Recent Progress in Radioimmunotherapy for Cancer

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(Drug information on cyclophosphamide) (Cytoxan, Neosar), carmustine(Drug information on carmustine) (BCNU), and etoposide(Drug information on 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(Drug information on 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.