Phase I Trial of Adoptive Immunotherapy With Cytolytic T Lymphocytes Immunized Against a Tyrosinase Epitope

Mitchell, Malcolm S.; Darrah, Denise D.; Yeung, David W.C.; Halpern, Samuel E.; Wallace, Anne M.; Voland, Joseph R.; Jones, Vicky; Kan‐Mitchell, June

doi:10.1200/jco.2002.20.4.1075

Cited by 55 publications

(43 citation statements)

References 13 publications

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“…The distribution of 111 In-labeled Melan-A-specific CTL was similar to the distribution of PBL which first appeared in the lung and after 24 h accumulated in liver and spleen (44). This is supported by several reports including a recent study with adoptively transferred tyrosinase-specific CTL (36,40). The most important difference, of course, was the localization of Melan-A-specific CTL to sites of tumor as early as 48 h after transfer.…”

Section: Discussionsupporting

confidence: 63%

Survival and Tumor Localization of Adoptively Transferred Melan-A-Specific T Cells in Melanoma Patients

Meidenbauer

Marienhagen

Laumer

et al. 2003

The Journal of Immunology

151

111

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Adoptive T cell therapy has been successfully used for treatment of viral and malignant diseases. However, little is known about the fate and trafficking of transferred Ag-specific T cells. Using the tetramer (TM) technology which allows for detection and quantification of Ag-specific CTL, we assessed the frequency of circulating Melan-A-specific CTL in advanced melanoma patients during adoptive T cell therapy. Melan-A-specific CTL were generated from HLA-A2.1+ patients by in vitro stimulation of CD8+ T cells with dendritic cells pulsed with a mutated HLA-A2-binding Melan-A (ELAGIGILTV) peptide. Eight patients received three infusions of 0.25–11 × 108 Melan-A-specific CTL i.v. at 2-wk intervals along with low-dose IL-2. The transferred T cell product contained a mean of 42.1% Melan-A-TM+ CTL. Before therapy, the frequencies of Melan-A-specific CTL in patients’ circulating CD8+ T cells ranged from 0.01 to 0.07%. Characterization of the TM frequencies before and at different time points after transfer revealed an increase of circulating Melan-A-specific CTL up to 2%, correlating well with the number of transferred CTL. An elevated frequency of TM+ T cells was demonstrated up to 14 days after transfer, suggesting long-term survival and/or proliferation of transferred CTL. Combining TM analysis with a flow cytometry-based cytokine secretion assay, unimpaired production of IFN-γ was demonstrated in vivo for at least 24 h after transfer. Indium-111 labeling of Melan-A-specific CTL demonstrated localization of transferred CTL to metastatic sites as early as 48 h after injection. Overall, the results suggest that in vitro-generated Melan-A-specific CTL survive intact in vivo for several weeks and localize preferentially to tumor.

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Section: Discussionsupporting

confidence: 63%

Survival and Tumor Localization of Adoptively Transferred Melan-A-Specific T Cells in Melanoma Patients

Meidenbauer

Marienhagen

Laumer

et al. 2003

The Journal of Immunology

151

111

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“…4), high-grade B-cell lymphomas relapsed after BMT (5), and EBV-associated lymphomas after BMT (6). Recently, some patients with melanoma have shown objective responses following gp100 (7) or tyrosinase (8) specific T-cell infusions. Some patients with renal cell carcinoma (9) have also responded to therapy.…”

Section: Introductionmentioning

confidence: 99%

Artificial Antigen-Presenting Cells Transduced with Telomerase Efficiently Expand Epitope-Specific, Human Leukocyte Antigen–Restricted Cytotoxic T Cells

Dupont

Latouche

et al. 2005

Cancer Research

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Human telomerase reverse transcriptase (hTERT) is overexpressed in most human tumors, making it a potential target for cancer immunotherapy. hTERT-derived CTL epitopes have been identified previously, including p865 (RLVDDFLLV) and p540 (ILAKFLHWL), which are restricted by the human leukocyte antigen (HLA) class I A*0201 allele. However, it remains a major challenge to efficiently and consistently expand hTERT-specific CTLs from donor peripheral blood T lymphocytes. To bypass the need for generating conventional antigen-presenting cells (APCs) on an autologous basis, we investigated the potential ability of fibroblast-derived artificial APCs (AAPCs) to activate and expand HLA-A*0201-restricted CTLs. We show here that AAPCs stably expressing HLA-A*0201, human B 2 -microglobulin, B7.1, intercellular adhesion molecule-1, and LFA-3, together with either p540 and p865 minigenes or the full-length hTERT, effectively stimulate tumoricidal, hTERT-specific CTLs. hTERT-expressing AAPCs stimulated both p540 and p865 CTLs as shown by peptide-specific cytolysis and tetramer staining, indicating that hTERT is processed by the AAPCs and that the two peptides are presented as codominant epitopes. The level of cytotoxic activity against a panel of tumors comprising hematologic and epithelial malignancies varied, correlating overall with the level of HLA-A2 and hTERT expression by the target cell. Starting from 100 mL blood, f100 million hTERTspecific CTLs could be generated over the course of five sequential stimulations, representing an expansion of f1 Â 10 5 . Our data show that AAPCs process hTERT antigen and efficiently stimulate hTERT-specific CTLs from human peripheral blood T lymphocytes and suggest that sufficient expansion could be achieved to be clinically useful for adoptive cell therapy. (Cancer Res 2005; 65(12): 5417-27)

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“…In mice, immunization with model and naturally expressed tumor Ags or their MHC class I (MHC-I) 6 epitopes induces antitumor CTL that mediate in vivo tumor rejection (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Patients with established disease have shown some response when given adoptively transferred tumorspecific CTL (13)(14)(15). Similarly, clinical trials testing the efficacy of immunizing with MHC-I tumor epitopes from the human papilloma virus Ag E7 have resulted in T cell responses in some patients with cervical cancer (16 -18).…”

mentioning

confidence: 99%

Identification and Characterization of the Immunodominant Rat HER-2/neu MHC Class I Epitope Presented by Spontaneous Mammary Tumors from HER-2/neu-Transgenic Mice

Ercolini

Machiels

Chen

et al. 2003

The Journal of Immunology

111

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The HER-2/neu (neu-N)-transgenic mice are a clinically relevant model of breast cancer. They are derived from the parental FVB/N mouse strain and are transgenic for the rat form of the proto-oncogene HER-2/neu (neu). In this study, we report the identification of a MHC class I peptide in the neu protein that is recognized by CD8+ T cells derived from vaccinated FVB/N mice. This 10-mer was recognized by all tumor-specific FVB/N T cells generated regardless of the TCR Vβ region expressed by the T cell or the method of vaccination used, establishing it as the immunodominant MHC class I epitope in neu. T cells specific for this epitope were able to cure FVB/N mice of transplanted neu-expressing tumor cells, demonstrating that this is a naturally processed peptide. Altered peptide analogs of the epitope were analyzed for immunogenicity. Vaccination with dendritic cells pulsed with a heteroclitic peptide provided FVB/N and neu-N mice with increased protection against tumor challenge as compared with mice immunized with dendritic cells loaded with either wild-type or irrelevant peptide. Discovery of this epitope allows for better characterization of the CD8+ T cell responses in the neu-N mouse model in which neu-specific tolerance must be overcome to produce effective antitumor immunity.

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Phase I Trial of Adoptive Immunotherapy With Cytolytic T Lymphocytes Immunized Against a Tyrosinase Epitope

Abstract: CTLs immunized against a single melanoma epitope were nontoxic but did not specifically localize to tumor sites. Nevertheless, two patients had disease regression. Additional therapeutic studies with specifically immunized CTL seem justified.

Cited by 55 publications

References 13 publications

Survival and Tumor Localization of Adoptively Transferred Melan-A-Specific T Cells in Melanoma Patients

Survival and Tumor Localization of Adoptively Transferred Melan-A-Specific T Cells in Melanoma Patients

Artificial Antigen-Presenting Cells Transduced with Telomerase Efficiently Expand Epitope-Specific, Human Leukocyte Antigen–Restricted Cytotoxic T Cells

Identification and Characterization of the Immunodominant Rat HER-2/neu MHC Class I Epitope Presented by Spontaneous Mammary Tumors from HER-2/neu-Transgenic Mice

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