放射免疫治疗非霍奇金淋巴瘤研究进展

放射免疫治疗（RIT）是非霍奇金淋巴瘤治疗的一种新方法,将单克隆抗体与放射性同位素结合,注入人体内与肿瘤细胞特异性结合,以实现对瘤体的内照射治疗。RIT是在分子靶向治疗的基础上发展起来的,因其具有放射性同位素的作用,故能补充分子靶向治疗的不足。近年来RIT的研究取得了显著进展,主要被应用于治疗复发、难治性、低度恶性、滤泡性、转化型B细胞淋巴瘤。     

New strategies in radioimmunotherapy for lymphoma

Treatment options for patients with indolent non-Hodgkin’s lymphoma historically involved radiation or chemotherapy. Although initial response rates are excellent, treatment is increasingly less effective with each successive relapse. The advent of immunotherapy heralds a new era for the treatment of these patients. Radioimmunotherapy adds the benefits of cytotoxic radiation to immunotherapy and represents a significant addition to the treatment armamentarium. Various antigens for lymphoma have been targeted, of which anti-CD20 antibodies are the furthest in development. Ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA), a ⁹⁰yttrium-labeled agent, and ¹³¹iodine-labeled tositumomab (Bexxar; Corixa, Seattle, WA) are approved by the US Food and Drug Administration. Both agents have shown utility in therapy for relapsed and refractory low-grade and transformed lymphomas. This review highlights features of radioimmunotherapy that are relevant to non-Hodgkin’s lymphoma, focusing on the two anti-CD20 antibodies.     

Novel concepts in radioimmunotherapy for non-Hodgkin's lymphoma

Tositumomab/iodine-131 tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin) are radioimmunoconjugates targeting the CD20 antigen. Both agents are approved in the United States for use in relapsed or refractory, indolent or transformed, B-cell lymphoma. These agents are well tolerated and have the highest levels of single-agent activity observed in these histologies. This review will summarize the key trials that led to approval of both I-131 tositumomab and ibritumomab tiuxetan, and then focus on four novel therapeutic concepts in radioimmunotherapy: retreatment, therapy of de novo indolent lymphoma, therapy of aggressive histologies, and incorporation in high-dose therapy programs utilizing autologous stem cell support.     

Focal radiation fibrosis after radioimmunotherapy for follicular non-Hodgkin lymphoma

A 75-year-old man with relapsed follicular non-Hodgkin lymphoma confined to a solitary lung mass was treated with radioimmunotherapy (RIT) using yttrium 90-ibritumomab tiuxetan. Imaging with positron emission tomography/computed tomography showed a complete response 3 months after RIT. Thirteen months after RIT, his positron emission tomography/computed tomography scan showed a fluorodeoxyglucose-avid infiltrate in the area of the previous lung mass. Bronchoscopy revealed the area to be obstructed with fibrosis, and cytologic washings and brushings did not show lymphoma. The patient remains asymptomatic, and the fluorodeoxyglucoseavid pulmonary infiltrate was unchanged 19 months after RIT. In view of the lack of respiratory symptoms or progressive imaging abnormalities, we believe radiation fibrosis is the most likely etiology. Radiation-induced lung injury after therapy with yttrium 90 was previously reported in the setting of intraarterial microspheres used to treat inoperable hepatic tumors. This is the first case in which radiation-induced radiographic changes are reported after RIT for lymphoma.     

Internal microdosimetry for single cells in radioimmunotherapy of B-cell lymphoma

Patients with B-cell lymphoma may have disease manifestations ranging in size from more than a 1000 cm3 down to the volume of a single cell. If targeted radionuclide therapy is to become a curative treatment, all individual tumor cells must also be eliminated. Given the vast differences in particle energy of different electron- emitting radionuclides, one questions whether the mean absorbed dose is a relevant parameter for use in single-cell dosimetry and whether it would not be more accurate to adopt a stochastic approach to dosimetry. Monte Carlo simulations were performed of energy deposition from 1000, 300, 100, or 10 electrons uniformly distributed in a sphere with a radius of 7.7 microm. The simulated electrons were monoenergetic (18 keV, 28 keV, 141 keV, or 935 keV). The absorbed dose per emitted electron, the absorbed fraction, the fraction of the cellular volume in which energy is deposited, and the dose-volume histograms were calculated. Absorbed fractions varied between 0.60 (18 keV) and 0.001 (935 keV), and the absorbed dose to the cell per electron emitted varied by a factor of 10, from 0.898 mGy (18 keV) to 0.096 mGy (935 keV). The specific energy varied between 0 and 46 mGy for the case showing the best uniformity (1000 18-keV electrons). The nonuniformity of the absorbed dose to a cell increases with increasing electron energy and decreases with the number of decays inside the studied volume. The wide distribution of energy deposition should be taken into account when analyzing and designing trials for targeted radionuclide therapy.     

Zevalin: the first radioimmunotherapy approved for the treatment of lymphoma

Conjugated antibodies have been in clinical trials for over 30 years. Immunotoxins, chemotherapy conjugates and radioimmunotherapies have been evaluated. Zevalin?, the first conjugated antibody for the treatment of non-hodgkin's lymphoma (NHL) (and the first radioimmunotherapeutic for cancer) was approved by the US FDA on 19 February 2002 (approval is pending in the EEC). Zevalin (⁹⁰Yttrium ibritumomab tiuxetan) has been in clinical trials since 1992. Several studies have been conducted including a randomized Phase III trial where it showed superiority to rituximab in overall response rate and in complete response rate. The current indications are: low-grade or follicular lymphoma refractory to rituximab, and relapsed or refractory, low-grade, follicular or transformed lymphoma. Additional studies have been initiated to further define the role of this new therapy in the treatment of patients with B-cell non-hodgkin's lymphoma.     

Zevalin: the first radioimmunotherapy approved for the treatment of lymphoma

Conjugated antibodies have been in clinical trials for over 30 years. Immunotoxins, chemotherapy conjugates and radioimmunotherapies have been evaluated. Zevalin, the first conjugated antibody for the treatment of non-hodgkin's lymphoma (NHL) (and the first radioimmunotherapeutic for cancer) was approved by the US FDA on 19 February 2002 (approval is pending in the EEC). Zevalin (90Yttrium ibritumomab tiuxetan) has been in clinical trials since 1992. Several studies have been conducted including a randomized Phase III trial where it showed superiority to rituximab in overall response rate and in complete response rate. The current indications are: low-grade or follicular lymphoma refractory to rituximab, and relapsed or refractory, low-grade, follicular or transformed lymphoma. Additional studies have been initiated to further define the role of this new therapy in the treatment of patients with B-cell non-hodgkin's lymphoma.     

Combined modality radioimmunotherapy with Taxol and 90Y-Lym-1 for Raji lymphoma xenografts

Despite effective therapies for non-Hodgkin's lymphoma (NHL), the majority of patients are not cured. Radioimmunotherapy (RIT) has shown good results in preclinical and clinical trials even in patients that are non-responsive to standard chemotherapy. To make RIT more effective, agents such as paclitaxel (Taxol), that can enhance radiation effects, are being tested. Nude mice bearing human Burkitt's lymphoma (Raji) xenografts were treated with: 1) 150 or 200 microCi (5.5 or 7.3 MBq) of 90Y-2IT-BAD-Lym-1 alone, 2) 600 micrograms of Taxol alone, 3) 150 or 200 microCi of 90Y-2IT-BAD-Lym-1 plus 600 micrograms of Taxol given 24 hours after RIT, or 4) no treatment. Tumor size, survival, mouse weight and blood counts were monitored to assess efficacy and toxicity. Survival for mice treated in this 84 day trial was: 71% for 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol, 29% for Taxol alone, 6% for 90Y-2IT-BAD-Lym-1 (200 microCi) alone and 14% in the untreated group. Average tumor volume in the 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol group was reduced by 89 and 99% compared to the RIT alone and Taxol alone groups, respectively. Mice treated with 150 microCi had less toxicity than those treated with 200 microCi of 90Y-2IT-BAD-Lym-1, however, the higher radiation dose, and Taxol, were required for improved survival. Mouse weights and myelotoxicity in the combined modality (RIT plus Taxol) groups were similar to those receiving the same dose of RIT alone. In the Raji tumored nude mouse model, addition of Taxol to 90Y-2IT-BAD-Lym-1, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity.     

Single-cell dosimetry for radioimmunotherapy of B-cell lymphoma patients with special reference to leukemic spread

AIMS: Many lymphoma patients have both macroscopic tumors and single-cell manifestations of their disease. Treatment efficacy could, therefore, depend on the radionuclide used. The aim of this study was to investigate dosimetry at a cellular level for three isotopes of radioiodine. METHODS: Cells were assumed to be spherical with radii of 6.35, 7.7, and 9.05 microm corresponding to the dimensions of the Raji cells. The radius of the nucleus was assumed to be 75% of the cellular radius. The electron energies were 18, 28, and 190 keV, corresponding to the mean electron energy per decay for (125)I, (123)I, and (131)I, respectively. S-values for different activity distributions were simulated using Monte Carlo and dose-volume histograms as well as absorbed doses, and absorbed dose rates were calculated. RESULTS: (125)I gives the highest absorbed dose (approximately 4-40 times that of (131)I), whereas (123)I will give the highest absorbed dose rate (approximately 100 times that of (131)I). Under the given assumptions, the absorbed dose at this level is more dependent on the size of the cells than on whether the radioimmunoconjugate is internalized. CONCLUSIONS: This enquiry showed that both (123)I and (125)I have greater potential than (131)I for the treatment of leukemic spread in patients with lymphoma.     

Current results and future applications of radioimmunotherapy management of non-Hodgkin's lymphoma

Monoclonal antibodies labeled with radionuclides have become an important therapeutic tool in the treatment of patients with non-Hodgkin's lymphomas (NHL). At the present time, their use in the US is approved for patients with rituximab-resistant, low-grade, follicular or transformed NHL. Encouraging responses seen in the relapsed and refractory patients have prompted their evaluation in earlier disease or in other histologic sub-types either alone or in combination with conventional chemotherapy. Additionally, they have been included as preparative regimens for stem cell transplant protocols within the context of clinical trials. This review discusses the latest clinical trials and future directions of radioimmunoconjugates in the treatment of NHL, with emphasis on US Food and Drug Administration (FDA) approved radioimmunoconjugates, namely ¹³¹I-tositumomab and ⁹⁰Y-ibritumomab tiuxetan.     

Radiobiology of radioimmunotherapy: targeting CD20 B-cell antigen in non-Hodgkin's lymphoma

The radiobiology of radioimmunotherapy is an important determinant of both the toxicity and the efficacy associated with the treatment of B-cell non-Hodgkin's lymphoma with radiolabeled anti-CD20 monoclonal antibodies. The properties of the target, CD20, and the mechanisms of action of both the monoclonal antibodies and the associated exponentially decreasing low-dose-rate radiotherapy are described. The radiation dose and dose-rate effects are discussed and related to both the tumor responses and normal organ toxicity. Finally, the use of either unlabeled or radiolabeled anti-CD20 monoclonal antibodies as a component of combined modality therapy (including the sequential or concurrent use of sensitizers) and future directions of the field are discussed.     

The L1 cell adhesion molecule as a target for radioimmunotherapy

Monoclonal antibodies directed against the L1 cell adhesion molecule were shown recently to inhibit growth of target tumor cells in vitro and the growth of tumor cells in vivo in nude mice. The biologic functions of L1 in tumor cells, which include growth-promoting activity linked to endocytosis and cellular processing of the L1 cell surface protein, make this protein an attractive target for antibodies. This update deals with recent results on L1 expression in normal tissues and in the tumors that were investigated until now. L1 expression outside of the nervous system is highly restricted to peripheral nerve bundles and kidney-collecting tubule cells. In tumors, L1 overexpression is not ubiquitous. It is prevalent in neuroblastomas and in malignant ovarian tumors, and is also found in certain subtypes of other nonneuroendocrine and nongynecologic tumors, such as renal-cell carcinomas. The structure of the L1 protein and what is known about its functional role in tumors will be described in this paper. L1 is not only a novel tumor marker, but it appears to have growth-promoting and antiapoptotic functions and may contribute to a more malignant phenotype. The preclinical studies and the clinical study to evaluate tumor-targeting properties and potential for therapy of radiolabeled anti-L1 antibodies will be described to date. Some of these studies underline the importance of L1 endocytosis for the targeting of radiolabeled antibodies.     

Secondary acute myelogenous leukemia with MLL gene rearrangement following radioimmunotherapy (RAIT) for non-Hodgkin's lymphoma

Targeted therapy with conjugated and unconjugated monoclonal antibodies for non-Hodgkin's lymphoma has revolutionized the approach to this disease. The efficacy and low toxicity of these agents have allowed introduction of this strategy in the early stages of therapy. Longer follow-up is needed before validating the safety of these agents. Since monoclonal antibodies are being given as front-line therapy, it is important to identify all potential adverse events. We report a case of secondary acute myelogenous leukemia (AML) with 11q23 cytogenetic abnormality and mixed lymphoid leukemia (MLL) gene expression in a patient treated with Y90 labeled anti-CD20 antibody (Zevalin). The patient was not exposed to topoisomerase II inhibitors. Our observations suggest a relationship between 11q23 leukemia and radioimmunotherapy (RAIT) and further studies are needed.     

Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma.

PURPOSE: Rituximab is commonly used as a single agent or in combination therapy for non-Hodgkin's lymphoma (NHL). Ibritumomab tiuxetan radioimmunotherapy targets the same antigen as rituximab and has demonstrated efficacy in rituximab-na?ve NHL. This study evaluated ibritumomab tiuxetan in the treatment of rituximab-refractory follicular NHL. PATIENTS AND METHODS: Eligible patients were refractory to rituximab; this was defined as no objective response to rituximab (375 mg/m(2) weekly for 4 weeks) or time to progression (TTP) of < or = 6 months. The ibritumomab tiuxetan treatment regimen consisted of pretreatment with rituximab (250 mg/m(2) intravenously on days 1 and 8) to deplete peripheral blood B cells, then yttrium-90 ibritumomab tiuxetan (0.4 mCi/kg; maximum, 32 mCi) intravenously on day 8, administered on an outpatient basis. An imaging/dosimetry dose of indium-111 ibritumomab tiuxetan (5 mCi) was injected after rituximab (day 1) in 28 patients. RESULTS: Fifty-seven patients were treated. The median age was 54 years, 74% had tumors > or = 5 cm, and all were extensively pretreated (median, four prior therapies; range, one to nine). The estimated radiation-absorbed doses to healthy organs were below the study-defined limit in all patients studied with dosimetry. The overall response rate for the 54 patients with follicular NHL was 74% (15% complete responses and 59% partial responses). The Kaplan-Meier-estimated TTP was 6.8 months (range, 1.1 to > or = 25.9 months) for all patients and 8.7 months for responders. Adverse events were primarily hematologic; the incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 35%, 9%, and 4%, respectively. CONCLUSION: Ibritumomab tiuxetan radioimmunotherapy is effective in rituximab-refractory patients. The only significant toxicity is hematologic.     

Pretargeted radioimmunotherapy (PRIT) using an antibody-streptavidin fusion protein in non-Hodgkin's lymphoma

Pretargeted radioimmunotherapy (PRIT) decreases the amount of time that radioactivity non-selectively circulates. Our PRIT approach is a multi-step method in which a monoclonal antibody is used to target streptavidin to a tumor-associated antigen and biotin is then used to target 90Y to the streptavidin. A genetically engineered antibody streptavidin fusion construct was used to target tumor in a patient with non-Hodgkin's lymphoma. Impressive localization of 90Y to known and previously unknown areas of adenopathy was observed, thus demonstrating that a genetically engineered fusion protein can selectively target lymphoma cells as part of a clinically meaningful PRIT strategy.