Characterisation of immune responses in pancreatic carcinoma patients after mutant p21 ras peptide vaccination

Klemp, Marianne; Sæterdal, Ingvil; Thorsby, E.; Gaudernack, Gustav

doi:10.1038/bjc.1996.638

Cited by 28 publications

(18 citation statements)

References 25 publications

(12 reference statements)

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“…Tumor-specific CD4 ϩ T cells restricted by MHC class II gene products have also been reported in patients with melanoma, lymphoma, sarcoma, colon cancer, and breast cancer (5)(6)(7). Responses of CD4 ϩ T cells against tumor-specific peptide sequences expressed in an idiotypic IgM of a B cell lymphoma (8), bcr-abl fusion proteins (9), HPV type 16 E7 oncoprotein (10), and k ras oncogene (11)(12)(13) have also been documented.…”

mentioning

confidence: 99%

Tumor-Specific CD4+ T Lymphocytes from Cancer Patients Are Required for Optimal Induction of Cytotoxic T Cells Against the Autologous Tumor

Baxevanis

Voutsas

Tsitsilonis

et al. 2000

The Journal of Immunology

154

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This study focuses on the specific CD4+ T cell requirement for optimal induction of cytotoxicity against MHC class II negative autologous tumors (AuTu) collected from patients with various types of cancer at advanced stages. CD4+ T cells were induced in cultures of cancer patients’ malignant effusion-associated mononuclear cells with irradiated AuTu (mixed lymphocyte tumor cultures (MLTC)) in the presence of recombinant IL-2 and recombinant IL-7. Tumor-specific CD4+ T cells did not directly recognize the AuTu cells, but there was an MHC class II-restricted cross-priming by autologous dendritic cells (DCs), used as APC. CD8+ CTL, also induced during the MLTC, lysed specifically AuTu cells or DCs pulsed with AuTu peptide extracts (acid wash extracts (AWE)) in an MHC class I-restricted manner. Removal of CD4+ T cells or DCs from the MLTC drastically reduced the CD8+ CTL-mediated cytotoxic response against the AuTu. AWE-pulsed DCs preincubated with autologous CD4+ T cells were able, in the absence of CD4+ T cells, to stimulate CD8+ T cells to lyse autologous tumor targets. Such activated CD8+ T cells produced IL-2, IFN-γ, TNF-α, and GM-CSF. The process of the activation of AWE-pulsed DCs by CD4+ T cells could be inhibited with anti-CD40 ligand mAb. Moreover, the role of CD4+ T cells in activating AWE-pulsed DCs was undertaken by anti-CD40 mAb. Our data demonstrate for the first time in patients with metastatic cancer the essential role of CD4+ Th cell-activated DCs for optimal CD8+ T cell-mediated killing of autologous tumors and provide the basis for the design of novel protocols in cellular adoptive immunotherapy of cancer, utilizing synthetic peptides capable of inducing T cell help in vivo.

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confidence: 99%

Tumor-Specific CD4+ T Lymphocytes from Cancer Patients Are Required for Optimal Induction of Cytotoxic T Cells Against the Autologous Tumor

Baxevanis

Voutsas

Tsitsilonis

et al. 2000

The Journal of Immunology

154

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“…IL-2 (10 units/ml; Amersham Pharmacia) was added after 2 days and the bulk cultures were tested for peptide specificity at day 10. Activated T cells from one responding bulk culture stimulated with p538 ϩ p540 were isolated with anti-CD25 coated Dynabeads (Dynal, Oslo) and cloned by limiting dilution (5͞1͞0.3 cells per well) as described (14). Clones were obtained from 24 of 600 wells seeded.…”

mentioning

confidence: 99%

“…The TILs that grew out of the biopsy were cultured with IL-2 for 17 days and then frozen. For generation of TIL clones, TILs were thawed, rested for 1 day in 15% human serum͞RPMI medium 1640 and cloned by limiting dilution (3 cells/well) as described (14). Autologous PBMCs used as APC were pulsed for 3 h at 37°C with a mixture of 1 M of each of the peptides p523, p573, p577, p578, p579, p538, p540, and p541.…”

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confidence: 99%

Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer

Sæterdal

Bjørheim

Lislerud

et al. 2001

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

238

166

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The functional role and specificity of tumor infiltrating lymphocytes (TIL) is generally not well characterized. Prominent lymphocyte infiltration is the hallmark of the most common form of hereditary colon cancer, hereditary nonpolyposis colon cancer (HNPCC) and the corresponding spontaneous colon cancers with the microsatellite instability (MSI) phenotype. These cancers are caused by inherited or acquired defects in the DNA mismatch-repair machinery. The molecular mechanism behind the MSI phenotype provides a clue to understanding the lymphocyte reaction by allowing reliable prediction of potential T cell epitopes created by frameshift mutations in candidate genes carrying nucleotide repeat sequences, such as TGF␤RII and BAX. These tumors therefore represent an interesting human system for studying TIL and characterizing tumor-specific T cells. We here describe T cell reactivity against several T helper cell epitopes, representing a common frameshift mutation in TGF␤RII, in TIL and peripheral blood lymphocytes from patients with MSI ؉ tumors. The peptide SLVRLSSCVPVALMSAMTTSSSQ was recognized by T cells from two of three patients with spontaneous MSI ؉ colon cancers and from all three patients with HNPCC. Because such mutations are present in 90% of cancers within this patient group, these newly characterized epitopes provide attractive targets for cancer vaccines, including a prophylactic vaccine for individuals carrying a genetic disposition for developing HNPCC.

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“…This view is also supported by studies with synthetic muRas peptides that demonstrated the induction of strong cytotoxic T-cell responses against this oncogene in vitro 30 and in clinical phase I trials in vivo. 12,31 Because recent investigations from our group demonstrated that most, if not all human cancers express multiple specific Ags, which are recognized by the autologous immune system, 32 the availability of a simple Ag presentation system such as the transfected autologous SP-LCL described here introduces the possibility of a safe and comparatively inexpensive Ag-specific active immunotherapy approach that can be offered to many patients with a wide range of human cancers.…”

Section: Discussionmentioning

confidence: 99%

Gene-modified spontaneous Epstein-Barr virus-transformed lymphoblastoid cell lines as autologous cancer vaccines: Mutated p21 ras oncogene as a model

et al. 2000

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The transfer of genes coding for tumor antigens (Ags) into Ag-presenting cells is a promising strategy to develop cancer vaccines for patients not limited by major histocompatibility complex restriction. To test whether autologous lymphoblastoid cell lines (LCL) can be used as an alternative to dendritic cells for Ag presentation, we established LCL by spontaneous growth in cyclosporin-containing medium in vitro (SP-LCL). SP-LCL, which have an advantage over B95-8-transfected LCL in that they carry no risk of introducing a new infectious agent when used for vaccination, served as a permanent source for transfection with an episomal Epstein-Barr virus-based expression vector encoding the Ki-ras p21 oncogene carrying a point mutation at codon 12 (muRas) as a model tumor Ag. The ability of muRas-transfected SP-LCL (muRas-LCL) to induce immunoreactivity was determined in vitro. After electroporation with an optimized protocol, muRas-LCL expressed mutated ras peptides for a considerable period of time (at least 8 weeks) on the cell surface. The transfection procedure did not affect the expression of the costimulatory molecules B7.1, intercellular adhesion molecule-1, and leukocyte function associated Ag-3 by SP-LCL. muRas-LCL were able to induce muRas-specific cytotoxic T lymphocytes from three of three healthy donors and one of one patient with pancreatic carcinoma. Our results suggest that the gene transfer of muRas sequences to SP-LCL leads to an endogenous processing of this Ag in the major histocompatibility complex class I pathway and to functional presentation of antigenic peptides to CD8 ϩ T lymphocytes. Autologous SP-LCL can serve as an unlimited renewable source for autologous cellular vaccines and appear to be good candidates as presenters for a wide range of human tumor Ags.

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Characterisation of immune responses in pancreatic carcinoma patients after mutant p21 ras peptide vaccination

Cited by 28 publications

References 25 publications

Tumor-Specific CD4+ T Lymphocytes from Cancer Patients Are Required for Optimal Induction of Cytotoxic T Cells Against the Autologous Tumor

Tumor-Specific CD4+ T Lymphocytes from Cancer Patients Are Required for Optimal Induction of Cytotoxic T Cells Against the Autologous Tumor

Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer

Gene-modified spontaneous Epstein-Barr virus-transformed lymphoblastoid cell lines as autologous cancer vaccines: Mutated p21 ras oncogene as a model

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