Intraclonal Variability of VH Genes in Follicular Lymphoma Patients Who Have Received Anti-Idiotypic Immunotherapy
Fecha
2006Resumen
Subclonal heterogeneity can affect idiotypic determinants present in the clonotypic immunoglobulin of B-cell follicular
lymphomas (FLs) and may limit the effect of antilymphoma
treatments performed by immunization of patients with their own
tumor-associated idiotypic immunoglobulin. Idiotype-secreting hybridomas were obtained by fusion of tumor cells from 5 patients with
FL, and the K6H6/B5 human heteromyeloma and rearranged VH
genes from tumor samples and hybridomas were amplified, cloned,
and sequenced. Sequences were aligned with germline genes and
somatic mutations, intraclonal heterogeneity and genealogic relations
of the B-cell clones in the different biopsy specimens were
determined. The VH sequence of the progenitor clone was determined
in samples of the tumoral population. Further diversification resulted in
the presence of 2 to 6 subclones in 4 of the 5 samples studied. Only in
1 patient did the hypermutation mechanism introduce differences
among most of the potential idiotopes present in individual
subclones. The VH sequence of the hybridoma that provided the
idiotypic-vaccine was identified in one of the tumor subclones in all
cases. No relapse has been demonstrated in 3 of the 4 vaccinated
patients (follow-up: 29–103 months). We conclude that despite
potential differences in the idiotypic region expressed by individual
tumor cells, at least some potential idiotopes may be preserved among
all the tumor subclones in most cases studied. All vaccinated patients
developed immune responses against the autologous tumor idiotypic
immunoglobulin. Polyclonal anti-idiotypic immune responses induced
with a vaccine obtained from 1 hybridoma may be effective against all
the idiotypic variants present in the tumor population.