T-cell genetic modification for re-directed tumor recognition.
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Female↗
Biomedical subjects
Michael Kalos
Publications and source records attributed to Michael Kalos.
Prostein expression is highly restricted to normal and malignant prostate tissues.
BACKGROUND: Prostein is a recently described molecule expressed at the mRNA level in a prostate-specific manner. A murine monoclonal antibody was developed, characterized, and used to evaluate the expression of prostein protein in prostatic, other normal tissue and tumor samples. METHODS: The murine anti-prostein monoclonal antibody 10E3-G4-D3 was generated using recombinant prostein. ELISA, FACS, and Western analyzes were used to characterize 10E3-G4-D3. Immunohistochemistry was used to characterize the expression of prostein in tissues. RESULTS: 10E3-G4-D3 specifically recognizes a linear intracellular epitope of prostein. IHC analysis demonstrates that prostein is expressed in the vast majority of normal and malignant prostatic tissues, regardless of grade and metastatic status. No protein expression is detected in a panel of approximately 4,700 normal and malignant tissue samples representing the great majority of essential tissues and tumors. CONCLUSIONS: Prostein is exquisitely specific for prostate tissues, indicating a potential clinical utility of 10E3-G4-D3 as a diagnostic biomarker, and support the use of prostein as a novel target for development of prostein-specific antibody and T-cell based therapeutic strategies for prostate cancer.
Animals↗
Molecular and immunological evaluation of the transcription factor SOX-4 as a lung tumor vaccine antigen.
The developmental transcription factor SOX-4 has been shown to be highly and differentially overexpressed in primary small cell lung carcinomas (SCLC). To examine the potential of SOX-4 for broad use as a lung cancer vaccine, we have evaluated the expression of SOX-4 in a panel of primary adenocarcinoma, squamous, and large cell tumor samples as well as in a panel of established small cell and non-small cell lung carcinoma tumor cell lines. SOX-4 mRNA is shown to be overexpressed in a substantial fraction of each of these lung tumor types. To examine the immunological potential of SOX-4, we have evaluated the presence of SOX-4-specific CD4 and CD8 T cells in PBMC of healthy donors and the presence of SOX4-specific Abs in sera from SCLC patients. We demonstrate the presence of both CD4 and CD8 T cells that recognize naturally processed epitopes derived from SOX-4 as well as the presence of SOX-4-specific Abs in sera from SCLC patients, but not in sera from healthy donors. The lung tumor-specific overexpression and demonstration of a comprehensive Ag-specific immune response specific for SOX-4 support the use of this molecule in the development of whole gene-, peptide-, or protein-based vaccination strategies against lung cancer. Furthermore, the identification of naturally processed T cell and Ab epitopes from SOX-4 provides valuable tools for the development of peptide-based vaccination strategies against lung cancer as well as to monitor SOX-4-specific responses in vaccinated patients.
Amino Acid Sequence↗
Identification of naturally processed CD8 T cell epitopes from prostein, a prostate tissue-specific vaccine candidate.
Prostein is a prostate tissue-specific protein that is uniquely and abundantly expressed in normal and cancerous prostate tissues. Due to this expression profile, we examined the immunogenicity of prostein as a potential vaccine candidate for prostate cancer. To determine the presence of CD8 T cells specific for naturally processed prostein-derived epitopes in healthy individuals, we developed and applied an in vitro stimulation protocol. Using this protocol, we identified CD8 T cells specific for prostein in the peripheral blood of a male and a female donor. Prostein-specific CD8 T cell clones specifically recognized prostein-expressing targets, including prostate tumor cell lines expressing the relevant HLA alleles. CD8 T cell clones isolated from the male donor were significantly less effective in recognizing target cells compared to cells isolated from the female donor and appeared to recognize subdominant epitopes. The identification of a prostein-specific CD8 T cell repertoire supports the development of prostein in vaccination strategies against prostate cancer. Furthermore, the naturally processed peptide epitopes identified provide tools for the development of peptide-based vaccination strategies against prostate cancer and for monitoring of prostein-specific responses in vaccinated patients.
Animals↗
Tumor antigen-specific T cells and cancer immunotherapy: current issues and future prospects.
The critical role of antigen-specific T cells in the eradication of cancer has been demonstrated in numerous animal models. Data compiled from both in vitro systems and human clinical trials indicate that T cells can be identified that recognize antigenic fragments derived from gene products expressed by tumors. Nonetheless, results from clinical trials have been for the most part disappointing, since vaccine protocols designed to elicit anti-tumor T cell activity have, in the majority of cases, failed to result in tumor eradication and enhanced patient survival. The focus of this review article is to summarize the current status of antigen-specific tumor immunotherapy and provide insight into potential future strategies for the successful activation of T cells for the immunotherapy of cancer.
Animals↗
Identification of naturally processed CD4 T cell epitopes from the prostate-specific antigen kallikrein 4 using peptide-based in vitro stimulation.
Kallikrein (KLK)4 is a recently described member of the tissue kallikrein gene family that is specifically expressed in normal and prostate tumor tissues. The tissue-specific expression profile of this molecule suggests that it might be useful as a vaccine candidate against prostate cancer. To examine the presence of CD4 T cells specific for KLK4 in PBMC of normal individuals, a peptide-based in vitro stimulation protocol was developed that uses overlapping KLK4-derived peptides spanning the majority of the KLK4 protein. Using this methodology, three naturally processed CD4 epitopes derived from the KLK4 sequence are identified. These epitopes are restricted by HLA-DRB1*0404, HLA-DRB1*0701, and HLA-DPB1*0401 class II alleles. CD4 T cell clones specific for these epitopes are shown to efficiently and specifically recognize both recombinant KLK4 protein and lysates from prostate tumor cell lines virally infected to express KLK4. CD4 T cells specific for these KLK4 epitopes are shown to exist in PBMC from multiple male donors that express the relevant class II alleles, indicating that a CD4 T cell repertoire specific for KLK4 is present and potentially expandable in prostate cancer patients. The demonstration that KLK4-specific CD4 T cells exist in the peripheral circulation of normal male donors and the identification of naturally processed KLK4-derived CD4 T cell epitopes support the use of KLK4 in whole gene-, protein-, or peptide-based vaccine strategies against prostate cancer. Furthermore, the identification of naturally processed KLK4-derived epitopes provides valuable tools for monitoring preexisting and vaccine-induced responses to this molecule.
Amino Acid Sequence↗
CD8(+) T cell tolerance to a tumor-associated antigen is maintained at the level of expansion rather than effector function.
CD8+ T cell tolerance to self-proteins prevents autoimmunity but represents an obstacle to generating T cell responses to tumor-associated antigens. We have made a T cell receptor (TCR) transgenic mouse specific for a tumor antigen and crossed TCR-TG mice to transgenic mice expressing the tumor antigen in hepatocytes (gag-TG). TCRxgag mice showed no signs of autoimmunity despite persistence of high avidity transgenic CD8+ T cells in the periphery. Peripheral CD8+ T cells expressed phenotypic markers consistent with antigen encounter in vivo and had upregulated the antiapoptotic molecule Bcl-2. TCRxgag cells failed to proliferate in response to antigen but demonstrated cytolytic activity and the ability to produce interferon gamma. This split tolerance was accompanied by inhibition of Ca(2+) flux, ERK1/2, and Jun kinase phosphorylation, and a block in both interleukin 2 production and response to exogenous interleukin 2. The data suggest that proliferation and expression of specific effector functions characteristic of reactive cells are not necessarily linked in CD8+ T cell tolerance.
Animals↗
Development and application of CD19-specific T cells for adoptive immunotherapy of B cell malignancies.
The graft-versus-leukemia (GVL)-effect achieved by donor-derived T cells arising from transplanted allogeneic hematopoietic stem cells or given as donor-leukocyte infusions (DLI) after allogeneic transplant, demonstrates that donor-derived T cells can eradicate B-lineage malignancies. However, graft-versus-host-disease (GVHD) occurring after allogeneic hematopoietic stem-cell transplant (HSCT) or polyclonal DLI can limit the efficacy of these interventions. This toxicity can be avoided by using autologous T cells and/or tumor-specific cytotoxic T lymphocytes (CTLs). To generate antigen-specific T cells that can be derived from the allogeneic donor or the patient, we have genetically manipulated T cells to express a CD19-specific chimeric immunoreceptor. This renders T cells specific for CD19, a cell surface molecule found on B-lineage leukemia and lymphoma. This review will demonstrate the redirected specificity of CD19-specific T cells and implementation of clinical trials using these cellular agents.
Antigens, CD19↗