Monoclonal antibodies (MoAbs) for cancer have
been the subject of intense clinical investigation for nearly 2
decades. Although the concept of MoAb therapy is simple, a host of
unforeseen difficulties hindered the realization of clinical benefit
from this therapeutic approach.
The review by McLaughlin and colleagues of rituximab (Rituxan), the
first MoAb approved for the treatment of cancer, describes one of the
success stories in this field. Many other candidate antibodies have
appeared to be equally promising during preclinical testing, only to
fail during subsequent clinical trials. The lessons learned from
these failures (eg, anti-B4-blocked ricin) and the successes, like
rituximab, highlight the challenges involved in the development of an
effective MoAb for cancer therapy.
Obstacles to the Development of Effective MoAbs
One challenge has been the selection of appropriate target antigens.
Although hematologic malignancies are relatively unique in their
expression of cell surface antigens not present on other tissues, not
every antigen has proven to be an optimal target. Studies with
antibodies targeting CD5,[2,3] CD19, and CD22 demonstrated that
these antigens internalize upon antibody binding, making them poor
targets for serotherapy with unconjugated antibodies.
Furthermore, the tumor must persistently express antigen despite
intense negative selection imposed by the antibody; otherwise, the
tumor could escape therapy. Rituximab recognizes CD20, which remains
stable in the face of antibody binding, making it a nearly ideal
Optimal dosing and adequate tissue penetration represent further
stumbling blocks to effective serotherapy. Unlike studies with
conventional cytotoxic agents, initial phase I studies with
rituximab never reached a maximum tolerated dose. Some published
studies have used larger doses than the currently approved 375
mg/m² weekly × 4 regimen, For example, Coiffier et al used
doses up to 500 mg/m² in a weekly × 8 regimen in patients
with intermediate- or high-grade lymphoma. Thus, the best dose and
schedule of rituximab remain to be established.[6,7]
Moreover, even when serum levels that correspond to effective in
vitro cytotoxicity can be achieved, tissue levels may still be
subtherapeutic, particularly within poorly vascularized lymphomatous
nodes. Studies of the Campath-1H MoAb (anti-CD52) demonstrate
effec-tive penetration into bone marrow and spleen but not into lymph
nodes and extranodal tissue sites. In contrast, rituximab has
shown efficacy even in bulky tumors. Whether its activity is
augmented in the minimal disease setting requires further investigation.
As with all therapies, the potential toxicities of MoAbs must always
be considered. Although acute reactions to all MoAbs are common,
particularly during initial infusions, few patients require
discontinuation of the agent. Subacute toxicities may vary
considerably, depending on the particular antibody. Campath-1H
induces significant T- and B-cell depletion, since it targets a cell
surface antigen common to both lymphocyte lineages. The resulting
profound lymphopenia significantly increases the risk of
To date, no major toxicity has been seen with rituximab, despite
prolonged B-cell depletion following therapy. This minimal side
effects profile therefore makes rituximab an attractive agent for
combination therapies and as salvage therapy for patients who may
have impaired marrow reserve and reduced tolerance for toxicity.
Rituximab Combined With Chemotherapy
In vitro data suggesting synergy of rituximab with conventional
chemotherapy represent the most exciting potential for this
agent.[9,10] A phase II trial of rituximab in combination with CHOP
(cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone)
chemotherapy in patients with previously untreated follicular or
low-grade non-Hodgkins lymphoma reported a 100% response rate,
with complete responses in approximately two-thirds of patients.
Furthermore, of eight patients who had detectable disease in
peripheral blood and bone marrow, based on polymerase chain reaction
(PCR) analysis for t(14;18), seven became PCR-negative in the blood
and bone marrow after therapy with rituximab plus CHOPan
unusual occurrence among patients treated with chemotherapy alone.
Ongoing Cooperative Group Trials
Several large cooperative group trials are exploring the potential
synergy between cytotoxic chemotherapy and rituximab and its value as
maintenance therapy. For example, the Cancer and Leukemia Group B
(CALGB) is studying the efficacy and incremental toxicity of the
addition of rituximab to CHOP chemotherapy in elderly patients with
aggressive non-Hodgkins lymphoma. Already existing data
demonstrate that rituximab adds little to the toxicity profile of
CHOP chemotherapy alone and may enhance response rates.[7,12] Given
the stability of CD20 expression, this trial also is exploring the
value of rituximab maintenance by randomizing all patients with
responsive disease to observation or four weekly doses of rituximab
every 6 months for 2 years.
The value of rituximab maintenance therapy in low-grade lymphoma is
the subject of two other cooperative group trials. The Eastern
Cooperative Oncology Group (ECOG) is conducting a phase III trial of
cyclophosphamide and fludarabine (Fludara) vs CVP (cyclophosphamide,
vincristine, and prednisone), followed by rituximab or observation.
The Southwest Oncology Group (SWOG) is performing a phase II trial of
CHOP followed by rituximab, with special attention to measurement of
minimal residual disease.
The CALGB also is examining whether the addition of rituximab to
fludarabine improves outcome in patients with chronic lymphocytic
leukemia (CLL). To date, no studies of rituximab in CLL have been
published, but early studies that included patients with small
lymphocytic lymphoma had a relatively low response rate, which was
attributed to the tumors relatively low level of CD20
expression. There is also the potential for synergistic toxicity
between fludarabine and rituximab due to combined immunosuppression.
Thus, rituximab represents a significant advance in the treatment of
lymphoma. It also demonstrates proof of principle that serotherapy is
feasible under the right conditions, including the targeting of
stable antigens, adequate tissue penetration, and a favorable
Advances also are being made in the development of MoAbs for the
treatment of solid tumor malignancies. Recently, Riethmuller et al
reported the 7-year follow-up results of a phase III trial of the
17-1A antibody in patients with resected Dukes C colon
cancer. They demonstrated a 32% decrease in overall mortality and
a 23% decrease in recurrence rate, compared with observation.
Similarly promising data have emerged from trials of trastuzumab
(Herceptin) in metastatic breast cancer and led to the recent FDA
approval of this MoAb for the treatment of metastatic breast cancer.
These trials demonstrated the efficacy of trastuzumab as a single
agent, as well as its synergy with conventional combination
chemotherapy. Although not discussed in this article, exciting
progress also is being made in the field of iodine and yttrium
radioimmunoconjugates. Response rates of 30% have been reported in
patients with refractory lymphoma.
Further studies with rituximab and other promising MoAbs will help
delineate a potentially important role of serotherapy in the
treatment of a variety of malignancies.
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