Blood, 15 November 2001, Vol. 98, No. 10, pp. 2885-2885
Finally, able to present ABL
Chronic myelogenous leukemia (CML) has long been a
hunting ground for specific therapies of cancer because the disease is initiated by a single, unique chromosomal translocation. The
translocation fusion gene product is the target of the first rationally
designed tumor inhibitor STI571 (imatinib mesylate, or Gleevec). The
unique amino acid sequences at the fusion point of this protein have also interested immunologists, who have seen it as a truly specific cancer antigen. What makes this target so appealing is its specificity for the tumor cell, its limited variability (there are only 2 major
breakpoints), and its role as the oncogene product responsible for
leukemogenesis. But the exclusively cytoplasmic location for the
fusion proteins led to considerable early pessimism that this target would find a use in immunotherapy. Despite this, a number of
groups have shown that the amino acid sequences that cross the
breakpoint are immunogenic to human T cells in vitro. We also have
recently shown that vaccination of patients with CML with these
sequences will generate a specific T-cell-mediated immune response to
the peptides. What has been most clearly lacking in this field is the
direct demonstration that the appropriate amino acid sequences derived
from the fusion point could be processed within the cell and
incorporated into HLA molecules for presentation on the surface of
target leukemia cells where they can be recognized and attacked by
cytotoxic T cells.
Clark and colleagues (page 2887) finally provide this direct evidence.
The authors do this by using mass spectrometry of sequences of peptides
stripped from the HLA molecules on the surface of CML cells. They are
able to show that sequences thus derived are identical to sequences
predicted (and shown) to be immunogenic. They follow these data
with a demonstration that human T cells stimulated to respond to
this peptide can be quantitated using HLA tetramers containing
the sequence and can kill fresh CML cells in an HLA-restricted,
peptide-specific manner. The authors conclude that these data provide a
sound basis for immunization of patients against the BCR-ABL protein.
As we finalize enrollment in our phase II vaccination trial using these
sequences, we heartily and retroactively applaud Clark and
colleagues's work and its conclusions.
David A. Scheinberg
Memorial Sloan-Kettering Cancer
Center
