Clinical radioimmunotherapy

Radioimmunotherapy (RIT) is a promising new therapy for the treatment of a variety of malignancies. General principles of RIT are discussed, including important considerations in the selection of monoclonal antibodies (MAb) and radionuclides for RIT. Results of clinical trials using RIT for the treatment of lymphoma, leukemia, and solid tumors are summarized. The results from many of these trials are promising, especially for the treatment of lymphohematopoietic malignancies, in which a variety of MAb, radionuclides, and study designs have resulted in high response rates with a number of durable responses. Encouraging results have also been obtained using RIT to treat some solid tumors, primarily in patients with relatively low tumor burdens. RIT is generally well tolerated, with the primary toxicity being transient reversible myelosuppression in most nonmyeloablative studies. Nonhematologic toxicity, especially at nonmyeloablative doses, has been minimal in most studies. Approaches for increasing the therapeutic index of RIT are reviewed, which may further potentiate the efficacy and decrease the toxicity of RIT.     

Experimental radioimmunotherapy

Experimental radioimmunotherapy (RIT) studies in animal models have contributed significantly to the design of clinical RIT protocols, although the results have not always been directly translated. Reviewed in this article are current areas of active research in experimental RIT to increase the therapeutic ratio that are likely to have a significant impact on the design of future clinical studies. Approaches for increasing the therapeutic efficacy of RIT include the development of new targeting molecules (genetically engineered monoclonal antibodies, antibody fragments, single-chain antibodies, diabodies and minibodies, fusion toxins, or peptides); improved labeling chemistry; novel radionuclide use and fractionation; locoregional administration; pretargeting; use of biological response modifiers or gene transfer techniques to increase target receptor expression; bone marrow transplantation; and combined modality therapy with external-beam radiation therapy, chemotherapy, or gene therapy. Further research with these new experimental approaches in preclinical animal models is necessary to contribute to advances in the treatment of cancer patients using radiolabeled antibodies and peptides.     

Recent developments in radioimmunotherapy

With the advent of monoclonal antibody techniques, there has been renewed interest in RIT as a treatment modality in patients with a variety of tumour types. There has been a considerable research effort to increase understanding of the scientific basis of such therapy at all levels. Antibody, chelator and radioisotope factors are all the subject of research aimed at producing a potent effector system capable of maximal target cell kill with acceptable normal tissue toxicity. Improved knowledge of the host and tumour factors which limit access to the target cell offers the possibility of optimizing targeting and increasing the therapeutic index. Target cell factors that influence response to low dose rate RIT have been elucidated and provide an opportunity to integrate the treatment modality into radical therapy regimens.A number of Phase I and II trials have now been performed in various tumour types. The results have been promising but, as yet, the prospect of radical RIT remains a research goal. Before it can be achieved it will be necessary to improve specific tumour cell targeting and to increase both the initial dose rates and the total dose delivered to tumour deposits. Until such time, it is likely that RIT will be incorporated into multimodality protocols to deliver a moderate (10–20 Gy) tumour boost, or in an adjuvant setting in patients with minimal residual disease.     

Technological advances in radioimmunotherapy

Radioimmunotherapy (RIT) is a method of selectively delivering radionuclides with toxic emissions to cancer cells, while reducing the dose to normal tissues. Although primary tumours can often be treated successfully with external beam radiotherapy or surgery, metastases often escape detection and treatment, leading to therapy failure, and these can be treated with systemic targeted therapies such as RIT. This review describes more recent developments in the field, including both technological developments from the laboratory and increasingly encouraging findings from clinical studies.     

Intraperitoneal radioimmunotherapy in treating peritoneal carcinomatosis of colon cancer in mice compared with systemic radioimmunotherapy

Peritoneal spread is one of major causes of mortality in colorectal cancer patients. In the current investigation, the efficacy of radioimmunotherapy (RIT) with i.p. administration of an anti-colorectal cancer IgG1, 131I-A7, was compared to that with i.v. administration in BALB/c female mice bearing peritoneal nodules of LS180 human colon cancer cells, at the same toxicity level. Distribution of either i.p. or i.v. administered 131I-A7 and i.p. administered irrelevant 131I-HPMS-1 was assessed. Based on the results of toxicity determination at increments of 2 MBq and estimated dosimetry, an i.p. dose of 11 MBq and an i.v. dose of 9 MBq were chosen for treatment. Mice were monitored for long-term survival: untreated mice (n = 11), mice undergoing i.p. RIT with 131I-A7 (n = 11), mice undergoing i.v. RIT with 131I-A7 (n = 11) and mice undergoing non-specific i.p. RIT with 131I-HPMS-1 (n = 5). Intraperitoneal injection of 131I-A7 produced faster and greater tumor accumulation than i.v. injection: 34.2 +/- 16.5% of the injected dose per g (% ID/g) and 11.1 +/- 3.6% ID/g at 2 h, respectively (P < 0.0001). Consequently, cumulative radioactivity in tumors was 1.73-fold higher with i.p. injection. 131I-HPMS-1 did not show specific accumulation. Non-specific RIT with 131I-HPMS-1 (mean survival, 26.0 +/- 2.5 days) did not affect the survival as compared to no treatment (26.7 +/- 1.9 days). Intravenous RIT with 131I-A7 prolonged the survival of mice to 32.8 +/- 1.8 days (P < 0.01). Intraperitoneal RIT with 131I-A7 improved the survival more significantly and attained cure in 2 of 11 mice (P < 0.05 vs. i.v. RIT). In conclusion, i.p. RIT is more beneficial in treating peritoneal carcinomatosis of colon cancer than i.v. RIT in a murine model.     

Optimization of radioimmunotherapy interactions with hyperthermia

The efficacy of radioimmunotherapy (RIT) employing radiolabelled monoclonal antibodies (MAb) is currently limited in most solid tumours. The combination of local hyperthermia (HT) with RIT has the potential to enhance tumour targeting of MAb; moreover, this approach may add an antitumour effect to radioresistant hypoxic and S-phase cells and may inhibit the cells from repairing sublethal damage or potentially lethal damage caused by ionizing radiation. There are distinct types of protocols in this combination. Hyperthermic temperature and timing relative to RIT administration appear to affect the efficacy of the combination therapy. Responses to heating at any particular condition are not always the same among different tumour types. There are many papers describing influence of HT on the biodistribution of radiolabelled MAb, but only limited information is currently available on ‘therapeutic’ outcomes regarding the dependency of combination protocols. A previous study suggested that the best therapeutic improvement would be achieved when HT was combined immediately after the administration of MAb, which significantly increases the radiation absorbed dose to tumours and produces a uniform intratumoural dose distribution. Further therapeutic investigation should be required to reach the optimal protocol of combining these two modalities.     

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。     

肿瘤放射免疫治疗的问题及对策

综述放射免疫治疗中肿瘤对抗体的摄取、靶/非靶的比、免疫原性、放射性核素的选择等问题.     

Use of second antibody in radioimmunotherapy

In this study, a second antibody was directed against the first antitumor antibody to accelerate clearance of the 131I-labeled first antibody and improve tumor to normal tissue ratios of radioactivity. The value of this method in improving the therapeutic index of radioimmunotherapy with 131I-antibody to CEA has been investigated in nude mice bearing xenografts of human colon carcinoma and in 5 patients with colorectal cancer. The xenografts did not become saturated with anti-CEA as the administered dose was increased to therapeutic levels. At these high dose levels, the second antibody increased tumor to blood ratios to a maximum of 155:1, 48 times the level in controls that did not receive the second antibody. In 5 patients given 50 mCi of anti-CEA, there was no significant toxicity with the second antibody; clearance of radioactivity was accelerated; and tumor imaging was enhanced. The second antibody appears to have the potential to improve the therapeutic index of radioimmunotherapy.     

Correlation of toxicity with treatment parameters for 131I-CC49 radioimmunotherapy in three phase II clinical trials

Analyses were performed on 40 patients with TAG-72 expressing metastatic cancer who were entered into three phase II clinical trials. The dose selected was the maximum tolerated dose in phase I studies. Patients all had unresectable metastatic colon or prostate cancer and had recovered from prior therapies. Patients in trials #1 and #2 received 75 mCi/m2 131I-CC49 antibody whereas those in trial #3 received a total of 75 mCi/m2 with equal amounts of 131I-CC49 and 131I-COL-1. The three trials have resulted in a reproducible degree of reversible marrow suppression; 72.5% of patients experienced moderate or severe toxicity. Comparisons were made between demographic, clinical and pharmacokinetical variables and the grade of WBC toxicity, platelet toxicity and the sum of the two as total toxicity. Whole body radiation dose had a statistically significant relationship with platelet toxicity (r = 0.38, p = 0.015) and total toxicity (r = 0.34, p = 0.035). The bone marrow radiation dose is significantly related to all toxicity indicators with correlation coefficients with WBC and platelet toxicities of 0.47 (p = 0.002) and 0.34 (p = 0.033), respectively. Plasma half-life had the strongest correlation with WBC toxicity and combined toxicities. Multivariate models were developed to help describe the simultaneous effect of these variables on toxicity. The results show that the MTD dose was safely given to patients who varied in age, disease burden and degree of marrow compromise. This supports the contention that a fixed dose of radiolabeled antibody per body mass or m2 can be given to a diverse group of non-lymphoma patients with a predictable toxicity range.     

Dosimetric impact of correcting count losses due to deadtime in clinical radioimmunotherapy trials involving iodine-131 scintigraphy

This study describes the use of a new method for correcting count losses due to deadtime in the context of quantitative imaging of patients undergoing scintigraphy after a 4 GBq therapeutic injection of iodine-131. This method, based on measuring the count rate observed throughout the spectrum detected (50-750 keV), had been validated in a previous study and was applied here to 10 patients. Imaging was performed 3, 6, 8 and 10 days after injection. Whole-body images were acquired in six steps in energy-indexed list mode. Before reconstruction of the whole-body image, each step was processed to obtain an appropriate correction. Three days after injection, corrective factors ranged between 1.01 (feet) and 1.20 (liver), and the increase in whole-body activity was estimated at around 10%. The difference between whole-body activities calculated from images corrected for deadtime and those estimated by urine collection was around 1% when urine collection was complete. Correction for count losses led to an 11% increase in whole-body cumulated activity. These results indicate that it is possible to integrate this correction into dosimetric studies in order to allow count rate variations to be taken into account as a function of the regions imaged. Although the complexity of acquisitions in energy-indexed list mode limits the systematic use of this method, it can be simplified if corrections are made only for those steps in which the correction factor exceeds a threshold value. However, this implies a selection of the regions to be corrected. Another possibility consists in acquiring spectrometric images in several windows, which also allows correction for count losses.     

Intracavitary radioimmunotherapy to treat solid tumors

Radioimmunotherapy (RIT) potentially is an attractive treatment for radiosensitive early-stage solid tumors and as an adjuvant to cytoreductive surgery. Topical administration of RIT may improve the efficacy because higher local concentrations are achieved. We reviewed the results of locally applied radiolabeled monoclonal antibodies for the treatment of solid tumors. Intracavitary RIT in patients with ovarian cancer and glioma showed improved targeting after local administration, as compared to the intravenous administration. In addition, various studies showed the feasibility of locally applied RIT in these patients. In studies that included patients with small-volume disease, adjuvant RIT in ovarian cancer and glioma showed to be at least as effective as standard therapy. The information about RIT for peritoneal carcinomatosis of colorectal origin is scarce, while results from preclinical data are promising. RIT may be applied for other, relatively unexplored indications. Studies on the application of radiolabeled antibodies in early urothelial cell cancer have been performed, showing that intracavitary RIT may hold a promise. Moreover, in patients with malignant pleural mesothelioma or malignant pleural effusion, RIT may play a role in the palliative treatment. Intracavitary RIT limits toxicity and improves tumor targeting. RIT is more effective in patients with small-volume disease of solid cancers. RIT may have potential for palliation in patients with malignant pleural mesothelioma or malignant pleural effusion. The future of RIT may, therefore, not only be in the inclusion in contemporary multimodality treatment, but also in the expansion to palliative treatment.     

Effective alpha-particle-mediated radioimmunotherapy of murine leukemia.

The specificity, toxicity, and efficacy of alpha-particle-mediated radioimmunotherapy of murine erythroleukemia was assessed by use of tumor-specific monoclonal antibody 103A labeled with 212Bi. Forty % of the injected dose/g tissue targeted to neoplastic spleens within 1 h after i.v. injection. When 212Bi-103A was injected on day 13 of disease, a dose-dependent response was achieved, as measured by a reduction in splenomegaly and absence of liver metastasis. Mice treated with 212Bi-103A on day 8 of disease showed no histological evidence of erythroleukemia on day 22 and survived significantly longer (median, 118 days) than mice treated with 212Bi-control IgG (78 days) or untreated mice (63 days), indicating successful specific radioimmunotherapy.     

Targeting tomoregulin for radioimmunotherapy of prostate cancer

Radiotherapy is an effective approach for the treatment of local prostate cancer. However, once prostate cancer metastasizes, radiotherapy cannot be used due to the distribution of multiple metastases to lymph nodes and bones. In contrast, radioimmunotherapy should still be efficacious in metastatic prostate cancer as radioisotopes are brought to tumor cells by targeting antibodies. Here we identify and validate a prostate-expressed molecule, tomoregulin, as a target for radioimmunotherapy of prostate cancer. Tomoregulin is a transmembrane protein selectively expressed in the brain, prostate, and prostate cancer, but not expressed in other normal tissues. Immunohistochemical studies of tomoregulin protein in clinical samples show its location in the luminal epithelium of normal prostate, benign prostatic hyperplasia, and prostatic intraepithelial neoplasia. More importantly, the tomoregulin protein is expressed in primary prostate tumors and in their lymph node and bone metastases. The nature of tomoregulin as a transmembrane protein and its tissue-specific expression make tomoregulin an attractive target for radioimmunotherapy, in which tomoregulin-specific antibodies will deliver a radioisotope to prostate tumor cells and metastases. Indeed, biodistribution studies using a prostate tumor xenograft model showed that the (111)In-labeled anti-tomoregulin antibody 2H8 specifically recognizes tomoregulin protein in vivo, leading to a strong tumor-specific accumulation of the antibody. In efficacy studies, a single i.p. dose of 150 microCi (163 microg) (90)Y-labeled 2H8 substantially inhibits the growth rate of established LNCaP human prostate tumor xenograft in nude mice but produces no overt toxicity despite cross-reactivity of 2H8 with mouse tomoregulin. Our data clearly validate tomoregulin as a target for radioimmunotherapy of prostate cancer.     

Optimization of radioimmunotherapy interactions with hyperthermia.

The efficacy of radioimmunotherapy (RIT) employing radiolabelled monoclonal antibodies (MAb) is currently limited in most solid tumours. The combination of local hyperthermia (HT) with RIT has the potential to enhance tumour targeting of MAb; moreover, this approach may add an antitumour effect to radioresistant hypoxic and S-phase cells and may inhibit the cells from repairing sublethal damage or potentially lethal damage caused by ionizing radiation. There are distinct types of protocols in this combination. Hyperthermic temperature and timing relative to RIT administration appear to affect the efficacy of the combination therapy. Responses to heating at any particular condition are not always the same among different tumour types. There are many papers describing influence of HT on the biodistribution of radiolabelled MAb, but only limited information is currently available on 'therapeutic' outcomes regarding the dependency of combination protocols. A previous study suggested that the best therapeutic improvement would be achieved when HT was combined immediately after the administration of MAb, which significantly increases the radiation absorbed dose to tumours and produces a uniform intratumoural dose distribution. Further therapeutic investigation should be required to reach the optimal protocol of combining these two modalities.     

血液系统肿瘤放射免疫治疗研究进展

近十余年血液系统肿瘤的治疗有了很大进展，但复发和难治仍然是亟待解决的主要问题，多药耐药和微量残留是白血病难治和复发的主要原因。免疫导向治疗有望克服这些问题，并逐步受到人们的重视。现综述放射免疫技术在血液系统肿瘤治疗中的研究进展、实验结果以及同位素的选择，并提出目前存在的问题。