Submitted April 11, 2006
Accepted July 12, 2006
Cytotoxic T-cells generated against heteroclitic peptides kill primary tumor cells independent of the binding affinity of the native tumor antigen peptide
Katja Mauerer Zirlik, David Zahrieh, Donna Neuberg, and John G. Gribben*
Department of Hematology/Oncology, Freiburg University Medical Center, Freiburg, Germany
Medical Oncology and Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston
Barts and The London School of Medicine, Charterhouse Square, London
* Corresponding author; email: john.gribben{at}cancer.org.uk.
Heteroclitic peptide modifications increase immunogenicity allowing generation of cytotoxic T lymphocytes (CTL) against weakly immunogenic tumor associated antigens (TAA). A critical issue is whether T cells generated against heteroclitic peptides retain the ability to recognize and kill tumor cells and more importantly, whether there is a lower threshold of binding affinity of the native peptides below which such CTLs can still kill primary tumor cells. To examine this we used a model examining the ability of native and heteroclitic immunoglobulin (Ig) derived peptides to generate CTLs that can kill chronic lymphocytic leukemia (CLL) cells. We demonstrate that CTLs generated against heteroclitic peptides have enhanced killing of CD40-activated B-cells pulsed with either heteroclitic (p=0.0003), or native peptide (p=0.04), and primary CLL cells (p=0.01). The novel finding here is that the rate-limiting factor appears to be the ability to generate CTLs and that once generated CTL lysis of primary tumor cells is independent of the binding affinity of the native peptide. These findings have implications for vaccination strategies in malignancies and are currently being further examined in vivo in murine models.
