Blood, 15 February 2001, Vol. 97, No. 4, pp. 833-833
When magic bullets miss their mark
The exquisite specificity of the adaptive immune response
underlies much of the promise of cancer immunotherapy. Ironically, however, this same specificity represents an Achilles heel if the
antigenic target mutates to no longer be recognizable by the ensuing
immune response. In this issue, 2 striking examples of this feared
occurrence are reported. Furukawa et al (page 987) examine changes in
the expression of HTLV-1 Tax protein in patients with adult T-cell
leukemia (ATL). Tax protein plays a pivotal role in immortalization of
HTLV-1-infected lymphocytes but, interestingly, is also the source of
the dominant MHC class I epitope recognized by HTLV-1-specific cytoxic
T lymphocytes (CTLs). Several ATL patients were identified in which a
mutation resulted either in a truncated Tax protein (with loss of
defined epitopes) or in an amino acid substitution in the dominant
HLA-A*02 restricted epitope that was no longer recognized by Tax
specific CTLs in HLA-A*02+ patients. Comparison of HTLV-1
isolates from ATL patients and their family members indicated that the
truncation was present only in patient samples. Given that Tax is
required for HTLV-1 transactivation, the truncated (nonfunctional)
Tax likely arose in the ATL patients after lymphocyte
immortalization, resulting in transformed cells that no longer require
Tax and that are invisible to Tax-specific CTLs.
Loss of tumor-associated antigens can have a profound impact on the
outcome of therapy, as graphically demonstrated by Gottschalk et al
(page 835). This elegant case report describes a patient with
post-marrow transplantation lymphoproliferative disease that was
unresponsive to adoptive immunotherapy with an Epstein-Barr virus
(EBV)-specific T-cell line. The authors systematically identify the
likely basis for this treatment failure to be the outgrowth of
tumor-harboring EBV with a deletion in EBNA-3B.
Whereas the T-cell line used for therapy was technically
polyclonal (and was stimulated using lymphoblastoid cells expressing
all 9 EBV latency antigens), as typically occurs, it demonstrated
highly restricted antigen specificity, in this case almost exclusively
recognizing 2 EBNA-3B epitopes, both of which were lost by the tumor.
Before treatment, both wild-type and truncated EBV sequences were
present in the patient, but after T-cell therapy only the truncated
variant could be identified, suggesting selective tumor-cell killing
and outgrowth of the antigen loss variant. In this case, as well as in
the studies of HTLV-1, it remains unclear what the origin of the
mutated viruses might be, and similar isolates have not been reported
in normal carriers. Taken together, these reports underscore the
inherent risks of taking aim at a heterogeneous tumor target with the
laser-like precision of an oligoclonal T-cell response. It is likely
that future strategies will need to engineer a more broadly polyvalent
response (such as the infusion of independently generated lines
targeting multiple antigens) or the identification of antigens that are
indespensible for maintaining the transformed phenotype.
Hyam I. Levitsky
Johns Hopkins University School of Medicine
