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Recent Progress in Radioimmunotherapy for Cancer

Recent Progress in Radioimmunotherapy for Cancer

ABSTRACT: Radioimmunotherapy allows for the delivery of systemically targeted radiation to areas of disease while relatively sparing normal tissues. Despite numerous challenges, considerable progress has been made in the application of radioimmunotherapy to a wide variety of human malignancies. The greatest successes have occurred in the treatment of hematologic malignancies. Radioimmunotherapy, with or without stem-cell transplant support, has produced substantial complete remission rates in chemotherapy-resistant B-cell lymphomas. Nonmyeloablative regimens have shown so much promise that they are now being tested as initial therapy for low-grade B-cell lymphomas. Although solid tumor malignancies have been less responsive to radioimmunotherapy, encouraging results have been obtained with locoregional routes of administration, especially when the tumor burden is small. Greater tumor-to-normal tissue ratios are achievable with regional administration. Even with intraperitoneal and intrathecal administration, bone marrow suppression remains the dose-limiting toxicity. Ongoing research into new targeting molecules, improved chelation chemistry, and novel isotope utilization is likely to extend the applications of this strategy to other tumor types. The potential for radioimmunotherapy will be enhanced if this modality can be optimally adapted for integration with other agents and if the administration method can be tailored to the type and distribution of malignancy. [ONCOLOGY 11(7):979-987, 1997]

Introduction

In the 22 years since the Nobel prize-winning development of hybridoma
technology for the production of monoclonal antibodies in 1975,[1] the
medical applications of antibodies have greatly expanded. Radioimmunotherapy
generally refers to the administration of a radionuclide conjugated to
an antibody or antibody-derived construct for therapeutic intent. The antibody,
directed to an antigen with enhanced or unique expression on tumor cells,
serves as a carrier for the radioactive component. This technique delivers
systemically targeted radiation to areas of disease while relatively sparing
normal tissues.

Successful use of radiolabeled antibodies for the treatment of cancer
has been more challenging than their application as diagnostic tools.[2-6]
Preclinical studies of radioimmunotherapy, including treatment of athymic
mice bearing human tumors, have been helpful, although the results of these
studies have not always directly translated into equivalent clinical progress.[7]
Despite numerous obstacles, considerable progress in radioimmunotherapy
has been made over the past decade. (Due to the large volume of literature
on this novel treatment strategy, many of the references listed in this
article are reviews.)

The application of antibody technology to cancer therapy has been more
difficult than its use as a diagnostic tool for a variety of reasons.[4-6]
The achievement of a therapeutic effect requires not only selectivity of
radionuclide localization but also delivery of adequate amounts of radionuclide
for generation of therapeutic radiation doses. Vascular dynamics and high
interstitial pressure in tumors have limited the delivery of antibody.
Problems in devising the optimal procedures for linking radionuclide metals
to antibodies have also posed serious hurdles. Additional difficulties
have included the immunogenicity of murine monoclonal antibodies, cross-reactivity
of antibodies with normal tissues, long circulatory half-lives of chimeric
or humanized antibodies, and dose-limiting bone marrow suppression.

Several radionuclides are considered suitable for radioimmunotherapy.
These have been the subject of several recent reviews.[5,8,9] The choice
of radionuclide depends on its radiation emissions, as well as various
characteristics of the target, antibody carrier, and clinical situation,
such as the bulk of disease to be treated.

One advantage of beta-emitting radionuclides as antibody conjugates
over chemotherapeutic agents or toxins is that their effective radiation
range extends beyond the antibody-bound target cell. Thus, beta-radiation
can kill surrounding tumor cells from a point of localization. This is
advantageous given the prominent variation in antigen expression and antibody/drug
delivery in various parts of tumor nodules.

Iodine-131 and ytrrium-90 have been the most extensively used beta-emitters
to date. Ytrrium-90 has the longer range in tissue, with an average of
2.5 mm compared to 0.3 mm for iodine-131. However, ytrrium-90 requires
a chelator and does not have gamma-emissions that allow direct imaging
of radioimmunconjugate distribution.

Certain non-beta-emitting radionuclides (eg, alpha-emitters, Auger electron
emitters) also have attractive features. For example, Auger electron emitters,
such as iodine-125, have such a short range of energy deposition that they
require internalization and translocation to the nuclear DNA to effectively
kill tumor cells. Thus, normal cells that do not express the target antigen
are not affected by Auger electron emission, as they are by the multi-cell-diameter
range of beta emissions. As a result, toxicity may be reduced.

The choice of antibody construct to be used as the carrier includes
full-size molecules of murine or "humanized" molecules (chimeric
or complementarity determining regions (CDR)-grafted), as well as traditional
fragments [FAb or F(Ab')2] or genetic constructs. Genetic constructs
vary in size, as well as in the number of antigen-combining sites, or have
been modified to alter their biology (eg, fusion proteins). These various
antibody constructs have been reviewed by Dion,[10] Frankel,[11] and others.[12]

Clinical
Results in Hematologic Malignancies

Thus far radioimmunotherapy has had the greatest success in the treatment
of lymphomas and leukemias. The hematologic malignancies have several features
that make them more suitable than solid malignancies for radioimmunotherapy.
First, malignant cells in the blood, spleen, lymph nodes, and bone marrow
are more accessible than are solid tumor cells. Also, knowledge of the
antigenic expression of the various lineages and stages of hematopoietic
differentiation have provided well-characterized monoclonal antibodies.

Although CD20 has been the target antigen for more than one clinically
successful antibody, several other target antigens for hematologic malignancies
have been identified. These include CD19, CD21, CD22, CD37, CD5, CD25,
CD33, and CD45, as well as anti-idiotypic antigens. Most of these antigens
are expressed on more than 90% of the malignant cells targeted.

Non-Hodgkin's Lymphomas

Knox[13] and Jurcic et al[14] recently reviewed the results of clinical
trials using radioimmunotherapy in the treatment of non-Hodgkin's lymphomas
that are resistant to standard therapy. (The review by Jurcic et al also
includes the leukemias.) High response rates (generally more than 50%),
as well as durable complete remissions, have been reported in hematologic
malignancies using a variety of antibodies labeled with iodine-131, copper-67,
or yttrium-90 administered in different treatment schemes.

Although patients with T-cell lymphomas have also responded to radioimmunotherapy,
fewer patients have been treated, and most studies have shown lower response
rates than have been seen in patients with B-cell lymphomas. The exception
is the use of yttrium-90-anti-CD25. In a recent study, this treatment achieved
a more than 50% response rate in patients with T-cell lymphoma.[15]

High-Dose Radioimmunotherapy With Stem-Cell Rescue--The highest response
rates and longest remissions have been reported in patients with B-cell
lymphoma who received high-dose radioimmunotherapy that required reinfusion
of bone marrow or peripheral stem cells for hematologic rescue.[16] Most
of these studies have shown complete response rates more than 50% and total
response rates more than 80%. Responses have been durable in a number of
patients, some of whom have maintained a continuous complete response for
over 6 years.

Radioimmunotherapy has an advantage over total-body irradiation, which
has been traditionally used in bone marrow transplant salvage programs,
in that it delivers a higher radiation dose to the tumor and a lower dose
to nontarget normal tissues. Accordingly, a Seattle team[17,18] has replaced
total-body irradiation with radioimmunotherapy in its marrow transplant
salvage protocol. In their studies, the use of high-dose radioimmunotherapy
followed by hematologic rescue was restricted to a more select group of
patients than in other nonmyeloablative trials since pretherapy biodistribution
studies were used to select patients in whom no normal organ would receive
a dose higher than tumor. Most patients with an unfavorable distribution
had bulky disease, including splenomegaly. The Seattle group has reported
an 84% complete response rate with a median duration of complete response
of over 18 months.[17]

Nonmyeloablative Regimens--Although the most impressive rates and durations
of response have been seen with high-dose radioimmunotherapy, clinical
responses have also been noted with nonmyeloablative doses of labeled antibody,
particularly when given with large doses of unlabeled antibody.[19-22]
In one of the most promising trials to date, nonmyeloablative iodine-131-labeled
anti-B1 (anti-CD20) produced responses in 19 of 21 patients with low-grade
non-Hodgkin's lymphoma, two-thirds of whom had a complete response.[21]
Side effects have been minimal, and close to half of the patients have
remained in complete remission for a longer time (median, 16 months) than
with their prior chemotherapy.

Based on these encouraging results, pivotal trials of nonmyeloablative
regimens are underway in patients with low-grade non-Hodgkin's lymphoma,
as are phase II trials in patients with previously untreated low-grade
B-cell lymphoma.

Hodgkin's Disease

Hodgkin's disease has also been treated with radioimmunotherapy, including
high-dose radioimmunotherapy followed by autologous marrow rescue. Vriesendorp
et al have reviewed several trials in which iodine-131- or yttrium-90-labeled
polyclonal antiferritin was used to treat more than 130 patients with chemotherapy-resistant
Hodgkin's disease.[23] Since antibody responses to radioimmunconjugates
have been uncommon in Hodgkin's disease patients, many patients were able
to receive multiple administrations of radiolabeled antiferritin.

Yttrium-90-antiferritin achieved significantly better therapeutic results
than iodine-131-antiferritin. Patients with a longer disease history (more
than 3 years) and a tumor volume less than 30 cm³ who received at
least 0.4 mCi/kg of body weight were more likely to respond than patients
without these characteristics. On average, patients who achieved a complete
response survived longer than those attaining a partial response. The average
survival was 8 months for patients treated in the initial trials; survival
analysis for the later trials is still in progress.

Hodgkin's disease has recurred in most of the patients. Failures occurred
in previously uninvolved sites in one-third of the patients, while responses
to radioimmunotherapy have been maintained at the initial disease sites.

The initial group of 17 patients treated with high-dose yttrium-90-antiferritin
had a 65% response rate (41% complete response rate).[23] This compares
favorably with the 17% complete response rate among patients in a lower-dose
group who were excluded from receiving high-dose therapy due to previous
bilateral iliac crest external-beam radiation or marrow involvement. More
severe hematologic toxicity was noted in this initial trial than in more
recent studies of high-dose iodine-131; three patients in the early trial
died of prolonged aplasia.

The yttrium-90-antiferritin conjugate has also been used in conjunction
with cyclophosphamide (Cytoxan, Neosar), carmustine (BCNU), and etoposide
(VePesid) chemotherapy followed by autologous marrow rescue at the University
of Nebraska.[24] Of the 14 patients in that series, 2 were unable to complete
therapy and 5 died early, while 3 of the 4 patients who survived for more
than 2 years showed no evidence of disease.

Thus, the efficacy of radioimmunotherapy in Hodgkin's disease seems
more limited than in B-cell lymphoma and awaits further clinical trial
development.

Leukemias

Contrary to most trials of radioimmunotherapy, which attempt to spare
the bone marrow since it is the dose-limiting organ, antileukemia strategies
target the marrow to eradicate all residual leukemic cells. This has allowed
higher doses to be delivered to the target cells than to most normal tissues.

The Memorial Sloan-Kettering Cancer Center Group[14] used an anti-CD33
antibody (M195) labeled with iodine-131 to intensify induction treatment
prior to bone marrow transplantation. This radiolabeled antibody was used
in conjunction with busulfan (Myleran) and cyclophosphamide in 19 patients
with refractory acute myelogenous leukemia or accelerated blast crisis
of chronic myelogenous leukemia. Of the 19 patients, 18 achieved a complete
response. In 3 of the 15 for whom this was the first transplant, the remission
was maintained for more than 18 to 29 months. Although little toxicity
was attributed to the iodine-131-labeled antibody, 10 patients died of
transplant-related complications while in complete remission.

The same regimen has also been used in six patients with relapsed acute
promyelocytic leukemia. Marrow deletion of a molecular marker of disease
was seen in two of these patients. This radioimmunotherapy plus chemotherapy
regimen compares favorably with other strategies for relapsed leukemia.

Matthews and colleagues added iodine-131-BC8 (anti-CD45 antibody) to
a standard transplant regimen and found no increment in toxicity, as compared
with cyclophosphamide plus total-body irradiation.[25] They have not reached
the maximum tolerated dose of the radioimmunotherapy in patients with leukemia.
With a median follow-up of 17 months, 9 of 13 patients in their series
treated for acute myelogenous leukemia or refractory anemia with excess
blasts and 2 of 7 patients treated for acute lymphocytic leukemia remain
disease-free.

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