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M J Visseren

Publications and source records attributed to M J Visseren.

9 recordsLinked to original sources
PubMed1997

Identification of HLA-A*0201-restricted CTL epitopes encoded by the tumor-specific MAGE-2 gene product.

MAGE-2 is expressed in many tumors, including melanoma, laryngeal tumors, lung tumors and sarcomas, but not in healthy tissue, with the exception of testis. Thus, MAGE-2-derived peptides that bind to HLA class I molecules and elicit cytotoxic T lymphocyte (CTL) responses could be of significant therapeutic importance. In this study, we show that several MAGE-2-derived peptides bind with high affinity to HLA-A*0201. Three of them form complexes with HLA-A*0201 that are stable at 37 degrees C and are immunogenic in HLA-A*0201Kb transgenic mice. Moreover, CTLs against 2 of them (M2 112-120, and M2 157-166) specifically recognize cells that express both the MAGE-2 protein and HLA-A*0201Kb. These 2 peptides are processed and presented in the context of HLA-A*0201. Therefore, these peptides are candidate components in peptide-based vaccines for the treatment and prevention of several types of MAGE-2-expressing cancers.

Animals↗
PubMed1997

Affinity, specificity and T-cell-receptor diversity of melanoma-specific CTL generated in vitro against a single tyrosinase epitope.

MHC-class-I-restricted cytotoxic T lymphocytes (CTL) specific for tumor-associated antigens expressed by malignant cells are important components of the immune response against cancer. Recently, tumor-specific CTL could be generated in vitro, with responding lymphocytes from the blood of healthy blood donors. In the present study, we confirm that peptide-specific stimulation in vitro can induce high-affinity CTL capable of recognizing tumor cells expressing the appropriate tumor antigen. These tyrosinase-specific CTL display a restricted usage of TCRAV and TCRBV gene segments but of diverse CDR3 regions, resulting in a distinct fine-specificity for each CTL clone. This suggests that, similar to in vivo priming, peptide-pulsed APC are capable of stimulating a T-cell response in vitro expressing a limited TCR repertoire against autologous tumors. The generated CTL can recognize their target structure with high affinity, and this correlates in part with tumor-cell lysis. This methodology may be used to treat melanoma patients with infusion of ex vivo-induced and -expanded CTL.

Amino Acid Sequence↗
PubMed1996

Immunogenicity of peptides bound to MHC class I molecules depends on the MHC-peptide complex stability.

The impact of the MHC class I peptide binding stability on the immunogenicity of particular peptide Ags in class I-restricted cytotoxic T lymphocyte responses is not clearly established. Therefore, we have determined the dissociation rate of each peptide from MHC class I at 37 degrees C and compared this to that of a consensus CTL epitope. Newly defined immunogenic peptides formed relatively stable MHC-peptide complexes as shown by their low dissociation rates, whereas nonimmunogenic peptides displayed high dissociation rates. In addition virtually all previously described HLA-A*0201-restricted T cell epitopes showed low dissociation rates. Furthermore, we show that the immunogenicity of HIV-1-derived peptides can be predicted more accurately by their dissociation rate than by the MHC class I binding affinity. Selection of peptides based on affinity and their dissociation rate leads to a more precise identification of candidate CTL epitopes than selection based on affinity alone. These results help to understand why some peptides are recognized by CTL and, along with detailed knowledge of protein processing rules, therefore have important implications for the selection of peptides in peptide-based vaccines.

Amino Acid Sequence↗
PubMed1996

Lysis of syngeneic tumor B cells by autoreactive cytotoxic T lymphocytes specific for a CD19 antigen-derived synthetic peptide.

Cytotoxic T lymphocytes (CTL) play an important role in the destruction of immunogenic tumors. A novel category of target antigens for CTL concerns normal differentiation antigens as most clearly demonstrated in human melanoma. In the case of B-cell cancers, differentiation antigens normally expressed on B cells may be useful targets. In this report, we have focused on the murine B-cell differentiation antigens CD19 and CD20. We have identified 18 peptide sequences on the basis of major histocompatibility complex (MHC) class-I binding-motifs as candidates for the induction of autoreactive CTL. Six of the peptides were capable of binding efficiently to either Kb or Db and were subsequently used for in vivo induction of CTL. Vaccination with each of three peptides led to peptide-specific CTL. Two peptides were derived from the mCD20 antigen and one from the mCD19 antigen. CTL specific for the mCD19-derived peptide were also capable of killing a syngeneic B-cell tumor line. Recognition of the peptide as well as the tumor cells was shown to be Kb restricted. This is the first report to show that autoreactive CTL recognizing peptides derived from B-cell-specific differentiation antigens can be generated by vaccination with a synthetic peptide.

Animals↗
PubMed1995

CTL specific for the tyrosinase autoantigen can be induced from healthy donor blood to lyse melanoma cells.

CTL that lyse melanoma cells were previously isolated from several melanoma patients. Such CTL recognize autologous proteins, indicating the occurrence of autoreactive T cells in melanoma patients. We have now raised CTL, using responding T lymphocytes from healthy donor blood, that lysed not only cells incubated with an HLA-A*0201-binding tyrosinase peptide but also melanoma cells endogenously processing and presenting the epitope. Our results suggest that autoreactive CTL precursors are present in healthy donor blood and can be activated in vitro with synthetic peptides presented on appropriate APCs. Therefore, tissue-specific, autoantigen-derived peptides might be useful in immunotherapy of both poorly and nonimmunogenic tumors.

Amino Acid Sequence↗
PubMed1994

Production of interleukin-2 by EL4 tumor cells induces natural killer cell- and T-cell-mediated immunity.

Systemic administration of recombinant interleukin (rIL)-2 to cancer patients has met with limited clinical success since, despite significant antitumor effects, its use is associated with severe toxicity. Local production of IL-2 by IL-2 gene transfected tumor cells in murine model systems has been reported to induce specific immunity--devoid of toxicity--to the parental non-IL-2-producing tumor cells. We now report enhanced resistance in nonimmunized mice to murine EL4 thymoma cells, producing murine IL-2 following gene transfer (EL4pIL-2). This effect is mediated by activated natural killer (NK) cells, since we observed the same effect in nude mice but not in NK-depleted mice. Additionally, in mice repeatedly vaccinated with irradiated EL4pIL-2 cells, we observed immunity to challenge with a tumorigenic dose of EL4 cells transfected with a control vector, EL4p. EL4-specific cytotoxic T-lymphocytes (CTLs) were detected in these mice. Mice vaccinated with irradiated EL4p cells were less protected against challenge with a tumorigenic dose of EL4p cells. This study indicates that although some IL-2-producing autologous tumor cells elicit NK-mediated responses and not CTL responses upon inoculation, tumor-specific CTL responses are generated upon repeated vaccinations with these cells. This strategy has potential application for treating a wide variety of cancer patients with autologous IL-2 producing tumor cells.

Animals↗
PubMed1994

Tumor rejection antigens and tumor specific cytotoxic T lymphocytes.

In several tumor models and in certain types of human malignancies, T cell mediated immune responses can be involved in the host's defences against cancer. Adoptively transferred tumor-specific T cells can mediate complete tumor regression in several animal models and the first effective therapeutic interventions with adoptively transferred (virus-specific) CTL in man have been reported. With the identification of tumor rejection antigens new antigen specific therapeutic approaches come into sight. The development of anti-tumor vaccines based upon known tumor rejection antigens might take off rapidly in the near future, since only the first few tumor rejection antigens of an enormous potential have been reported. This development will go hand in hand with the utilization of cytokines in these vaccines. Cytokines might promote T cell activity or antigen presentation, but can also be used to counteract tumor immune escape mechanisms. Escape from immune surveillance and T cell mediated elimination by tumor cells might account for the failure of the immune system to eradicate or prevent the outgrowth of many types of tumors. The identification of tumor rejection antigens and tumor-specific immune responses, together with a better understanding of the mechanisms by which tumors escape from T cell mediated immunity brings fresh encouragement in the field of tumor immunology.

Animals↗
PubMed1993

Enhancement of the antibody-dependent cellular cytotoxicity of human peripheral blood lymphocytes with interleukin-2 and interferon alpha.

Antibody-dependent cellular cytotoxicity (ADCC) is regarded as an important mechanism by which monoclonal antibodies (mAb) can exert an antitumour effect in vivo. It may be possible, therefore, to enhance the therapeutic efficacy of mAb by cytokines that are able to enhance the ADCC of human CD3-, CD56+, CD16+ natural killer (NK) cells. We investigated in vitro the effects of recombinant interferon alpha (rIFN alpha) and recombinant interleukin 2 (rIL-2), alone or in combination, on the ADCC of human peripheral blood NK cells. Both cytokines enhanced the ADCC of the human effector cells. rIFN alpha induced a maximally increased ADCC after an exposure of human effector cells to 20 IU/ml for 15-30 min, while rIL-2 induced optimal ADCC after incubation of the cells for 2 days in 20-50 U/ml. We now show that activation of the NK cells with a combination of rIL-2 and rIFN alpha induced significantly higher levels of ADCC than either cytokine alone. The highest ADCC was induced if the cells were first exposed to rIL-2 before rIFN alpha was added to the culture. Culture of NK cells in medium or rIL-2 decreased the expression of Fc gamma RIII (CD16), indicating that intensity of CD16 expression and level of ADCC are not directly correlated, although blocking experiments with a mAb directed against CD16 showed that this Fc gamma R was essential for ADCC of the human effector cells.

Antibodies, Monoclonal↗