Using Peptides and Their Analogs to Kill CLL Cells

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Blood First Edition Paper, prepublished online August 10, 2006;

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, Zahrieh, Donna Neuberg, and 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

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 (mouse) models.

*Analogs of parent (usually naturally occuring) peptide. Using

peptides to kill cancer cells is a relatively new idea. There are a

variety of efforts to use this idea to enhance cancer-killing

potential.