Central memory self/tumor-reactive CD8
            <sup>+</sup>
            T cells confer superior antitumor immunity compared with effector memory T cells

Klebanoff, Christopher A.; Gattinoni, Luca; Torabi‐Parizi, Parizad; Kerstann, Keith W.; Cardones, Adela R.; Finkelstein, Steven E.; Palmer, Douglas C.; Antony, Paul A.; Hwang, Samuel T; Rosenberg, Steven A.; Waldmann, Thomas A.; Restifo, Nicholas P.

doi:10.1073/pnas.0503726102

Cited by 825 publications

(786 citation statements)

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“…2C). These data are well in line with previous reports that exposure of antigenstimulated P14 or pmel-1 T cells to IL-2 or IL-15 generates effector or central memory-like CD8 T cells, respectively [6,[8][9][10]12]. We also noted that P14 IL-2 and P14 IL-15 cells differed in functional CD95L/Fas ligand expression since co-culture of P14 IL-2 cells and L1210 target cells expressing CD95/Fas resulted in antigen-independent cell killing whereas co-culture of the same target cells and P14 IL-15 cells had no effect (Fig.…”

Section: Resultssupporting

confidence: 91%

“…The results reported here are well in line with these findings, although our regimen of adoptive T-cell therapy was notably different since it did not involve lymphodepletion, additional antigen boostering or cytokine treatment. In the pmel-1 transfer model, the low in vivo efficacy of pmel-1 effector cells was explained by impaired priming of the transferred T cells due to inefficient trafficking to secondary lymphoid tissues [10] and due to their terminal-differentiation stage [8].In the transfer systems described here, P14 T cells cultured in saturate amounts of IL-2 (P14 IL-2 cells) were inefficient in eliminating tumor cells or reducing LCMV titers in contrast to P14 cells that exhibited high efficacy in vivo. Moreover, the experiments revealed that P14 IL-2 cells disappeared rapidly in the recipient mice after transfer whereas P14 IL-15 cells persisted for prolonged time.…”

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confidence: 99%

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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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Section: Resultssupporting

confidence: 91%

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confidence: 99%

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

2008

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“…1, open symbols). CD8 1 MELOE-1-specific T cells were then phenotyped for CD45RA, CD62L, CD28 and CD27 by multiparametric flow cytometry [21,22].…”

Section: Resultsmentioning

confidence: 99%

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

et al. 2010

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We recently showed that the infusion of tumor infiltrating lymphocytes specific for the MELOE-1 antigen was associated with a prolonged relapse-free survival for HLA-A2 1 melanoma patients who received tumor infiltrating lymphocytes therapy. Here, we characterized the MELOE-1/A2-specific T-cell repertoire in healthy donors and melanoma patients to further support an immunotherapy targeting this epitope. Using tetramer enrichment followed by multicolor staining, we found that MELOE-1-specific T cells were present in the blood of healthy donors and patients at similar frequencies (around 1 in 1 Â 10 5 CD8 1 cells). These cells mainly displayed a naïve phenotype in 4/6 healthy donors and 3/6 patients, whereas high proportions of memory cells were observed in the remaining individuals of both groups. There was a recurrent usage of the Va12.1 chain for 17/18 MELOE-1-specific T-cell clones derived from healthy donors or patients, associated with diverse Vb chains and V(D)J junctional sequences. All clones derived from melanoma patients (9/9) were reactive against the MELOE-1 36-44 peptide and against HLA-A2 1 melanoma cell lines. This study documents the existence of a large TCR repertoire specific for the MELOE-1/A2 epitope and its capacity to give rise to antitumor CTL that supports the development of immunotherapies targeting this epitope.Key words: Immunotherapy . Melanoma . MELOE-1 . T-cell repertoire . TCR Introduction A key advance in tumor immunology in the past 15 years has been the elucidation of the antigenic basis of tumor cell recognition and destruction, which has opened the way to development of antigen-based immunotherapy in cancer patients. Tumor-associated antigens (TAA) have been grouped into categories according to their expression pattern in neoplastic and normal tissues. TAA can be roughly subdivided into two main classes: proteins expressed specifically by tumor cells, and proteins that are expressed by both tumor cells and by normal cells to a significant level. The first category includes cancergermline antigens, proteins expressed by unconventional gene expression and mutated antigens (see [1] for review). TAA belonging to the second category are the differentiation antigens, mainly expressed in the melanocytic lineage, and the antigens overexpressed by various tumor tissues. Although the immunogenicity of a number of TAA has been documented in clinical Ã These authors contributed equally to this work. We recently showed a correlation between the infusion of T cells reactive against an HLA-A2 epitope derived from another melanoma antigen, MELOE-1, and time to progression of patients treated with autologous tumor infiltrating lymphocytes (TIL) [10]. This antigen is encoded by the meloe gene, overexpressed in human melanoma cell lines, when compared to normal melanocytes, and dramatically underexpressed in other cancer cell lines (colon, renal, breast and lung carcinoma cell lines) and in a variety of normal tissues [10]. This expression profile and the potential involvement of MELOE-1-specific...

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“…[20][21][22] Nevertheless, despite an apparent correlation between immunity and clinical outcome (as measured by time to progression), 20 there were no objective clinical responses (defined by RECIST criteria) in any of these phase-I trials. Evidence from preclinical 23 and clinical studies, especially those involving adoptive T-cell therapy, 9,10 suggested that a robust, continuous presence of TAAspecific T cells with minimal interference by immune inhibitory mechanisms was a prerequisite for an objective tumor response. In addition, it has been suggested that the effector profile and other less well-understood properties of discrete TAA-specific T-cell subpopulations may also have an important role in tumor regression.…”

Section: Introductionmentioning

confidence: 99%

Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination

et al. 2010

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Active immunotherapy of cancer has yet to yield effective therapies in the clinic. To evaluate the translatability of DNA-based vaccines we analyzed the profile of T-cell immunity by plasmid vaccination in a murine model, using transcriptome microarray analysis and flow cytometry. DNA vaccination resulted in specific T cells expressing low levels of co-inhibitory molecules (most notably PD-1), strikingly different from the expression profile elicited by peptide immunization. In addition, the T-cell response primed through this dual-antigen-expressing plasmid (MART-1/Melan-A and tyrosinase) translated into a substantial proliferation capacity and functional conversion to antitumor effector cells after tyrosinase and MART-1/Melan-A peptide analog boost. Furthermore, peptide boost rescued the immune response against the subdominant tyrosinase epitope. This immunization approach could be adapted to elicit potent immunity against multiple tumor antigens, resulting in a broader immune response that was more effective in targeting human tumor cells. Finally, this study sheds light on a novel mechanism of immune homeostasis through synchronous regulation of co-inhibitory molecules on T cells, highly relevant to heterologous prime boost approaches involving DNA vaccines as priming agents.

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Central memory self/tumor-reactive CD8 ⁺ T cells confer superior antitumor immunity compared with effector memory T cells

Abstract: Central memory CD8 ؉ T cells (TCM) and effector memory CD8

Cited by 825 publications

References 27 publications

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

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

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination

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Central memory self/tumor-reactive CD8 + T cells confer superior antitumor immunity compared with effector memory T cells

Abstract: Central memory CD8 ؉ T cells (TCM) and effector memory CD8

Cited by 825 publications

References 27 publications

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

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

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination

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Product

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Central memory self/tumor-reactive CD8 ⁺ T cells confer superior antitumor immunity compared with effector memory T cells