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CANCER BIOTHERAPY & RADIOPHARMACEUTICALS Volume 21, Number 1, 2006 © Mary Ann Liebert, Inc.
131I-chTNT
Radioimmunotherapy of 43 Patients with Advanced Lung Cancer Like Yu,1 Dian Wen Ju,2 Wenping Chen,1 Tian Li,1 Zhaoqiang Xu,3 Changying Jiang,4 Shaoliang Chen,5 Qun Tao,2 Dan Ye,2 Peisheng Hu,6 Leslie A. Khawli,6 Clive R. Taylor,6 and Alan L. Epstein6 1Nanjing Pulmonary Hospital, Nanjing, China 2Shanghai MediPharm Biotech Co., Ltd., Shanghai, China 3Jiangsu People’s Hospital, Nanjing, China 4Tumor Hospital, Shanghai, China 5Shanghai Zhongshan Hospital, Fudan University, Shanghai, China 6Keck School of Medicine at the University of Southern California, Los Angeles, CA
ABSTRACT The treatment of advanced lung cancer remains a major challenge in clinical medicine, justifying an urgent need for new therapeutic approaches. In a rather unique international collaboration, 43 patients with advanced lung cancer were treated using iodine-131-labeled tumor necrosis therapy chimeric antibody (131I-chTNT). Methods: Patients were treated either with intravenous (i.v.) infusion (n 22), intratumoral injection using a computer tomography (CT)-guided catheter (n 16), or combination i.v. and intratumoral infusion (n 5). All patients, regardless of route of administration, received 2 doses of 131I-chTNT on days 1 and 14. Results: The results showed that of those patients receiving i.v. injection alone, 2 achieved partial response (PR) (9%), 16 had stable disease (73%), and 4 progressed (18%). Of those patients receiving intratumoral injection only, 1 had a complete response (CR) (6%), 8 achieved PR (50%), 7 had stable disease (44%), and none (0%) progressed. Finally, of those patients receiving both i.v. and intratumoral administration, 1 had a CR (20%), 1 achieved PR (20%), 2 had stable disease (40%), and 1 (20%) showed progression. Conclusions: These promising results demonstrate that sufficient doses of radiolabeled antibody can be safely delivered to tumors to cause significant therapeutic effects in advanced lung cancer. Key words: monoclonal antibody, oncology,
131I-chTNT,
INTRODUCTION Lung cancer is one of the most common malignancies worldwide and has one of the highest mortality rates.1,2 In China alone, there are more than Address reprint requests to: Alan L. Epstein; Department of Pathology, Keck School of Medicine, University of Southern California; 2011 Zonal Avenue, Los Angeles, CA 90033; Tel.: (323) 442-1172; Fax: (323) 442-3049 E-mail:
[email protected]
lung cancer, radioimmunotherapy
500,000 cases annually, and the 5-year survival is less than 5%. At the time of initial diagnosis, most patients have advanced disease and are not eligible for surgical resection that can be curative for patients with early stages. Hence, for most patients, external beam radiation therapy and/or chemotherapy are the treatments of choice but are, at best, palliative and can cause significant side-effects in this poor-risk group. Furthermore, facilities for thoracic surgery, radiotherapy, and multiagent chemotherapy are not widely available or 5
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affordable in China and other evolving countries. It is, therefore, essential to seek more effective and less toxic modes of therapy for advanced lung cancer to improve these dismal statistics. The current search for new treatment modalities for non-small-cell lung cancer has generated a number of new approaches that are now being tested in the clinic.3,4 Among these is a new class of drugs that acts as signal transduction inhibitors for epidermal growth factor.5,6 One of these drugs, “Iressa,7 appears to be limited to a minority of nonsmall-cell lung cancer patients and is tumor stabilizing, not curative. Another promising approach has been the use of monoclonal antibodies linked to therapeutic radionuclides. Radioimmunotherapy, as a field, is just beginning to flourish as a treatment modality and offers the promise of killing tumors microregionally.8 Our laboratory has been involved in the development of an innovative form of radioimmunotherapy that targets therapeutic radionuclides to necrotic areas of solid tumors. Designated as tumor necrosis therapy (TNT),9–11 this treatment modality utilizes nuclear antigens that are present in all cells, but are exposed to antibody only in degenerating cells, as a means of targeting solid tumors, regardless of their cell of origin. Because necrosis is a common feature of most malignancies and comprises from 30% to 80% of the tumor mass.12,13 radiolabeled TNT antibodies can be cytotoxic to adjacent viable areas of the tumor by delivering sufficient dosages into central necrotic regions,11,14 Moreover, as new areas of the tumor become necrotic by treatment, subsequent doses of TNT will be able to bind to these new areas of degeneration, causing a “gangrene-like” effect throughout the tumor.14 Finally, TNT antibodies, unlike those directed against tumor cell-surface antigens, have been found to have a long retention time in tumors, making them ideal delivery agents of cytotoxic reagents, such as radiation.9,10,14 To test this approach, 43 patients with late-stage lung cancer were treated with 131I-chTNT from March 1999 to June 2000. The results of this study demonstrate that monoclonal antibody radioimmunotherapy is a viable option for the treatment of advanced lung cancer, as measured by the induction of significant remissions. MATERIALS AND METHODS Patient Eligibility A total of 43 patients with lung cancer entered into this phase IIa clinical trial to evaluate the 6
therapeutic effectiveness, safety, and pharmacokinetics of 131I-chTNT for the treatment of advanced lung cancer. All 43 patients had a cytological and histological confirmed diagnosis of stage IIIB (30 of 43) or IV (13 of 43) lung cancer (Table 1). All patients had failed prior therapies with a mean of three times. These prior therapies included radiotherapy, irinotecan-based chemotherapy, platinum-containing regimens, or other combined chemotherapy regimens. The average patient age was 57.3 years (31–74 years), and 33 patients (77%) were male. All patients had a Karnofsky performance status of 60 or better. Twenty-four (24) patients (56%) had a diagnosis of adenocarcinoma, 12 patients (28%) had squamous carcinoma, 6 patients (14%) had small-cell lung cancer, and 1 patient (2%) had a diagnosis of adenosquamous carcinoma. A condition for entry into the study was an anticipated survival of at least 3 months, according to the clinical judgment of the clinicians. Other entry criteria included no radiotherapy for 2 months or chemotherapy for 1 month prior to entrance, and all patients had to demonstrate progressing and measurable disease, as shown by thoracic radiograph or computer tomography (CT). Finally, patients were required to have tumor masses that were easy to aspirate by fine-needle biopsy to confirm the diagnosis. Follow-up was assured to the ex-
Table 1.
Patient Characteristics and Disease Status
Characteristic Gender Male Female Age, years Mean Median Range Stage at study entry III IV Histology Small-cell lung cancer Non-small-cell lung cancer Squamous Adenocarcinoma Adenosquamous carcinoma Low-grade lung cancer Not specified
Number of patients 33 10
% 76.7 23.3
57.3 61.0 31–74 30 13
69.7 30.2
6 37 12 24 1 1 2
14.0 86.0 27.9 55.8 2.3 2.3 4.7
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tent of allowing assessment of the short-term effects of the treatment. Preparation of
131I-chTNT
131I-chTNT was provided by Shanghai Medipharm
Biotech Co. Ltd (Shanghai, China). Recombinant human–mouse chimeric TNT antibody was produced in NS0 murine myeloma cells cultured in bioreactor and is 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 chrolamine T as the oxidant, and the products were purified and tested for radioactivity and pathogen contamination, as previously described.14 The purity of 131I-chTNT was over 95% with a specific radioactivity between 8–12 mCi/mL. Treatment To block uptake of free iodine-131 by the thyroid, patients received a solution of potassium iodine orally, beginning 3 days before therapy and continuing until 7 days after therapy. Each patient also received dexamethasone and diphenhydramine 30 minutes before each treatment to prevent allergic reactions known to occur with the administration of monoclonal antibodies. The 43 patients who qualified for the study were divided into three groups in order to test the effectiveness of different methods of drug administration. The rationale for testing the intratumoral route of administration, despite the fact that some of these patients had metastatic disease (including possible occult disease) was to try and obtain good local control of the primary malignancy in patients in which surgery was not possible. Of the 43 patients who entered the study, 22 received systemic administration (Group 1) and 21 patients received local administration (Groups 2 and 3). All the patients were randomized to systemic or local administration groups to assure that both sets of patients were homogeneous with respect to disease load. Among the 21 locally treated patients, 16 received local injection exclusively (Group 2), and 5 patients received a split dose consisting of 75% local and 25% systemic (Group 3) in an effort to simultaneously treat both primary and metastatic lesions. Based upon data generated from an escalating-dose phase I trial performed from 1997 to 1999 in which 16 patients were used to
determine the MTD and 23 patients were used to generate pharmacokinetic data (unpublished), all patients received 2 doses of 0.8 mCi/kg administered 2 weeks apart. For intravenous injection, 131I-chTNT was dissolved in 250 mL normal saline and the solution was administered through a free-flowing intravenous (i.v.) line. For intratumoral injection, 131I-chTNT (10 mCi/ mL) was injected directly into the tumor mass, using thoracic CT guidance and a Fine Core needle (DR Japan Co.; Tokyo, Japan). CT scans clearly showed the location of the tumor and the pathway of the needle. Its use assured the proper placement of the needle to enable widespread dissemination of the radiolabeled antibody into the tumor mass. The same total dose was used in both the systemic and intratumoral arms so that efficacy data could be compared directly. Finally, all patients gave their informed consent to receive 131I-chTNT radioimmunotherapy. In addition, this phase II clinical trial was approved by the Ethical Committee (IRB) of Zhongshan Hospital, Fudan University in China. Treatment Evaluation Each patient underwent a complete history and physical examination and a battery of laboratory tests, including radiologic studies, electrocardiogram (ECG), complete blood count (CBC), and chemistry panels to evaluate the status of liver and renal functions. Other investigations, in all cases, included blood HACA and HAMA determinations performed before the initiation of therapy and every 4 weeks thereafter. Tumor size was recorded 4 weeks before and 10 weeks after treatment using thoracic radiograph and CT. Responses were defined according to the World Health Organization (WHO) criteria for measuring solid tumors as a complete response (CR), a partial response (PR), no change (NC), or progressive disease (PD). Finally, toxicity was graded using the WHO toxicity criteria. 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 5–10 cm/min). Regions of interest (ROIs) were drawn to calculate the ratio of tumor to nontumor (normal lung) uptake. 7
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PR efficacy was 9.1%. By comparison, the combined CR PR efficiency for Groups 2 and 3 receiving intratumoral injections was 52.4%. Although the primary endpoint of this study was tumor response measured by the reduction of tumor size of all measurable lesions, duration of tumor response was also determined. At the 1-year follow-up, approximately 35% of patients were still alive after treatment. Finally, a breakdown of the results with respect to histological subtype showed the following results: squamous carcinoma CR PR 4 of 12 (33%); adenocarcinoma CR PR 6 of 12 (50%); and small cell lung cancer CR PR 3 of 6 (50%).
Pharmacokinetics Blood samples at different time points after therapy were taken into tubes containing anticoagulant to measure whole blood radioactivity. Urine was collected at different time points after treatment, and daily cumulative urinary excretions of 131I were determined. The content of radioactivity at each time point in the blood was estimated by deriving the total blood volume from standard monograms, using the patient’s gender and body surface area. The total amount of radioactivity excreted per day in the urine was calculated from the volume of urine collected in the day. All radionuclide imaging was performed to document the biodistribution of the 131I activity in the tumor sites and the whole body.
Biodistribution of
This was a phase IIa study to test the therapeutic efficacy and safety of 131I-chTNT administrated systemically or locally. It was a purely observational clinical trial, even though, by design, all patients were randomized into two parallel injection groups—systemic and intratumoral. RESULTS Clinical Efficacy All three groups received 2 doses of 0.8 mC/Kg As shown in Table 2, among the 43 patients, 2 patients (4.7%) achieved a complete response (CR), 11 patients (25.5%) had a partial response (PR), 25 patients (58.1%) had no change (NC), and 5 patients (11.7%) had progressive disease. The overall CR PR efficacy was, therefore, 30.2%. For Group 1 (i.v. only), the CR 131I-chTNT.
Table 2. Clinical Efficacy of Intravenous or Intratumoral Injection of Administration of Cancer Patients
Intravenous Intratumoral
Total %
Group Group 1 Groups 2/3 Group 2 Group 3
Number points 22 21 16 5 43
131I-chTNT
in 43 Advanced Lung
CR
PR
NC
PD
CR PR
0 2 1 1 2 4.7%
2 9 8 1 11 25.5%
16 9 7 2 25 58.1%
4 1 0 1 5 11.6%
9.1% 52.4% 56.3% 40.0% 13 30.2%
CR, complete response; PR, partial response; NC, no change; PD, progressive disease.
8
in Patients
The biodistribution of 131I-chTNT in tumor versus nontumor areas (T/NT) was measured in 39 of 43 patients. T/NT of the remaining 4 patients could not be assessed because of the high capture of 131IchTNT in pre-existing effusions in the thorax that precluded measurement of areas of interest. Consistent with the clinical outcome, there was a difference in the T/NT levels 1 week after TNT administration between the patients receiving i.v. infusion alone (Group 1, n 19, T/NT 1.36) and those patients in Group 2 (n 15, T/NT 14.6) and Group 3 (n 3, T/NT 9.38) who received intratumoral injections. Four (4) to 6 days after treatment, the highest background activity in these images was seen in the heart and large vessels in patients in Group 1, along with significant radioactivity in the liver. By contrast, patients in Groups 2 and 3 showed little detectable radioactivity in the liver and heart areas. In Figure 1A, anterior and posterior whole-body images of a patient with non-small-cell lung carcinoma injected 5 days previously with 131I-chTNT is shown. ROI chest
Statistics
Administration method
131I-chTNT
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A Figure 1. (A) Whole-body radioscintigram of patient with non-small-cell lung carcinoma injected 5 days previously with 131I-chTNT, using the intratumoral route of administration. Note the relative lack of radiolabel outside the tumor mass, including the thyroid. (B) Scintigram showing region of interest (ROI) of intratumoral injection in posterior chest at 5 days. (C) Scintigram of posterior chest showing remarkable retention of 131I-chTNT 14 days after intratumoral injection.
C
B
shown). At 1 hour and 1 day, uptake is seen in the heart (blood pool) and tumor. Three (3)- and 6-day images, however, show a decrease in blood pool and retention of 131I-chTNT in tumor, including the primary lung lesion and a metastatic tumor of the leg (arrows). Finally, in Figure 3, fusion images consisting of CT and radioimmunoscintigraphy provide evidence that the location of the radiolabel coincides with the anatomic position of the tumor.
scintigrams shown in Figure 1B and 1C show the localization of an intratumoral injection at 1 and 14 days postinjection and demonstrate the remarkable retention of radiolabeled antibody in the vicinity of the tumor mass over time. In Figure 2, whole-body scans are shown for a patient receiving systemic administration who had a large primary lung tumor and metastatic disease to the leg confirmed by magnetic resonance imaging (MRI) (MRI data not
1h
3d
6d
9d
Figure 2. Whole-body radioscintigram of latestage lung cancer patient treated systemically with 131I-chTNT at 1 hour, 3 days, 6 days, and 9 days post-therapy, showing long retention of radiolabeled antibody in lung tumor (upper arrow). Note the increased uptake of radiolabel in the leg of the patient (lower arrow), where metastatic disease produced decreased limb function. The presence of metastatic disease in the leg lesion was confirmed by magnetic resonance imaging (MRI).
9
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A
B
C
D
Figure 3. Computed tomography (CT) and radioimmunoscintigraphy composite images of male patient with non-small-cell lung carcinoma after intratumoral injection of 131I-chTNT. Radioscintigrams were obtained 10 days after intratumoral injection. (A) Transaxial, coronal, and sagittal CT scans of lung tumor, (B) transaxial, coronal, and sagittal scintigrams of lung tumor after intratumoral injection of 131I-chTNT, (C) fusion images of transaxial, coronal, and sagittal CT and radioimmunoscintigraphy, and (D) X-ray (scout view) and radioimmunoscintigraphy of lung tumor.
In those patients receiving intratumoral injection, clinicians were careful to produce a homogeneous diffusion of radiolabel in tumor using CT to monitor treatment injection. Pharmacokinetics The pharmacokinetic clearance profiles of both systemically and intratumorally administered 131IchTNT are shown in Figure 4. As shown in Figure 4A, the half-life of systemically administered 131I-chTNT in the blood was approximately 2 days. For intratumorally administered 131IchTNT, the peak radioactivity levels in the blood 10
were observed on day 1, whereas half-life values after that time were on day 3.5 (Fig. 4B). To complete these profiles, the urine excretion of 131I for both systemic (Fig. 4C) and intratumorally administered antibody (Fig. 4D) are provided. Interestingly, the 50% levels for both were approximately 6 days post-therapy. Adverse Experiences No adverse affects were detected in liver, renal, and thyroid functions in the 43 patients during the 10-week treatment and follow-up periods. None of the 43 patients developed a HACA or
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A
C
B D
Figure 4. Blood and urine clearance of 131I-chTNT in patients with advanced lung cancer. For blood clearance, the data are shown after (A) intravenous adminstration and (B) intratumoral adminstration, and, for urinary clearance, after (C) intravenous adminstration and (D) intratumoral administration. Data for 131I excretion were expressed as the cumulative percentage of total injected radioactivity during the study.
HAMA response. Seven (7) patients did, however, report fatigue and appetite loss in the first week of treatment. Table 3 lists the hematological toxicities that were the major adverse effects detected in this study. Specifically, a decreased neutrophil count was seen in 10 of 22 patients in Group 1 (2 patients with grade 3 toxicity), in 10 of 16 patients in Group 2 (all with grade 1 toxicity), and in 0 of 5 patients in Group 3. Similar toxicity results were seen in platelets and hemoglobin. None of these adverse side-effects required additional supportive care. DISCUSSION Advanced lung cancer is a major clinical problem encountered by oncologists and is deemed
incurable, largely because of the poor response rate and toxicity obtained with conventional chemotherapy. The clinical outcome for patients with this disease is very poor and is characterized by a short survival and few viable treatment options.15 Hence, there is a very real need for more effective methods to treat advanced lung cancer in order to improve survival rates and quality of life during treatment. On the horizon are new classes of drugs, such as epidermal growth factor receptor tyrosine kinase inhibitors4 and differentiation-inducing drugs, to slow the progression of aggressive locally advancing tumors or metastatic lesions.16–18 One example, “Iressa,” which acts as a signal transduction inhibitor for the epidermal growth factor, has been shown to produce disease stabilization, little toxicity, and an increased sense of well-being in a 11
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Table 3.
Hematological Toxicity in
Administration method Intravenous Intratumoral
Page 12
Group Group 1 Groups 2/3 Group 2 Group 3
Total
131I-chTNT
Treated Advanced Lung Cancer Patients
WBC toxicity grade
Platelets toxicity grade
Hemoglobin toxicity grade
Number points
I
II
III
IV
I
II
III
IV
I
II
III
IV
22 21 16 5 43
7 10 10 0 17
1 0 0 0 1
2 0 0 0 2
0 0 0 0 0
15 9 8 1 24
2 0 0 0 2
2 0 0 0 2
0 0 0 0 0
12 12 11 1 24
1 0 0 0 1
0 0 0 0 0
0 0 0 0 0
WBC, white blood cell.
subset of patients.7,19 Clinical data with this drug are still preliminary, and the drug is only available in some countries on a trial basis. One problem is that its clinical efficacy appears to be limited to an unpredictable minority of patients. Alternatively, methods that target regions of the tumor instead of individual cells are under study in a number of laboratories. These innovative approaches include antiangiogenesis reagents,20–22 and monoclonal antibodies for the radioimmunotherapy of solid tumors.8,23–25 Our laboratory has been exploring the use of this latter approach to target therapeutic radionuclides into the core of tumors in order to achieve effective results in the treatment of solid tumors.10,26 For these studies, radiolabeled I-131 and Y-90 have provided some notable successes, especially in patients with malignant lymphomas,27 but most solid tumors, including lung tumors, have not been adequately studied by this approach. These radionuclides are capable of killing tumors microregionally by lethally irradiating spherical regions of 150–300 cells deep at sites of antibody binding and retention. The target site in the tumor is critical, as it is important to have adequate coverage and tumoricidal exposure, both to rapidly advancing areas of the tumor characterized by high proliferative rates and to hypoxic regions known to be relatively dormant and radioinsensitive.28 In the last several years, our laboratory has developed a new approach, using monoclonal antibodies, that target intracellular antigens exposed in degenerating cells found in solid tumors. One of these antibodies, chTNT, is a human–mouse chimeric MAb directed against single-stranded DNA exposed in necrotic regions of tumors.29 Because of its specificity and long retention time in tumors, this MAb is a promising delivery ve12
hicle for therapeutic radionuclides, such as I-131. In addition, new degenerating areas of tumors produced from initial doses of radiolabeled chTNT can act as additional targets for subsequent doses, thereby causing a gangrene-like effect within the tumor. This progressive and enhanced killing by radiolabeled TNT MAbs has been well demonstrated in animal models.11 It is the recognition of this effect that influenced the design of this study to include 2 doses appropriately spaced to take advantage of this unique characteristic of TNT. Although a 1-week interval between doses might have been more beneficial, as suggested by previous experimental animal data, it was decided to administer the doses in 2-week intervals as a compromise to alleviate concerns of possible bone marrow toxicity for those patients receiving intravenous doses. The data presented in this study clearly show that the intratumoral route, which represented 75% of the dose given to patients in Group 3 and 100% of the dose administered to patients in Group 2, gave superior results over the intravenous route of inoculation administered to patients in Group 1 (CR PR rate of 52.4% for Groups 2 and 3 versus 9.1% for Group 1). Nuclear scans showed that the average ratio of tumor uptake verses nontumor uptake in Group 1 was 1.36 (highest ratio only 1.7). By comparison, the ratio in the intratumoral injection group was 14.6. The use of locoregional administration of radiolabeled antibodies is not new. As described by Riva et al.,29 radiolabeled monoclonal antibodies have been used in the treatment of highgrade glioblastomas as a new approach to try and treat brain lesions, which, characteristically, infiltrate surrounding brain tissue. Owing to the relative insensitivity of normal brain to radiation, higher overall doses were able to be used in these
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studies, compared to those performed in our study involving human lung. As mentioned previously, along with the tumor/nontumor ratio and quantity of antibody bound to tumor, the retention time of the radionuclide in the tumor is a very important characteristic to achieve successful therapy. Previous animal studies have shown that radiolabeled chTNT, after intravenous infusion, remains localized at the tumor site for up to 10 days, as demonstrated by autoradiographic and biodistribution methods.30,31 The results of this study and of a previously published work32 suggest that this characteristic of the TNT approach is also true in patients with advanced lung cancer. Because of the stability of nucleic acids retained in degenerating cells compared to the known high turnover rate of antigens expressed on tumor cell surfaces, TNT MAbs have a lengthened retention time in the tumors compared to other antibodies, which may be lost because of degradation of antigen, modulation of antigen expression, or protein turnover. The lack of toxicity to normal tissues is a reflection of the high functional specificity of 131IchTNT for tumor. This “functional specificity” is, at first sight, paradoxical because the DNA antigen is, in fact, present in all nucleated cells of the body. The functional specificity is the result of a major difference in the pathophysiology of normal tissues, as compared to most malignancies. Because normal cells have intact cellular membranes that are impermeable by nature, the introduction of 131IchTNT into the extracellular environment, either by intravenous or intratumoral injection, cannot actually penetrate viable cells to access the internal nuclear DNA target, thereby accounting for the relative lack of uptake in normal tissues. By contrast, the accumulation of dead and dying cells within tumors is a hallmark of malignancy and accounts for the observed uptake and retention of 131I-chTNT in the patients described in this study. This physiologic characteristic of TNT may also explain the observation that adverse events attributable to the nonspecific binding of 131I-chTNT were rare, because TNT MAbs can only bind to nuclei of tissues that contain pre-existing necrosis. This study did reveal that the only significant adverse event of 131I-chTNT was bone marrow–related toxicity. Of the 43 treated patients, only 2 patients (4.65%) developed grade 3 neutropenia. This incidence is much lower than that seen in patients undergoing systemic chemotherapy. Unlike chemotherapy patients, who commonly require G-CSF support during treatment, no cytokine supplementation
was required in this study. Three (3) patients (6.98%) also showed severe thrombocytopenia, which is a comparable incidence to that seen with systemic chemotherapy. This marrow toxicity is thought not to be a manifestation of “nonspecific” binding of the 131I-chTNT, but rather is a result of the simple passive effect of circulating radiolabel upon passage through the bone marrow following intravenous infusion. Adverse effects were dramatically reduced in those patients receiving only intratumoral injection, as diffusion of radiolabeled antibody from the tumor into the systemic circulation is minimal. Lastly, 131I-chTNT is a humanmouse chimeric antibody, with a theoretical reduced chance of eliciting an antimouse immune reaction. In this study, none of the 43 patients developed a HAMA or HACA response (data not shown. An enzyme-linked immunosorbent assay (ELISA) method was used for detection in these studies. Chimeric TNT was used for the capturing of the anti-TNT antibodies, and HRP labeled TNT were used for detection). The other side-effects, such as transient fatigue, appetite loss, and vomiting, did not require acute medical attention. CONCLUSIONS In summary, the data presented in this study demonstrate that 131I-chTNT has significant clinical efficacy with tolerable adverse effects in the treatment of patients with advanced lung cancer of varying histology. Moreover, the injection of 131I-chTNT directly into tumors showed high tumor/nontumor ratios and high efficacy, with less bone-marrow toxicity and less adverse experiences. The data suggest that 131I-chTNT is suitable for late-stage lung cancer and, possibly, also for the radioimmunotherapy of other solid tumors that can be injected intratumorally. Additional clinical studies are required to determine if 131IchTNT can be used in conjunction with, or between cycles of, systemic chemotherapy or other cytotoxic treatment modalities capable of inducing necrosis, which, in theory, could further enhance the size of the target and improve the effectiveness of TNT radioimmunotherapy. ACKNOWLEDGMENTS The authors wish to acknowledge the expert technical assistance of Aoyun Yun. This work was supported by MediPharm, Inc. (Los Angeles, 13
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CA) and Cancer Therapeutics Laboratories, Inc. (Los Angeles, CA).
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