Phenotypic Analysis of Antigen-Specific T Lymphocytes

Altman, John D.; Moss, Paul; Goulder, Philip; Barouch, Dan H.; McHeyzer‐Williams, Michael G.; Bell, John I.; McMichael, Andrew J.; Davis, Mark M.

doi:10.1126/science.274.5284.94

Cited by 3,317 publications

(2,570 citation statements)

References 29 publications

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“…In the further phase II trial, cellular immunity will be assessed by ELISPOT and Tetramer methods in certain patients with a defined tumor. 35,36 In conclusion, H103 is well tolerated and can be safely administered by intratumoral injection and displays oncolytic activity at a total dose of 3.0 Â 10 12 VP as evidenced by local partial response responses. The results of this study suggest a potential role for this in vivo personalized vaccination strategy against tumors.…”

Section: Discussionmentioning

confidence: 89%

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

Li¹,

Liu

Xr³

et al. 2008

Gene Ther

105

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Our pre-clinical studies demonstrated that intratumoral vaccination with a recombinant oncolytic type 2 adenovirus overexpressing the heat shock protein (HSP)70 protein, designated as H103, can inhibit primary and metastatic tumors through enhanced oncolytic activity and HSPmediated immune responses against shared and mutated tumor antigens. In the pre-clinical studies of local H103 administration, no significant toxicity was observed in the animal trials with mice, cavy or rhesus monkeys. A phase I clinical trial of intratumoral injection of H103 was conducted in the patients with advanced solid tumors. A total of 27 patients were injected intratumorally with H103 in a dose-escalation study from a dose of 2.5 Â 10 7 to 3.0 Â 10 12 viral particles (VPs). The maximum tolerated dose of H103 was not defined. Two patients developed dose-limiting toxicities of grade III fever at the dose of 1.5 Â 10 12 VP and transient grade IV thrombocytopenia at the dose of 3.0 Â 10 12 VP. The common adverse events were mainly mild to moderate (grade I/II) in nature, including fever, mild injection-site reaction, leucopenia, lymphopenia, thrombocytopenia and hypochromia. The objective response (complete response+partial response) to H103-injected tumors was 11.1% (3/27), and the clinical benefit rate (complete response+partial response+minor response+stable disease) was 48.1%. Interestingly, transient and partial regression of distant, uninjected tumors was observed in three patients. The numbers of immune cells (CD4 + and CD8 + T cells, and natural killer cells) were elevated after H103 administration, but without statistical significance. This phase I trial demonstrates that intratumoral administration of H103 can be safely applied to cancer patients and shows promising clinical antitumor activity, warranting a further clinical investigation.

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Section: Discussionmentioning

confidence: 89%

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

Li¹,

Liu

Xr³

et al. 2008

Gene Ther

105

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“…with HEK293 (negative control) or LCMV-infected HEK cells (7 Â 10 6 ) treated as LyUV. After 7 days, splenocytes were obtained and stained with 0.5-1 mg of PE-labeled tetramers [36] as described previously [37]. Alternatively, epitope-specific CTL were expanded in vitro before performing ICS assays as described previously [7].…”

Section: Antigen Presentation Assays and Tetramer Stainingmentioning

confidence: 99%

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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The initiation of CD8 1 T cell (CTL) immune responses can occur via cross-priming. Recent data suggested a relationship between cross-presentation and immunodominance of epitope-specific T cells. To test this association, we evaluated the efficacy of crosspresentation for several virus epitopes in vitro and examined if this can be extrapolated in vivo. Employing lymphocytic choriomeningitis virus (LCMV), we demonstrate that the cross-presentation and cross-priming of LCMV antigens were dominated by NP396, but not NP205 when analyzing the LCMV-NP. Although with LCMV-GP, cross-presentation was dominated by GP276, and cross-priming was dominated by GP33. Importantly, although NP396 was significantly more efficient than GP33 in cross-presentation, cross-priming of their specific CTL was comparable. In a subsequent virus challenge after cross-priming, GP33-specific CTL dominated the response. Accordingly, based on our data, the ability of viral epitopes to be cross-presented in vitro does not entirely reflect what would occur in cross-priming. Thus, weak cross-presenting antigens may still cross-prime an efficient CTL response depending on other in vivo elements such as the naïve T-cell precursor frequencies.

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“…Although the specific peptides seen by a wide variety of TCRs on CD8 + cells had been known for some time, the interactions of monomeric MHC class I–peptide complexes with the TCR were of too low an affinity to result in stable binding. This problem was solved by Altman et al 12, who engineered a unique bacterial biotinylation substrate at the COOH terminus of recombinant MHC class I molecules. Refolding of biotinylated heavy chains with specific peptides and subsequent incubation with fluorescent avidin resulted in the formation of tetrameric MHC class I–peptide complexes that bound stably and specifically to the appropriate TCR.…”

Section: Cd1d–α-galcer Tetramersmentioning

confidence: 99%

Cd1d–Glycolipid Tetramers

MacDonald

2000

The Journal of Experimental Medicine

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Phenotypic Analysis of Antigen-Specific T Lymphocytes

Cited by 3,317 publications

References 29 publications

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

Cd1d–Glycolipid Tetramers

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