultured in IL-2-containing medium for 7 days (P14 IL-2 ) exhibited potent effector cell functions in vitro but did not confer protection against melanoma growth or viral infection. In contrast, P14 T cells cultured in IL-15 (P14 ) were highly effective in vivo although they displayed only moderate effector functions in vitro. Therapeutic efficacy correlated with the survival of the transferred T cells in the recipients: P14 IL-2 cells disappeared rapidly whereas P14 IL-15 cells persisted for prolonged time. Decreasing the IL-2 concentration in the culture media improved in vivo survival and efficacy but also lowered the cell yield of the cultures. Finally, we could extend the findings with monoclonal P14 T cells to polyclonal CD8 T cells. Thus, in vitro expansion of antigen-specific CD8 T cells in IL-15 allowed the generation of substantial numbers of T cells without inducing terminally differentiated effector cells that turned out to be unfavorable in the transfer model examined here.Key words: Cytotoxic T cells . Rodent . Tumor immunity . Viral IntroductionAdoptive transfer of antigen-specific CD8 T cells into hosts represents a promising approach to treat tumors and viral infections [1][2][3][4]. To generate sufficient numbers of T cells for this therapy, T cells have to be stimulated and expanded in vitro. In most protocols used today, IL-2 is added to the culture medium to ensure T-cell proliferation, differentiation and survival. Besides IL-2, IL-15 also supports CD8 T-cell growth [5]; however, the phenotype and the functional activity of IL-2-versus IL-15-cultured CD8 T cells differ considerably. Manjunath et al. [6] were the first to show that CD8 T cells from P14 TCR-tg mice specific for gp33 epitope of lymphocytic choriomeningitis virus (LCMV) acquired an effector memory phenotype with high cytolytic activity when cultured in the presence of IL-2 whereas addition of IL-15 led to a central memory phenotype with low effector cell functions. Further analysis in the same TCR transgenic system revealed that these two cytokines were equivalent mitogens for antigen-stimulated CD8 T cells but that IL-2 was more potent in inducing amino acid uptake and protein synthesis [7].For adoptive T-cell therapy, it is important to generate CD8 T cells in vitro, which are efficient in inducing tumor regression or virus clearance in vivo. The degree of specific target cell lysis and the amount of antigen-triggered IFN-g production are frequently used to predict the efficacy of CD8 T cells in vivo. However, several recent studies in the pmel-1 TCR-tg model specific for the self/tumor antigen gp100 of B16 melanoma cells indicated that antigen-stimulated CD8 T cells with a less differentiated phenotype were sup...

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“…Adoptive immunotherapy with T cells can effectively treat patients with EBV-associated malignancies and metastatic melanoma, and application of this treatment is broadening as our ability to generate T cells targeting diverse tumor antigens improves (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Our expanding capacity to target novel antigens is driven, in part, by advances in genetic engineering that permit high efficiency transfer of genes encoding tumor specific T-cell receptors (TCR) into open repertoire mature T cells.…”

mentioning

confidence: 99%

Adoptively transferred effector cells derived from naïve rather than central memory CD8 ⁺ T cells mediate superior antitumor immunity

Hinrichs

Borman

Cassard

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

347

271

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Effector cells derived from central memory CD8 ؉ T cells were reported to engraft and survive better than those derived from effector memory populations, suggesting that they are superior for use in adoptive immunotherapy studies. However, previous studies did not evaluate the relative efficacy of effector cells derived from naïve T cells. We sought to investigate the efficacy of tumor-specific effector cells derived from naïve or central memory T-cell subsets using transgenic or retrovirally transduced T cells engineered to express a tumor-specific T-cell receptor. We found that naïve, rather than central memory T cells, gave rise to an effector population that mediated superior antitumor immunity upon adoptive transfer. Effector cells developed from naïve T cells lost the expression of CD62L more rapidly than those derived from central memory T cells, but did not acquire the expression of KLRG-1, a marker for terminal differentiation and replicative senescence. Consistent with this KLRG-1 ؊ phenotype, naïve-derived cells were capable of a greater proliferative burst and had enhanced cytokine production after adoptive transfer. These results indicate that insertion of genes that confer antitumor specificity into naïve rather than central memory CD8 ؉ T cells may allow superior efficacy upon adoptive transfer.

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Principles of adoptive T cell cancer therapy

Cited by 226 publications

References 132 publications

IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Adoptively transferred effector cells derived from naïve rather than central memory CD8 ⁺ T cells mediate superior antitumor immunity

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Principles of adoptive T cell cancer therapy

Cited by 226 publications

References 132 publications

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Adoptively transferred effector cells derived from naïve rather than central memory CD8 + T cells mediate superior antitumor immunity

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IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

Adoptively transferred effector cells derived from naïve rather than central memory CD8 ⁺ T cells mediate superior antitumor immunity