PR1-specific T cells are associated with unmaintained cytogenetic remission of chronic myelogenous leukemia after interferon withdrawal.
BACKGROUND
Interferon-alpha (IFN) induces complete cytogenetic remission (CCR) in 20-25% CML patients and in a small minority of patients; CCR persists after IFN is stopped. IFN induces CCR in part by increasing cytotoxic T lymphocytes (CTL) specific for PR1, the HLA-A2-restricted 9-mer peptide from proteinase 3 and neutrophil elastase, but it is unknown how CCR persists after IFN is stopped.


RESULTS
We reasoned that PR1-CTL persist and mediate CML-specific immunity in patients that maintain CCR after IFN withdrawal. We found that PR1-CTL were increased in peripheral blood of 7/7 HLA-A2+ patients during unmaintained CCR from 3 to 88 months after IFN withdrawal, as compared to no detectable PR1-CTL in 2/2 IFN-treated CML patients not in CCR. Unprimed PR1-CTL secreted IFNgamma and were predominantly CD45RA+/-CD28+CCR7+CD57-, consistent with functional naïve and central memory (CM) T cells. Similarly, following stimulation, proliferation occurred predominantly in CM PR1-CTL, consistent with long-term immunity sustained by self-renewing CM T cells. PR1-CTL were functionally anergic in one patient 6 months prior to cytogenetic relapse at 26 months after IFN withdrawal, and in three relapsed patients PR1-CTL were undetectable but re-emerged 3-6 months after starting imatinib.


CONCLUSIONS
These data support the hypothesis that IFN elicits CML-specific CM CTL that may contribute to continuous CCR after IFN withdrawal and suggest a role for T cell immune therapy with or without tyrosine kinase inhibitors as a strategy to prolong CR in CML.
Kanodia
Shreya
S
Section of Transplant Immunology, Department of Blood and Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
Wieder
Eric
E
Lu
Sijie
S
Talpaz
Moshe
M
Alatrash
Gheath
G
Clise-Dwyer
Karen
K
Molldrem
Jeffrey J
JJ
D000328:Adult; D020732:Cytogenetic Analysis; D005260:Female; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000652:urine*; D007371:Interferon-gamma / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D012074:Remission Induction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015789:HLA-A2 Antigen; D016898:Interferon-alpha; D010455:Peptides; D007371:Interferon-gamma