David H Sherr

Publications (2)15.34 Total impact

• Article: Identification of a new HLA-A*0201-restricted cryptic epitope from CYP1B1.

  Britta Maecker, Michael S von Bergwelt-Baildon, David H Sherr, Lee M Nadler, Joachim L Schultze
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  ABSTRACT: Cytochrome P450 1B1 (CYP1B1) was recently shown to be a candidate tumor antigen broadly expressed in solid and hematologic malignancies. Nevertheless, use of such self-antigens as targets for immune intervention can be limited because of loss of high-avidity T cells during negative selection in the thymus. Recent data suggest that targeting of cryptic epitopes may represent a way to circumvent such self-tolerance and induce efficient antitumor CTL responses. Here, we present the identification and characterization of a novel, cryptic HLA-A*0201-binding peptide from CYP1B1. The nanomer CYP246 was identified by epitope deduction using algorithms to predict HLA-A*0201-binding peptides. CYP246 is characterized by strong initial HLA-A*0201 binding but a short MHC/peptide binding half-life. Expansion of high-avidity CTL was readily possible using autologous CD40-activated B cells from normal donors and cancer patients as antigen-presenting cells, suggesting that an intact T-cell repertoire can be expanded for this epitope. Lysis of CYP1B1-expressing, HLA-A*0201+ tumor cell lines and primary tumor cells confirmed that sufficient levels of CYP246 are presented by tumor cells for effector CTL killing. These findings indicate that CYP246 is a candidate cryptic epitope for immune interventions in which tumor CYP1B1 is targeted.
  International Journal of Cancer 07/2005; 115(2):333-6. · 5.44 Impact Factor
• Article: The shared tumor-associated antigen cytochrome P450 1B1 is recognized by specific cytotoxic T cells.

  Britta Maecker, David H Sherr, Robert H Vonderheide, Michael S von Bergwelt-Baildon, Naoto Hirano, Karen S Anderson, Zhinan Xia, Marcus O Butler, Kai W Wucherpfennig, Carl O'Hara, Geoffrey Cole, Silvia S Kwak, Urban Ramstedt, Andy J Tomlinson, Roman M Chicz, Lee M Nadler, Joachim L Schultze
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  ABSTRACT: Cytochrome P450 1B1 (CYP1B1), a drug-metabolizing extrahepatic enzyme, was recently shown to be overexpressed in multiple types of cancer. Such tumor-associated genes may be useful targets for anticancer therapy, particularly cancer immunotherapeutics. We identified HLA-A*0201-binding peptides and a naturally processed and presented T-cell epitope capable of inducing CYP1B1-specific cytotoxic T lymphocytes (CTLs) in HLA-A2 transgenic mice. Furthermore, the induction of CYP1B1-specific T cells was demonstrated in healthy donors and cancer patients. These T cells efficiently lysed target cells pulsed with the cognate peptide. More important, HLA-A2-matched tumor cell lines and primary malignant cells were also recognized by CYP1B1-specific CTLs. These findings form the basis of a phase 1 clinical trial exploring a DNA-based vector encoding CYP1B1 for widely applicable cancer immunotherapy conducted at the Dana-Farber Cancer Institute.
  Blood 12/2003; 102(9):3287-94. · 9.90 Impact Factor