Autologous Human Monocyte-Derived Dendritic Cells Genetically Modified to Express Melanoma Antigens Elicit Primary Cytotoxic T Cell Responses In Vitro: Enhancement by Cotransfection of Genes Encoding the Th1-Biasing Cytokines IL-12 and IFN-α

Tüting, Thomas; Wilson, Cara C.; Martin, Dina M.; Kasamon, Yvette L.; Rowles, Jennifer L.; Debora, I.; Slingluff, Craig L.; Wagner, Stephan N.; Bruggen, Pierre van der; Baar, Joseph; Lotze, Michael T.; Storkus, Walter J.

doi:10.4049/jimmunol.160.3.1139

Cited by 125 publications

References 48 publications

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Induction of tyrosinase-reactive T cells by treatment with dacarbazine, cisplatin, interferon-alpha � interleukin-2 in patients with metastatic melanoma

Schmittel

Keilholz

Max³

et al. 1999

Int. J. Cancer

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We have shown the presence of tyrosinase‐reactive T cells in the peripheral blood of melanoma patients, who had been in remission after treatment with IL‐2‐containing regimens. In this consecutive study, we analyzed the T‐cell response to various peptides derived from tyrosinase in serial blood samples obtained from 7 stage‐IV melanoma patients before, during and following treatment. All patients were treated within a randomized trial (EORTC 18951) with cisplatin (CDDP), dacarbazine (DTIC), interferon‐α (IFN‐α) ± interleukin‐2 (IL‐2). Using an ELISPOT assay detecting peptide‐specific IFN‐γ release, we measured the T‐cell response to 4 different HLA class I‐binding peptide epitopes derived from tyrosinase containing an HLA‐A2.1‐, HLA‐A24‐ or HLA‐B44‐binding motif in peripheral‐blood mononuclear cells (PBMC). In one patient, tyrosinase‐reactive T cells were detected before therapy. In 4 out of 7 patients, tyrosinase‐reactive T cells against both HLA‐A2.1‐binding peptides and the B44‐binding peptide became detectable at frequencies of up to 30 in 5 × 105 lymphocytes following treatment. These patients received CDDP, DTIC and IFN‐α, 2 of them without IL‐2 and 2 with IL‐2, resulting in one complete remission and 3 partial remissions. Two patients relapsed 8 and 9 months after treatment. At the time of relapse, no T cells reactive with tyrosinase were detectable. Our results show that high frequencies of tyrosinase‐reactive T cells in the peripheral blood of melanoma patients can be induced by chemotherapy in combination with IFN‐α, regardless of concomitant IL‐2 administration. Int. J. Cancer 80:39–43, 1999. © 1999 Wiley‐Liss, Inc.

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Induction of tyrosinase-reactive T cells by treatment with dacarbazine, cisplatin, interferon-alpha � interleukin-2 in patients with metastatic melanoma

Schmittel

Keilholz

Max³

et al. 1999

Int. J. Cancer

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Influence of HLA-DR on the phenotype of CD4+ T lymphocytes specific for an epitope of the 16-kDa α-crystallin antigen ofMycobacterium tuberculosis

Agrewala

Wilkinson

1999

Eur. J. Immunol.

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T helper phenotype may be influenced by cytokine milieu, the differential expression of co‐stimulatory molecules, antigen dose, and by differences in affinity at the TCR‐peptide‐MHC interface. We investigated the latter hypothesis by examining the response of six HLA‐DR‐restricted CD4+ T cell lines specific for the immunodominant and permissively recognized p91‐110 epitope of the 16‐kDa α‐crystallin protein of Mycobacterium tuberculosis. Each line was generated from a sensitized HLA‐DR‐heterozygous donor and all proliferated when peptide was presented by autologous irradiated peripheral blood mononuclear cells. However, when HLA‐DR‐matched homozygous Epstein‐Barr‐virus‐transformed B cell lines (L‐BCL) were used as peptide‐presenting cells there was heterogeneity in the response. The most pronounced proliferative response, and the highest IFN‐γ secretion and cytolytic activity was stimulated by L‐BCL expressing molecules (DRB1*0101, *1501 and *0401) with high affinity (IC50 < 10 μM) for the 16p91‐110 peptide. By comparison, IL‐4 secretion or a lower proliferative response could occur when peptide was presented by alleles of high, or of intermediate (10 μM < IC50 < 100 μM), affinity. These data support the hypothesis that the host MHC can influence CD4+ phenotype and have implications for subunit vaccination against tuberculosis.

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Spleen-derived dendritic cells engineered to enhance interleukin-12 production elicit therapeutic antitumor immune responses

et al. 2000

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The major goal in cancer immunotherapy is the induction of tumor‐specific T lymphocytes capable of killing tumor cells. As both dendritic cells (DCs) and interleukin‐12 (IL‐12) can play immunostimulatory roles in vivo, the use of a combination of these has become a promising approach. In the present study, we used a murine tumor model to examine whether spleen‐derived DCs transduced with the IL‐12 gene could elicit tumor‐specific immune responses. BALB/c mice injected peritumorally with adenovirus‐mediated IL‐12 gene‐transduced antigen‐unpulsed DCs inhibited the growth of day 5‐established subcutaneous CT26 tumors. Splenocytes from treated mice responded specifically to parental tumor cells and showed increased production of interferon gamma (IFN‐γ) and antitumor cytotoxic T‐lymphocyte (CTL) activity. Increased numbers of both CD4+ and CD8+ T cells were detected in the treated tumors. The inhibition of tumor growth was significantly greater in mice injected with IL‐12 gene‐transduced DCs than in those injected with IL‐12 gene‐transduced fibroblasts or the IL‐12 gene‐encoding adenovirus itself. Taken together, these results indicate that DCs transduced with the IL‐12 gene by a recombinant adenovirus are effective in inducing tumor‐specific Th1 and CTL responses that inhibit the growth of established subcutaneous tumors. Int. J. Cancer 87:665–672, 2000. © 2000 Wiley‐Liss, Inc.

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Autologous Human Monocyte-Derived Dendritic Cells Genetically Modified to Express Melanoma Antigens Elicit Primary Cytotoxic T Cell Responses In Vitro: Enhancement by Cotransfection of Genes Encoding the Th1-Biasing Cytokines IL-12 and IFN-α

Cited by 125 publications

References 48 publications

Induction of tyrosinase-reactive T cells by treatment with dacarbazine, cisplatin, interferon-alpha � interleukin-2 in patients with metastatic melanoma

Induction of tyrosinase-reactive T cells by treatment with dacarbazine, cisplatin, interferon-alpha � interleukin-2 in patients with metastatic melanoma

Influence of HLA-DR on the phenotype of CD4+ T lymphocytes specific for an epitope of the 16-kDa α-crystallin antigen ofMycobacterium tuberculosis

Spleen-derived dendritic cells engineered to enhance interleukin-12 production elicit therapeutic antitumor immune responses

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