Pivotal Study of Iodine-131–Labeled Chimeric Tumor Necrosis Treatment Radioimmunotherapy in Patients With Advanced Lung Cancer
http://www.100md.com
《临床肿瘤学》
the Zhongshan Hospital and Tumor Hospital, Fudan University, Shanghai
Nanjng Chest Hospital Oncology Department, Nanjing
Zhujiang Hospital Oncology Center, First Military Medical University, Guangzhou
Second Hospital, Zhejiang University Medical School, Hangzhou
Department of Oncology, Liaoning Tumor Hospital, Shenyang
309 Hospital Oncology Department, Beijing
Shanghai MediPharm Biotech Co Ltd, Shanghai, China
University of Southern California Keck School of Medicine, Los Angeles, CA
ABSTRACT
PATIENTS AND METHODS: Patients with advanced lung cancer were treated with systemic or intratumoral injection of 131I-chTNT in eight oncology centers in China. The objective response rate (ORR) was assessed as the primary end point.
RESULTS: All 107 patients who were entered onto the study and completed therapy had experienced treatment failure after prior radiotherapy or chemotherapy a mean of three times. The results showed an ORR of 34.6% (complete response, 3.7%; partial response, 30.8%; no change, 55.1%; and progressive disease, 10.3%) in all patients and 33% in 97 non–small-cell lung cancer patients. A biodistribution study demonstrated excellent localization of the radioactivity in tumors in both systemically and intratumorally injected patients. The most obvious adverse side effect was mild and reversible bone marrow suppression.
CONCLUSION: Radioimmunotherapy with 131I-chTNT was well tolerated and can be used systemically or locally to treat refractory tumors of the lung.
INTRODUCTION
In recent years, targeted radiotherapy using radiolabeled monoclonal antibodies has emerged as a new treatment option, especially for the treatment of radiosensitive lymphomas.5-10 For solid tumors, however, which tend to be more radioresistant in nature, radioimmunotherapy has not yielded significant results largely due to insufficient dosing to the tumor.11-13 In the last several years, a new antibody targeting methodology has been developed for the targeting of solid tumors. Designated tumor necrosis therapy (TNT), this approach targets necrotic regions found in tumors but absent from normal tissues and organs.14-17 Unlike other antibody targeting approaches that bind to cell surface antigens expressed on viable tumor cells, TNT antibodies recognize nonviable zones found principally in hypoxic areas of the tumor, regions that represent 30% to 80% of the tumor mass.18,19 Normal tissues, which are policed by the reticuloendothelial system consisting of fixed tissue and circulating phagocytic cells, do not contain necrotic areas and hence cannot bind TNT antibodies, as shown by tissue biodistribution studies,14,20 autoradiography,21 and imaging studies15,22 performed in both experimental animals and humans.14,15
1999 to 2001, 62 patients with lung cancer, glioblastoma, lymphoma, head and neck cancer, colorectal carcinoma, hepatocellular carcinoma, and other malignant solid tumors were treated with iodine-131–labeled recombinant chimeric TNT monoclonal antibody (131I-chTNT). From these initial studies, it became clear that lung cancer was an excellent candidate to study the clinical efficacy of TNT radioimmunotherapy. From 2001 to 2002, these clinical trials were continued in an additional 45 patients. The results of this pivotal registration clinical trial were presented to the Chinese State Food and Drug Administration and on June 13, 2003, 131I-chTNT was approved for the treatment of advanced lung cancer in China, making it the second of three approved radiolabeled antibodies (ibritumomab [Zevalin; Biogen Idec, San Diego, CA] and tositumomab [Bexxar; GlaxoSmithKline, Philadelphia, PA]) and the first for the treatment of solid tumors worldwide. Currently, additional trials are ongoing in China to expand the utility of this product for the treatment of brain cancer, hepatocellular carcinoma, and other solid tumors, and trials are ongoing in the United States for both systemic (gastrointestinal tumors) and intratumoral use (recurrent glioblastoma). We report the clinical data obtained during this pivotal trial as part of an international collaboration that began in the late 1980s and early 1990s when TNT was originally developed as a new approach for the targeting of solid tumors.
PATIENTS AND METHODS
The study was approved by the Chinese State Food and Drug Administration and the Research Ethics Committee of Zhongshan Hospital, Fudan University, Shanghai. Informed consent was obtained for all of the enrolled patients.
Preparation of 131I-chTNT
131I-chTNT was provided by Shanghai MediPharm Biotech Co Ltd (Zhangjiang HiTech Park, Shanghai, China). Recombinant human and mouse chimeric TNT antibody was produced in NS0 murine myeloma cells cultured in a bioreactor and was purified by a series of steps including protein A chromatography and measures to inactivate and remove viruses. The purified chTNT antibody with purity of at least 98% was radiolabeled with Na131I (Syncor International, Shanghai, China) using chloramine T as the oxidant, and the products were purified and tested for radioactivity and pathogen contamination as previously described.15 The purity of 131I-chTNT was more than 95% and the specific radioactivity of the radiolabeled product was between 8 and 12 mCi/mL.
Therapeutic Regimen
All patients received a saturated solution of potassium iodine (10 drops orally tid) 3 days before the initiation of radioimmunotherapy and continued until 7 days after completion of therapy to block uptake of free 131I by the thyroid. All patients received dexamethasone and diphenhydramine 30 minutes before each treatment to prevent allergic reactions. The 107 patients in eight clinical oncology centers were injected with 131I-chTNT intravenously or intratumorally. In all cases, the patients received two doses of 131I-chTNT administered 2 to 4 weeks apart. For intravenous injection, 131I-chTNT at a dose of 0.8 mCi/kg of body weight was diluted in normal saline and administered through a free-flowing intravenous line during a 1-hour period. Patients were monitored for symptoms and vital signs were measured every 15 minutes. For intratumoral injection, 131I-chTNT at a dose of 0.8 mCi/cm3 of tumor size was injected directly into the tumor mass using thoracic CT or x-ray guidance and a fine core needle (Dr Japan Co, Tokyo, Japan). CT scans or x-rays clearly showed the location of the tumor and the pathway of the needle. In this way, the proper placement of the needle and the extent of dissemination of the radiolabeled antibody into the tumor mass were monitored. Patients remained in radiation isolation until their whole-body radiation had reached acceptable limits (≤ 5 mR/h at 1 m).
Response Criteria and Evaluation
Efficacy was assessed as the objective response rate to treatment, which was the primary end point of the study. Responses were defined according to WHO criteria for measuring solid tumors as a complete response (CR), a partial response (PR), no change (NC), or progressive disease (PD). Objective response rate (ORR) was defined as CR plus PR.23 Tumor growth was monitored by the same imaging method used to establish baseline tumor measurements and was performed after each administration. Confirmation of response required a repeated imaging study 10 weeks after treatment using thoracic x-rays and CT.
Imaging and Biodistribution
All radionuclide imaging was performed to document the biodistribution of the 131I radioactivity in the tumor sites and the whole body. A series of anterior and posterior images were obtained at different time points after systemic or intratumoral administration of 131I-chTNT (scan speed of 5 to 10 cm/min). Regions of interest were drawn to calculate the ratio of tumor to nontumor (normal lung) uptake. MIRDOSE 3.0 (Medical Internal Radiation Dose Committee, Society of Nuclear Medicine, Reston, VA) was used for the estimation of the radiation-absorbed organ doses.
Evaluation of Toxicity
Adverse experiences were graded using the WHO toxicity criteria. Lung cancer patients underwent a complete physical examination, blood counts, and a battery of laboratory tests including radiological studies, ECG, CBC, and chemistry panels to evaluate the status of liver and renal functions at baseline and 2, 3, 4, 5, 6, and 10 weeks after the first administration. In addition, blood HACA and HAMA determinations were performed in all patients before the initiation of the therapy and 4 and 10 weeks after the start of therapy. Samples were assayed for HAMA using murine immunoglobulin G–coated enzyme-linked immunosorbent assay plates and for HACA using chTNT-coated plates followed by horseradish peroxidase–labeled antihuman Fc antibody and colorimetric agent.15 Thyroid function tests were performed at baseline and at 4 and 10 weeks after the start of therapy.
Statistical Analysis
This was a purely observational registration clinical trial, even though by design there were two parallel injection methods—systemic and intratumoral. No attempt was made to assign the 107 participating patients randomly into systemic or intratumoral groups. The authors did not compare statistical outcomes between the two administration methods.
RESULTS
Clinical Efficacy
Eight different oncology centers in China participated in the pivotal study. All patients received two doses of TNT radioimmunotherapy either by systemic (0.8 mCi/kg of body weight) or intratumoral (0.8 mCi/cm3 of tumor size) administration at 2- or 4-week intervals. Assessments of objective response used WHO criteria and responses were observed regardless of type or number of prior radiotherapy or chemotherapy regimens. As shown in Table 2, among the 107 patients, four patients (3.7%) achieved a CR, 33 patients (30.8%) had a PR, 59 patients (55.1%) had NC, and 11 patients (10.3%) had PD. The overall therapeutic efficacy ORR (CR plus PR) was therefore 34.6%.
For the 10 patients with small-cell lung cancer, the ORR was 50%, with one CR and four PRs. For the 97 patients with non–small-cell lung cancer, the ORR was 33%, with three CRs and 29 PRs. Among the 39 non–small-cell lung cancer patients with squamous cancer, one patient had a CR and 17 patients had a PR, with an ORR of 46.2%. For the 50 non–small-cell lung cancer patients with adenocarcinoma, the ORR was 24%, with two CRs and 10 PRs. Patients with different stages of disease at entry onto the study had different therapeutic responses. In 14 patients with stage II disease, the ORR for six patients was 25%, and in 62 patients with stage III disease, the ORR was 37.1%. In contrast, in 31 patients with stage IV disease, one patient achieved a CR and seven patients achieved a PR, with an ORR of 25.8%. Sixty-two patients received systemic administration of 131I-chTNT; two of the systemically treated patients achieved a CR and 20 patients achieved a PR, with an ORR of 35.5%. Forty-five of the cancer patients were treated with intratumoral injection of 131I-chTNT, and in this group two patients achieved a CR and 13 patients achieved a PR, with an ORR of 33.3%. In 58 patients evaluated for overall survival, median survival time was 11.7 months and the 1-year survival rate was 41.4% (Fig 1). Determination of therapeutic efficacy of this radioimmunotherapy was based mainly on ORR without evidence of an effect on overall survival.
Imaging and Biodistribution of 131I-chTNT in Patients
Imaging was conducted in all 131I-chTNT–treated patients. Figures 2A to 2G show whole-body images of representative patients after systemic or intratumoral administration of 131I-chTNT. Data in Figures2A to 2D demonstrated visual uptake of 131I activity in the tumor obtained at 0.5 and 5 hours, and 2 and 8 days after systemic administration of 131I-chTNT. These images reveal the remarkable retention of radiolabeled antibody in the vicinity of the tumor mass over time. Figures 2E to 2G show whole-body scintigraphy of a lung cancer patient at 5 (Fig 2E), 15 (Fig 2F), and 25 days (Fig 2G) after intratumoral administration of 131I-chTNT, demonstrating minimal diffusion of radioactivity from tumor site of injection. To demonstrate that the location of the radiolabel coincides with the anatomic position of the tumor, fusion images consisting of transaxial, coronal, and sagittal CT and single-photon emission CT, and x-ray (scout view) and single-photon emission CT of the lung tumor were prepared (Figs 2H to 2K) in a patient receiving intratumoral injection of 131I-chTNT 5 days previously. These images again demonstrated excellent localization of the radiolabel in the tumor, with little evidence of diffusion over time. The biodistribution of 131I radioactivity in the tumor versus nontumor areas (normal lung fields, T-to-NT ratio) was measured in 11 patients in each group. As shown in Figure 3, the average absorbed doses for tumor and normal lung tissue were 8.45 and 2.35 Gy in patients receiving systemic radioimmunotherapy. For patients receiving intratumoral injection, the average absorbed doses for tumor and normal lung tissue were 30.0 and 2.65 Gy, respectively. The T-to-NT ratio was 3.8:1 for systemically administered antibody and 16.1:1 for intratumorally injected reagent.
Radiation-absorbed dose estimation for 131I-chTNT was performed using sequential whole-body images and the MIRDOSE 3.0 software program. The data for both systemic and intratumoral administration are shown in Table 3. As expected, most organs except for the lungs (site of intratumoral injection), received about half of the dose of those patients receiving intratumoral injection compared with those administered systemic 131I-chTNT.
Adverse Experiences
Toxicity was graded according to the WHO toxicity criteria. As listed in Table 4, the major site of adverse effects was the bone marrow. All-grade platelet toxicity was found in 59.7% of systemically treated patients and 24.4% of intratumorally treated patients. For patients receiving systemic administration, 11.3% and 8.1%, respectively, experienced grade 3 or 4 platelet toxicity compared with 4.4% and 0% for patients receiving intratumoral injection. Grade 1 to 4 neutrophil toxicity was found in about one third of all patients, and for patients receiving systemic administration, 8.1% and 1.6%, respectively, had grade 3 and 4 neutrophil toxicity compared with 2.2% and 0% for those patients receiving intratumoral injection. All-grade hemoglobin toxicity was found in 41.9% of systemically treated patients and 20% of intratumorally treated patients. Only two patients receiving systemic therapy and one patient receiving intratumoral therapy had grade 3 hemoglobin toxicity, and no patient was reported with grade 4 hemoglobin toxicity.
Other adverse reactions are listed in Table 5 for patients receiving either systemic or intratumoral injection of 131I-chTNT. In general, no adverse effects were detected in the liver or kidneys during the treatment and follow-up periods. Likewise, no patient developed a HACA or HAMA response during the time it was tested. Because absorption of released radionuclide was imaged in the thyroid of some patients undergoing 131I-chTNT therapy, total T3, total T4, free T3, free T4, and thyroid-stimulating hormone before and after radioimmunotherapy were determined. The results demonstrated that total T3, total T4, free T3, and free T4 decreased slightly and thyroid-stimulating hormone increased significantly 1 and 2 months after 131I-chTNT administration. These changes, however, were all within the normal range (data not shown).
DISCUSSION
Although most prior studies with radiolabeled antibodies have been performed using systemic administration,5,9 a number of investigators are now focusing on the locoregional use of these reagents to treat identifiable lesions in solid tumor patients. Reasons for this include the low amount of uptake seen in tumors after intravenous injection, poor penetration into larger lesions, and heterogeneity of antibody uptake. Locoregional injection has been used most frequently in studies with malignant glioblastomas, which are tumors that are especially difficult to treat due to local extension of tumor tendrils into the white and gray matter of the brain. One such study by Riva et al24 using radiolabeled antitenascin antibodies found that catheter-directed administrations of 131I-antitenascin antibodies produced an increase in both the duration of remission and survival time in these difficult-to-treat patients, with little or no toxicity. In these studies, the results were dependent on the size of the tumor at the time of treatment. In addition, studies performed at multiple centers in the United States with 131I-chTNT-1 plus biotin produced dramatic results despite the dismal prognosis of these patients. In these studies, an infusion pump was used to deliver the radiolabeled antibody into the tumor over a 20-hour period via a surgically implanted catheter (unpublished observation). The use of the infusion pump to deliver the radiolabeled antibody slowly and forcefully may have improved the effectiveness of locoregional delivery by ensuring a more homogeneous distribution of reagent into the substance of the tumor. Although this may be an important consideration for glioblastoma, the method used in our study appears to have successfully infiltrated the full substance of the tumor, as shown by images taken shortly after infusion of tumor by the radiolabeled antibody (Fig 2). Because of the lower toxicity of this approach and the ability of radiolabeled antibody to infiltrate even large tumor masses effectively, locoregional or intratumoral injection may be a useful method of treating individual lesions such as those seen in glioblastoma or lung cancer, as described in this report.
Despite these hopeful findings, the number of complete responders in all the above-described studies was small, indicating that radioimmunotherapy might require additional treatment modalities to be used in combination for this form of therapy to reach its full potential. For example, it may be possible to improve the clinical efficacy of 131I-chTNT if it is used in combination with methods to increase the radiosensitivity of the tumor.25 In addition, as demonstrated by Anderson et al,26 prior treatment of tumors with ablative therapies increases the target size for TNT antibodies. In this study, it was demonstrated that prior radiofrequency ablation therapy of hepatic metastases, which generally produces a 1- to 5-cm zone of necrosis, significantly enhanced 131I-chTNT-1/biotin uptake in the tumor lesions. Anderson et al is the first patient study to take advantage of the basic property of TNT; namely, its proclivity to bind to dead and dying cells. When used in this manner, 131I-chTNT may become an adjuvant to other cytotoxic therapies. Chemotherapeutic drugs may also be used to generate larger areas of necrosis in tumors, and some of these drugs, such as doxorubicin, are also radiosensitizing because of their inhibition of DNA repair mechanisms. In addition, methods such as hormonal therapy used in prostate cancer patients can produce massive tumor destruction in a short period of time, thereby providing an excellent opportunity to test the adjuvant effects of 131I-chTNT in this setting.
With the approval of 131I-chTNT radioimmunotherapy for refractory lung cancer in China, it becomes possible for clinicians to study these more advanced concepts with 131I-chTNT radioimmunotherapy. It is hoped that ongoing studies in the United States and China with 131I-chTNT may provide new indications for its use or reveal its role as an adjuvant to current treatment approaches.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported by MediPharm Biotech Co, Shanghai, China.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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2. Pass H, Mitchell J, Johnson D, et al: Lung Cancer: Principles and Practice. Philadelphia, PA, Lippincott-Raven, 1996, pp 305-321
3. Patel JD, Bach PB, Kris MG: Lung cancer in US women: A contemporary epidemic. JAMA 291:1763-1768, 2004
4. Tyczynski JE, Bray F, Aareleid T, et al: Lung cancer mortality patterns in selected Central Europe and Southern European countries. Int J Cancer 109:598-610, 2004
5. Denardo GL, O’Donnell RT, Kroger LA, et al: Strategies for developing effective radioimmunotherapy for solid tumors. Clin Cancer Res 5:3219s-3223s, 1999
6. Vose JM: Bexxar: Novel radioimmunotherapy for the treatment of low-grade and transformed low grade non-Hodgkin's lymphoma. Oncologist 9:160-172, 2004
7. Borghaei H, Schilder RJ: Safety and efficacy of radioimmunotherapy with yttrium 90 ibritumomab tiuxetan (Zevalin). Semin Nucl Med 1:4-9, 2004
8. Forero A, Lobuglio AF: History of antibody therapy for non-Hodgkin's lymphoma. Semin Oncol 6:1-5, 2003 (suppl A)
9. Goldenberg DM: The role of radiolabeled antibodies in the treatment of non-Hodgkin's lymphoma: The coming of age of radioimmunotherapy. Crit Rev Oncol Hematol 39:195-201, 2001
10. Illidge T, Johnson P: The emerging role of radioimmunotherapy in hematological malignancies. Br J Haematol 108:679-688, 2000
11. Wilder R, DeNardo G, DeNardo S: Radioimmunotherapy: Recent results and future directions. J Clin Oncl 14:1383-1400, 1996
12. Meredith R, LoBuglio A, Spencer E: Recent progress in radioimmunotherapy for cancer. Oncology 11:979-984, 1997
13. Knox S, Meredith R: Clinical radioimmunotherapy. Semin Rad Oncol 10:73-93, 2000
14. Epstein AL, Chen FM, Taylor CR: A novel method for the detection of necrotic lesions in human cancers. Cancer Res 48:5842-5848, 1988
15. Epstein AL, Chen D, Ansari A, et al: Radioimmunodetection of necrotic lesions in human tumors using I-131 labeled TNT-1 F(ab')2 monoclonal antibody. Antibody Immunoconjugates Radiopharm 4:151-161, 1991
16. Epstein AL, Khawli LA, Chen F-M, et al: Tumor necrosis imaging and treatment of solid tumors. In: Torchilin VP, ed. Handbook of Targeted Delivery of Imaging Agents. Boca Raton, FL, CRC Press, 1995, pp 259-288
17. Chen FM, Taylor CR, Epstein AL: Tumor necrosis treatment of ME-180 human cervical carcinoma model with 131I-labeled TNT-1 monoclonal antibody. Cancer Res 49:4578-4585, 1989
18. Cooper E: Cell death in normal and malignant tissues. Adv Cancer Res 21:59-120, 1975
19. Steel G: Cell loss as a factor in the growth rate of human tumors. Eur J Cancer 3:381-387, 1967
20. Hornick JL, Hu P, Khawli LA, et al: A new chemically modified chimeric TNT-3 monoclonal antibody directed against DNA for the radioimmunotherapy of solid tumors. Cancer Biother Radiopharm 13:255-268, 1998
21. Chen FM, Epstein AL, Li Z, et al: A comparative autoradiographic study demonstrating differential intratumor localization of monoclonal antibodies to cell surface (Lym-1) and intracellular (TNT-1) antigens. J Nucl Med 31:1059-1066, 1990
22. Khawli LA, Alauddin MM, Hu P, et al: Tumor targeting properties of 111In-labeled genetically engineered Fab' and F(ab')2 constructs of chTNT-3. Cancer Biother Radiopharm 18:933-942, 2003
23. Gatzemeier U, Shepherd FA, Le Chevalier T, et al: Activity of gemcitabine in patients with non-small cell lung cancer: A multicentre, extended phase II study. Eur J Cancer 32:243-248, 1996
24. Riva P, Franceschi G, Arista A, et al: Local application of radiolabeled monoclonal antibodies in the treatment of high grade malignant gliomas: A six-year clinical experience. Cancer 80:2733-2741, 1997 (suppl)
25. Gold DV, Modrak DE, Schutsky K, et al: Combined 90 yttrium DOTA-labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft. Int J Cancer 109:618-626, 2004
26. Anderson PM, Wiseman GA, Lewis BD, et al: A phase I safety and imaging study using radiofrequency ablation (RFA) followed by 131I-chTNT-1/B radioimmunotherapy adjuvant treatment of hepatic metastases. Cancer Ther 1:297-306, 2003(Shaoliang Chen, Like Yu, )
Nanjng Chest Hospital Oncology Department, Nanjing
Zhujiang Hospital Oncology Center, First Military Medical University, Guangzhou
Second Hospital, Zhejiang University Medical School, Hangzhou
Department of Oncology, Liaoning Tumor Hospital, Shenyang
309 Hospital Oncology Department, Beijing
Shanghai MediPharm Biotech Co Ltd, Shanghai, China
University of Southern California Keck School of Medicine, Los Angeles, CA
ABSTRACT
PATIENTS AND METHODS: Patients with advanced lung cancer were treated with systemic or intratumoral injection of 131I-chTNT in eight oncology centers in China. The objective response rate (ORR) was assessed as the primary end point.
RESULTS: All 107 patients who were entered onto the study and completed therapy had experienced treatment failure after prior radiotherapy or chemotherapy a mean of three times. The results showed an ORR of 34.6% (complete response, 3.7%; partial response, 30.8%; no change, 55.1%; and progressive disease, 10.3%) in all patients and 33% in 97 non–small-cell lung cancer patients. A biodistribution study demonstrated excellent localization of the radioactivity in tumors in both systemically and intratumorally injected patients. The most obvious adverse side effect was mild and reversible bone marrow suppression.
CONCLUSION: Radioimmunotherapy with 131I-chTNT was well tolerated and can be used systemically or locally to treat refractory tumors of the lung.
INTRODUCTION
In recent years, targeted radiotherapy using radiolabeled monoclonal antibodies has emerged as a new treatment option, especially for the treatment of radiosensitive lymphomas.5-10 For solid tumors, however, which tend to be more radioresistant in nature, radioimmunotherapy has not yielded significant results largely due to insufficient dosing to the tumor.11-13 In the last several years, a new antibody targeting methodology has been developed for the targeting of solid tumors. Designated tumor necrosis therapy (TNT), this approach targets necrotic regions found in tumors but absent from normal tissues and organs.14-17 Unlike other antibody targeting approaches that bind to cell surface antigens expressed on viable tumor cells, TNT antibodies recognize nonviable zones found principally in hypoxic areas of the tumor, regions that represent 30% to 80% of the tumor mass.18,19 Normal tissues, which are policed by the reticuloendothelial system consisting of fixed tissue and circulating phagocytic cells, do not contain necrotic areas and hence cannot bind TNT antibodies, as shown by tissue biodistribution studies,14,20 autoradiography,21 and imaging studies15,22 performed in both experimental animals and humans.14,15
1999 to 2001, 62 patients with lung cancer, glioblastoma, lymphoma, head and neck cancer, colorectal carcinoma, hepatocellular carcinoma, and other malignant solid tumors were treated with iodine-131–labeled recombinant chimeric TNT monoclonal antibody (131I-chTNT). From these initial studies, it became clear that lung cancer was an excellent candidate to study the clinical efficacy of TNT radioimmunotherapy. From 2001 to 2002, these clinical trials were continued in an additional 45 patients. The results of this pivotal registration clinical trial were presented to the Chinese State Food and Drug Administration and on June 13, 2003, 131I-chTNT was approved for the treatment of advanced lung cancer in China, making it the second of three approved radiolabeled antibodies (ibritumomab [Zevalin; Biogen Idec, San Diego, CA] and tositumomab [Bexxar; GlaxoSmithKline, Philadelphia, PA]) and the first for the treatment of solid tumors worldwide. Currently, additional trials are ongoing in China to expand the utility of this product for the treatment of brain cancer, hepatocellular carcinoma, and other solid tumors, and trials are ongoing in the United States for both systemic (gastrointestinal tumors) and intratumoral use (recurrent glioblastoma). We report the clinical data obtained during this pivotal trial as part of an international collaboration that began in the late 1980s and early 1990s when TNT was originally developed as a new approach for the targeting of solid tumors.
PATIENTS AND METHODS
The study was approved by the Chinese State Food and Drug Administration and the Research Ethics Committee of Zhongshan Hospital, Fudan University, Shanghai. Informed consent was obtained for all of the enrolled patients.
Preparation of 131I-chTNT
131I-chTNT was provided by Shanghai MediPharm Biotech Co Ltd (Zhangjiang HiTech Park, Shanghai, China). Recombinant human and mouse chimeric TNT antibody was produced in NS0 murine myeloma cells cultured in a bioreactor and was purified by a series of steps including protein A chromatography and measures to inactivate and remove viruses. The purified chTNT antibody with purity of at least 98% was radiolabeled with Na131I (Syncor International, Shanghai, China) using chloramine T as the oxidant, and the products were purified and tested for radioactivity and pathogen contamination as previously described.15 The purity of 131I-chTNT was more than 95% and the specific radioactivity of the radiolabeled product was between 8 and 12 mCi/mL.
Therapeutic Regimen
All patients received a saturated solution of potassium iodine (10 drops orally tid) 3 days before the initiation of radioimmunotherapy and continued until 7 days after completion of therapy to block uptake of free 131I by the thyroid. All patients received dexamethasone and diphenhydramine 30 minutes before each treatment to prevent allergic reactions. The 107 patients in eight clinical oncology centers were injected with 131I-chTNT intravenously or intratumorally. In all cases, the patients received two doses of 131I-chTNT administered 2 to 4 weeks apart. For intravenous injection, 131I-chTNT at a dose of 0.8 mCi/kg of body weight was diluted in normal saline and administered through a free-flowing intravenous line during a 1-hour period. Patients were monitored for symptoms and vital signs were measured every 15 minutes. For intratumoral injection, 131I-chTNT at a dose of 0.8 mCi/cm3 of tumor size was injected directly into the tumor mass using thoracic CT or x-ray guidance and a fine core needle (Dr Japan Co, Tokyo, Japan). CT scans or x-rays clearly showed the location of the tumor and the pathway of the needle. In this way, the proper placement of the needle and the extent of dissemination of the radiolabeled antibody into the tumor mass were monitored. Patients remained in radiation isolation until their whole-body radiation had reached acceptable limits (≤ 5 mR/h at 1 m).
Response Criteria and Evaluation
Efficacy was assessed as the objective response rate to treatment, which was the primary end point of the study. Responses were defined according to WHO criteria for measuring solid tumors as a complete response (CR), a partial response (PR), no change (NC), or progressive disease (PD). Objective response rate (ORR) was defined as CR plus PR.23 Tumor growth was monitored by the same imaging method used to establish baseline tumor measurements and was performed after each administration. Confirmation of response required a repeated imaging study 10 weeks after treatment using thoracic x-rays and CT.
Imaging and Biodistribution
All radionuclide imaging was performed to document the biodistribution of the 131I radioactivity in the tumor sites and the whole body. A series of anterior and posterior images were obtained at different time points after systemic or intratumoral administration of 131I-chTNT (scan speed of 5 to 10 cm/min). Regions of interest were drawn to calculate the ratio of tumor to nontumor (normal lung) uptake. MIRDOSE 3.0 (Medical Internal Radiation Dose Committee, Society of Nuclear Medicine, Reston, VA) was used for the estimation of the radiation-absorbed organ doses.
Evaluation of Toxicity
Adverse experiences were graded using the WHO toxicity criteria. Lung cancer patients underwent a complete physical examination, blood counts, and a battery of laboratory tests including radiological studies, ECG, CBC, and chemistry panels to evaluate the status of liver and renal functions at baseline and 2, 3, 4, 5, 6, and 10 weeks after the first administration. In addition, blood HACA and HAMA determinations were performed in all patients before the initiation of the therapy and 4 and 10 weeks after the start of therapy. Samples were assayed for HAMA using murine immunoglobulin G–coated enzyme-linked immunosorbent assay plates and for HACA using chTNT-coated plates followed by horseradish peroxidase–labeled antihuman Fc antibody and colorimetric agent.15 Thyroid function tests were performed at baseline and at 4 and 10 weeks after the start of therapy.
Statistical Analysis
This was a purely observational registration clinical trial, even though by design there were two parallel injection methods—systemic and intratumoral. No attempt was made to assign the 107 participating patients randomly into systemic or intratumoral groups. The authors did not compare statistical outcomes between the two administration methods.
RESULTS
Clinical Efficacy
Eight different oncology centers in China participated in the pivotal study. All patients received two doses of TNT radioimmunotherapy either by systemic (0.8 mCi/kg of body weight) or intratumoral (0.8 mCi/cm3 of tumor size) administration at 2- or 4-week intervals. Assessments of objective response used WHO criteria and responses were observed regardless of type or number of prior radiotherapy or chemotherapy regimens. As shown in Table 2, among the 107 patients, four patients (3.7%) achieved a CR, 33 patients (30.8%) had a PR, 59 patients (55.1%) had NC, and 11 patients (10.3%) had PD. The overall therapeutic efficacy ORR (CR plus PR) was therefore 34.6%.
For the 10 patients with small-cell lung cancer, the ORR was 50%, with one CR and four PRs. For the 97 patients with non–small-cell lung cancer, the ORR was 33%, with three CRs and 29 PRs. Among the 39 non–small-cell lung cancer patients with squamous cancer, one patient had a CR and 17 patients had a PR, with an ORR of 46.2%. For the 50 non–small-cell lung cancer patients with adenocarcinoma, the ORR was 24%, with two CRs and 10 PRs. Patients with different stages of disease at entry onto the study had different therapeutic responses. In 14 patients with stage II disease, the ORR for six patients was 25%, and in 62 patients with stage III disease, the ORR was 37.1%. In contrast, in 31 patients with stage IV disease, one patient achieved a CR and seven patients achieved a PR, with an ORR of 25.8%. Sixty-two patients received systemic administration of 131I-chTNT; two of the systemically treated patients achieved a CR and 20 patients achieved a PR, with an ORR of 35.5%. Forty-five of the cancer patients were treated with intratumoral injection of 131I-chTNT, and in this group two patients achieved a CR and 13 patients achieved a PR, with an ORR of 33.3%. In 58 patients evaluated for overall survival, median survival time was 11.7 months and the 1-year survival rate was 41.4% (Fig 1). Determination of therapeutic efficacy of this radioimmunotherapy was based mainly on ORR without evidence of an effect on overall survival.
Imaging and Biodistribution of 131I-chTNT in Patients
Imaging was conducted in all 131I-chTNT–treated patients. Figures 2A to 2G show whole-body images of representative patients after systemic or intratumoral administration of 131I-chTNT. Data in Figures2A to 2D demonstrated visual uptake of 131I activity in the tumor obtained at 0.5 and 5 hours, and 2 and 8 days after systemic administration of 131I-chTNT. These images reveal the remarkable retention of radiolabeled antibody in the vicinity of the tumor mass over time. Figures 2E to 2G show whole-body scintigraphy of a lung cancer patient at 5 (Fig 2E), 15 (Fig 2F), and 25 days (Fig 2G) after intratumoral administration of 131I-chTNT, demonstrating minimal diffusion of radioactivity from tumor site of injection. To demonstrate that the location of the radiolabel coincides with the anatomic position of the tumor, fusion images consisting of transaxial, coronal, and sagittal CT and single-photon emission CT, and x-ray (scout view) and single-photon emission CT of the lung tumor were prepared (Figs 2H to 2K) in a patient receiving intratumoral injection of 131I-chTNT 5 days previously. These images again demonstrated excellent localization of the radiolabel in the tumor, with little evidence of diffusion over time. The biodistribution of 131I radioactivity in the tumor versus nontumor areas (normal lung fields, T-to-NT ratio) was measured in 11 patients in each group. As shown in Figure 3, the average absorbed doses for tumor and normal lung tissue were 8.45 and 2.35 Gy in patients receiving systemic radioimmunotherapy. For patients receiving intratumoral injection, the average absorbed doses for tumor and normal lung tissue were 30.0 and 2.65 Gy, respectively. The T-to-NT ratio was 3.8:1 for systemically administered antibody and 16.1:1 for intratumorally injected reagent.
Radiation-absorbed dose estimation for 131I-chTNT was performed using sequential whole-body images and the MIRDOSE 3.0 software program. The data for both systemic and intratumoral administration are shown in Table 3. As expected, most organs except for the lungs (site of intratumoral injection), received about half of the dose of those patients receiving intratumoral injection compared with those administered systemic 131I-chTNT.
Adverse Experiences
Toxicity was graded according to the WHO toxicity criteria. As listed in Table 4, the major site of adverse effects was the bone marrow. All-grade platelet toxicity was found in 59.7% of systemically treated patients and 24.4% of intratumorally treated patients. For patients receiving systemic administration, 11.3% and 8.1%, respectively, experienced grade 3 or 4 platelet toxicity compared with 4.4% and 0% for patients receiving intratumoral injection. Grade 1 to 4 neutrophil toxicity was found in about one third of all patients, and for patients receiving systemic administration, 8.1% and 1.6%, respectively, had grade 3 and 4 neutrophil toxicity compared with 2.2% and 0% for those patients receiving intratumoral injection. All-grade hemoglobin toxicity was found in 41.9% of systemically treated patients and 20% of intratumorally treated patients. Only two patients receiving systemic therapy and one patient receiving intratumoral therapy had grade 3 hemoglobin toxicity, and no patient was reported with grade 4 hemoglobin toxicity.
Other adverse reactions are listed in Table 5 for patients receiving either systemic or intratumoral injection of 131I-chTNT. In general, no adverse effects were detected in the liver or kidneys during the treatment and follow-up periods. Likewise, no patient developed a HACA or HAMA response during the time it was tested. Because absorption of released radionuclide was imaged in the thyroid of some patients undergoing 131I-chTNT therapy, total T3, total T4, free T3, free T4, and thyroid-stimulating hormone before and after radioimmunotherapy were determined. The results demonstrated that total T3, total T4, free T3, and free T4 decreased slightly and thyroid-stimulating hormone increased significantly 1 and 2 months after 131I-chTNT administration. These changes, however, were all within the normal range (data not shown).
DISCUSSION
Although most prior studies with radiolabeled antibodies have been performed using systemic administration,5,9 a number of investigators are now focusing on the locoregional use of these reagents to treat identifiable lesions in solid tumor patients. Reasons for this include the low amount of uptake seen in tumors after intravenous injection, poor penetration into larger lesions, and heterogeneity of antibody uptake. Locoregional injection has been used most frequently in studies with malignant glioblastomas, which are tumors that are especially difficult to treat due to local extension of tumor tendrils into the white and gray matter of the brain. One such study by Riva et al24 using radiolabeled antitenascin antibodies found that catheter-directed administrations of 131I-antitenascin antibodies produced an increase in both the duration of remission and survival time in these difficult-to-treat patients, with little or no toxicity. In these studies, the results were dependent on the size of the tumor at the time of treatment. In addition, studies performed at multiple centers in the United States with 131I-chTNT-1 plus biotin produced dramatic results despite the dismal prognosis of these patients. In these studies, an infusion pump was used to deliver the radiolabeled antibody into the tumor over a 20-hour period via a surgically implanted catheter (unpublished observation). The use of the infusion pump to deliver the radiolabeled antibody slowly and forcefully may have improved the effectiveness of locoregional delivery by ensuring a more homogeneous distribution of reagent into the substance of the tumor. Although this may be an important consideration for glioblastoma, the method used in our study appears to have successfully infiltrated the full substance of the tumor, as shown by images taken shortly after infusion of tumor by the radiolabeled antibody (Fig 2). Because of the lower toxicity of this approach and the ability of radiolabeled antibody to infiltrate even large tumor masses effectively, locoregional or intratumoral injection may be a useful method of treating individual lesions such as those seen in glioblastoma or lung cancer, as described in this report.
Despite these hopeful findings, the number of complete responders in all the above-described studies was small, indicating that radioimmunotherapy might require additional treatment modalities to be used in combination for this form of therapy to reach its full potential. For example, it may be possible to improve the clinical efficacy of 131I-chTNT if it is used in combination with methods to increase the radiosensitivity of the tumor.25 In addition, as demonstrated by Anderson et al,26 prior treatment of tumors with ablative therapies increases the target size for TNT antibodies. In this study, it was demonstrated that prior radiofrequency ablation therapy of hepatic metastases, which generally produces a 1- to 5-cm zone of necrosis, significantly enhanced 131I-chTNT-1/biotin uptake in the tumor lesions. Anderson et al is the first patient study to take advantage of the basic property of TNT; namely, its proclivity to bind to dead and dying cells. When used in this manner, 131I-chTNT may become an adjuvant to other cytotoxic therapies. Chemotherapeutic drugs may also be used to generate larger areas of necrosis in tumors, and some of these drugs, such as doxorubicin, are also radiosensitizing because of their inhibition of DNA repair mechanisms. In addition, methods such as hormonal therapy used in prostate cancer patients can produce massive tumor destruction in a short period of time, thereby providing an excellent opportunity to test the adjuvant effects of 131I-chTNT in this setting.
With the approval of 131I-chTNT radioimmunotherapy for refractory lung cancer in China, it becomes possible for clinicians to study these more advanced concepts with 131I-chTNT radioimmunotherapy. It is hoped that ongoing studies in the United States and China with 131I-chTNT may provide new indications for its use or reveal its role as an adjuvant to current treatment approaches.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported by MediPharm Biotech Co, Shanghai, China.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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