Simultaneous radiotherapy and radioimmunotherapy of malignant gliomas with anti-EGFR antibody labelled with iodine 125. Preliminary results (original) (raw)
Related papers
International Journal of Radiation Oncology*Biology*Physics, 2004
A Phase I/II clinical trial was undertaken between January 29, 1987 and January 25, 1997 to assess the efficacy of 125 I-labeled monoclonal antibody 425 ( 125 I-MAb 425) in controlling high-grade brain gliomas. A total of 180 patients diagnosed with glioblastoma multiforme (GBM) and astrocytoma with anaplastic foci (AAF) were administered 125 I-MAb 425 as an adjuvant treatment. All underwent initial surgery followed by postoperative external beam radiation therapy and a cumulative dose of 140 mCi of 125 I-MAb 425. Biodistribution of radioactivity after antibody administration showed increased uptake in brain tumor cells due to enhanced expression of epidermal growth factor receptors. A longer half-life of 125 I-MAb 425 in brain tumor cells compared to blood was observed. All patients were followed up for at least 5 years. Overall actuarial survival range for GBM and AAF patients showed 4-150 and 4-270 months, respectively. GBM and AAF patients under age 40 years with a Karnofsky performance status >70 had an actuarial median survival of 22.5 and 65 months, respectively. This adjuvant therapy demonstrates a significant increase in median survival and should be considered in the management of high-grade brain gliomas. © 2004 Elsevier Inc.
131I- Nimotuzumab – A potential radioimmunotherapeutic agent in treatment of tumors expressing EGFR
Applied Radiation and Isotopes, 2015
Nimotuzumab labeled with 131 I by both Chloramine T and Iodogen methods exhibited radiochemical purity of 4 95% with good in vitro stability. Cell binding studies of 131 I-Nimotuzumab showed good immunoreactivity of the radioconjugate. Minimal thyroid uptake and fast clearance by both renal and gastrointestinal routes within 5 days post injection in normal Swiss mice.
Cancer Biology Therapy, 2006
The poor prognosis of patients with high-grade glioma has led to the search for new therapeutic strategies. More than half of these tumors overexpress Epidermal Growth factor Receptor (EGFR). h-R3 is a humanized monoclonal antibody that recognize the EGFR external domain with high affinity, inhibiting tyrosine kinase activation. In order to evaluate safety, immunogenicity and preliminary efficacy of h-R3 in newly diagnosed high-grade glioma patients, we conducted a Phase I/II trial. Patients received six weekly infusions of h-R3 at the dose of 200 mg in combination with external beam radiotherapy. Twenty-nine patients (mean age, 45 years and median KPS 80) were entered into the study. Tumor types were: glioblastoma (GB) (16 patients), anaplastic astrocytoma (AA) (12 patients) and anaplastic oligodendroglioma (AO) (1 patient). All patients underwent debulking surgery or biopsy before entering the trial. The antibody was very well tolerated. No evidences of grade 3/4 adverse events were detected. None of the patients developed acneiform rash or allergic reactions. One patient developed a positive anti-idiotypic response. Objective response-rate was 37.9% (17.2% complete response, 20.7% partial response) while stable disease occurred in 41.4% of the patients. With a median follow up time of 29 months, the median survival is 22.17 months for all subjects. Median survival time (MST) is 17.47 months for GB, whereas MST is not reached for AA patients.
International Journal of Radiation Oncology*Biology*Physics, 2011
Objective Despite evolution in surgical technique, radiotherapy technology, and targeted systemic therapies, prognosis for patients with high-grade gliomas remains poor. Standard treatment consisting of surgery, adjuvant chemoradiation, and chemotherapy has marginally improved survival in these patients. A recent novel approach has been the addition of adjuvant radioimmunotherapy with 125 I-labeled antiepidermal growth factor receptor monoclonal antibody 425 (125 I-epidermal growth factor receptor (EGFR) monoclonal antibody (MAb) 425), which demonstrated safety and efficacy in patients with glioblastoma. Many institutions choose to treat grade 3 gliomas in an identical fashion to grade 4 tumors. In this phase II clinical trial, we tested the efficacy of adjuvant radioimmunotherapy in patients with pathologic diagnosis of high-grade glioma comprising either glioblastoma (GBM) or astrocytoma with anaplastic foci (AAF). Methods Patients with newly diagnosed high-grade gliomas were eligible. Adjuvant radiotherapy was delivered with a median dose of 60 Gy after surgery. 125 I-EGFR MAb 425 was given by three weekly intravenous injections of 1.85 GBq of radiolabeled 125 I-EGFR MAb 425 following surgery and adjuvant radiation. When administered, temozolomide was given concominantly (75 mg/m 2 /day, 35-42 days) with radiotherapy followed by 6 cycles of adjuvant temozolomide (TMZ) (150-200 mg/m 2 /day×5 days, every 28 days q28d). Median survival was the primary endpoint. We compared survival in three treatment groups: patients who underwent surgery followed by radiation (CTL), patients who underwent surgery and radiation followed by radioimmunotherapy (RIT), and patients who underwent RIT with the additional of temozolomide (RIT + TMZ). Results Between 1988 and 2008, a total of 390 patients with high-grade glioma underwent treatment at Hahnemann
Cancer Biology & Therapy, 2006
The poor prognosis of patients with high-grade glioma has led to the search for new therapeutic strategies. More than half of these tumors overexpress Epidermal Growth factor Receptor (EGFR). h-R3 is a humanized monoclonal antibody that recognize the EGFR external domain with high affinity, inhibiting tyrosine kinase activation. In order to evaluate safety, immunogenicity and preliminary efficacy of h-R3 in newly diagnosed high-grade glioma patients, we conducted a Phase I/II trial. Patients received six weekly infusions of h-R3 at the dose of 200 mg in combination with external beam radiotherapy. Twenty-nine patients (mean age, 45 years and median KPS 80) were entered into the study. Tumor types were: glioblastoma (GB) (16 patients), anaplastic astrocytoma (AA) (12 patients) and anaplastic oligodendroglioma (AO) (1 patient). All patients underwent debulking surgery or biopsy before entering the trial. The antibody was very well tolerated. No evidences of grade 3/4 adverse events were detected. None of the patients developed acneiform rash or allergic reactions. One patient developed a positive anti-idiotypic response. Objective response-rate was 37.9% (17.2% complete response, 20.7% partial response) while stable disease occurred in 41.4% of the patients. With a median follow up time of 29 months, the median survival is 22.17 months for all subjects. Median survival time (MST) is 17.47 months for GB, whereas MST is not reached for AA patients.
Clinical Cancer Research, 2005
Monoclonal antibodies and tyrosine kinase inhibitors specific for the epidermal growth factor receptor (EGFR) have been shown to enhance the effect of external beam radiation on EGFR-positive tumors. The effect of EGFR signaling abrogation by EGFR tyrosine kinase inhibitor on the efficacy of radioimmunotherapy has not been reported previously. This study investigated the effect of EGFR tyrosine kinase inhibition on the efficacy of radioimmunotherapy in a human cancer xenograft model. Experimental Design: The humanized anti^LewisYantibody hu3S193 and the EGFR tyrosine kinase inhibitor AG1478 were studied. BALB/c nude mice were engrafted with A431 squamous carcinoma cells. Initial biodistribution properties of the 90 Y-CHX-A 00-DTPA-hu3S193 were evaluated in this model. In therapy experiments, cohorts of four to five xenografted mice were treated with saline as placebo, 0.4 mg AG1478 i.p. (six doses over 2 weeks), single i.v. injections of unlabeled hu3S193, or 90 Y-CHX-A 00-DTPA-hu3S193 (12.5, 25, 50, or 100 ACi). The combination of 0.4 mg AG1478 i.p. and 25 ACi 90 Y-CHX-A 00-DTPA-hu3S193 i.v. was subsequently evaluated in the A431model. Results: 90 Y-CHX-A 00-DTPA-hu3S193 retained excellent immunoreactivity after radiolabeling. The biodistribution study showed excellent uptake in tumor (90.33 F 38.84%ID/g) peaking at 24 to 72 hours after injection and with prolonged retention. 90 Y-CHX-A 00-DTPA-hu3S193 significantly inhibited A431xenograft growth at 25, 50, and 100 ACi doses. The combination of 0.4 mg AG1478 with a single dose of 25 ACi 90 Y-CHX-A 00-DTPA-hu3S193 resulted in a significant enhancement of efficacy compared with either agent alone (P = 0.013). Conclusions: The efficacy of radioimmunotherapy with 90 Y-CHX-A 00-DTPA-hu3S193 is significantly enhanced by EGFR tyrosine kinase inhibitor AG1478. Further investigations of dosing regimens using EGFR tyrosine kinase inhibitors and radioimmunotherapy in the treatment of EGFR expressing tumors are warranted.
Hybridoma, 2001
Ior egf/r3, a neutralizing monoclonal antibody (mAb) against Epidermal Growth Factor Receptor (EGFR) was generated at the Cuban Institute of Oncology. Immunoscintigraphic studies in 148 patients with this 99-m Technetium (99 Tc) labeled mAb, showed a high sensitivity and specificity for in vivo detection of epithelial tumors. To study safety, pharmacokinetic and immunogenicity of ior egf/r3 at high doses, a phase I clinical trial was conducted. Nineteen patients with advanced epithelial tumors received 4 mAb intravenous infusions at 6 dose levels: from 50 to 500 mg. Previously, immunoscintigraphic images using the same mAb labeled with 99 Tc were acquired. Blood samples were collected for pharmacokinetic analysis and HAMA response. After mAb therapy, objective response was classified according to WHO criteria. Ior egf/r3 was well tolerated in spite of the high-administered doses. Only a severe adverse reaction consisting of hypotension and lethargy was observed. In 13 patients, selective accumulation of 99 Tc-labeled mAb was observed at the site of the primary tumor or the metastasis. Pharmacokinetic analysis revealed that elimination half-life and the area under the time-concentration curve increased linearly with dose. HAMA response was detected in 17 patients. After 6 months of mAb therapy, 4 patients had stable disease. One patient had a tumor partial remission after 3 cycles of ior egf/r3.
Journal of Radiation Oncology, 2012
Objective The efficacy and safety of adjuvant radioimmunotherapy with 125 I-labeled anti-epidermal growth factor receptor 425 murine antibody (125 I-425 mAb) in patients with newly diagnosed anaplastic astrocytoma (AA) is evaluated in this single-institution phase II study. Methods Patients with newly diagnosed and histologically proven AA were eligible. A total of 80 patients received three weekly intravenous injections of 1.8 GBq of 125 I-425 mAb following surgery and radiation therapy to a median dose of 60 Gy. Median overall survival was the primary endpoint and the secondary endpoint was toxicity. Results The median age was 43 years (range 22-75 years), and the median Karnofsky Performance Status was 80 (range 50-100). The percentage of patients who underwent surgical debulking, radiation therapy, temozolomide, and nitrosourea-based chemotherapy are 57.5, 99, 25, and 25 % respectively. The overall median survival was 55.6 months (95 % CI 42.7-68.5 months). The 2-and 5-year survivals were 74 and 47 %, respectively. There was no grade 3 or higher toxicity with the administration of 125