Blood, 1 February 2002, Vol. 99, No. 3, pp. 729-730
Another piece of the puzzle
Carton and colleagues (page 754) have added to the controversy
regarding the dominant mechanism of action of rituximab in vivo. They
determined the effect of a Fc
RIIIa-158V/F receptor polymorphism in
patients treated with 4 infusions of rituximab as initial therapy for
low-risk follicular NHL. Twenty percent were homozygous for valine
(158V), 35% homozygous for phenylalanine (158F), and 45%
heterozygous. Patients with homogenous 158V were found to have a
greater response rate and a greater molecular response at 1 year
compared with patients with either the homozygous 158F or the
heterozygous patients with 158F/V genotype. Despite these findings, the
time-to-tumor progression did not differ between the 2 groups, likely
due to the small numbers of patients. FcRIIIa-158V/V receptors have
higher affinity interaction with IgG1, promoting more efficient
antibody-dependent cell-mediated cytotoxicity (ADCC). These
results are consistent with other observations that point to the
importance of ADCC as a mechanism of rituximab killing. Interestingly,
there was not a clear gene-dose relationship, as the patients with
homozygous 158F had a similar response rate to the patients with
158V/F. Ultimately, whether this observation is actually due to
FcRIIIa genotype or to another closely linked gene remains to be settled.
But this is not the whole story, as 67% of the 158F carriers
with less efficient interaction with IgG1 had remissions
and patients homozogous for 158V continue to relapse. Possible factors include other Fc receptors, complement-mediated cytotoxicity, and
direct effects of antibody binding. Longer follow-up, a larger series
of patients, and extension of these observations to patients receiving
rituximab for relapsed disease or concurrently with chemotherapy will
be important. Nevertheless, these observations may lead to strategies
to augment ADCC. Options include engineering a better IgG1 antibody
that allows more efficient interaction with 158F carrier genotype or
increasing the number of or activation of the ADCC effector
cells through administration of cytokines. Ultimately, a better
understanding of these mechanisms of action and resistance will provide
the rationale for new approaches that will increase response rates to
antibody therapy.
David G. Maloney
Fred Hutchinson Cancer Research Center
