Barry Wessels - Academia.edu (original) (raw)
Papers by Barry Wessels
Cancer Research, Feb 1, 1990
Progress in animal radioimmunotherapy has been reviewed by high lighting 22 successful experiment... more Progress in animal radioimmunotherapy has been reviewed by high lighting 22 successful experiments using human \enografts in rodent models. Significant tumor growth delay has been observed in all experi ments with five groups reporting tumor control 100 days post-tumor implantation. The radiobiological significance of these experiments is analyzed through a proposed framework for the comparison of radioim munotherapy to external beam therapy in both animals and humans. The limits of applicability of animal modeling to the clinical setting are evaluated in terms of intrinsic radiosensitivity, tumor volume effects, tumor bed effects, and the host defense mechanism. A generalized strat egy for the development of clinical radioimmunotherapy is proposed based on utilization of radioimmunotherapy as a boost therapy in com bination with external beam radiation.
International Journal of Radiation Applications and Instrumentation Part B Nuclear Medicine and Biology, 1986
Rhenium-186 has been theoretically determined to be among the best therapy radiolabels due to its... more Rhenium-186 has been theoretically determined to be among the best therapy radiolabels due to its unique half-life, particulate and gamma emissions and chelation properties. Traditionally, rhenium chelates have been synthesized by the tin reduction method at low pH which frequently produces denaturation of acid labile proteins. A comparative study has been carried out to assess three techniques of reducing 186ReO-4 in order to label biologically active macromolecules (i.e. human serum albumin (HSA), anti-human serum albumin antibody (HSA-Ab) and a monoclonal antibody to T-cells [T-101]). These experiments showed that stannous and dithionite reduction methods provide for an overall labeling yield of between 5 and 18% with an associated immunoreactivity of 12-40%. The hypophosphorous acid (H3PO2) reduction method, however, yielded no usable radiolabeled product. The preparation of 186Re-DTPA-HSA produced an 18.2% radiochemical yield (7.4 X 10(6) Bq/mg) and 40% retention of binding affinity. Using the stannous or dithionite reduction methods for the radiolabeling of HSA-Ab and T-101 resulted in a relatively low yield (9%), but the labeled product retained binding affinity of 12.25% with Protein A.
Int J Radiat Oncol Biol Phys, 1980
ABSTRACT
Thesis University of Notre Dame 1975 Source Dissertation Abstracts International Volume 35 12 Section B Page 6033, 1975
Cancer, 1998
As a direct result of the use of the absorbed dose unit the 'Gray&#39... more As a direct result of the use of the absorbed dose unit the 'Gray' as the gold standard for predicting response in external beam radiotherapy, the physicist role has been essential to clinical practice for many decades. However, although the dosimetry for internal emitters has proven useful in managing health physics concerns and diagnostic nuclear medicine, the relative success of correlating absorbed dose with response from radionuclide therapy has been limited. This overview presents the relative success and/or failure of model-based dosimetry for radionuclide therapy in comparison to results quoted for external beam therapy dosimetry. Using the standard MIRD formalism for macroscopic dosimetry, the marked non-uniform distribution of radionuclide in both tumor and normal tissue has resulted in limited correlation between computed absorbed dose and biological response in clinical trials. Several efforts are underway aimed at improving this dose-response correlation which include individualized patient specific dosimetry and selected biological parameters. The physicist role in helping the clinician determining which patients will succeed on given radionuclide therapy has been improved with simplified methods such as the assessment of tracer whole body absorbed dose on a per patient basis. The dose-response correlations are now in the moderate range of significance when individualized patient dosimetry is included. These correlations are expected to improve as unified treatment planning programs are instituted and standard methods of clinically based dosimetry are widely accepted and practiced universally.
Journal of Nuclear Medicine, Sep 1, 2006
Loevinger-Berman Award for Excellence in Internal Dosimetry, presented June 4 by the Medical Inte... more Loevinger-Berman Award for Excellence in Internal Dosimetry, presented June 4 by the Medical Internal Radiation Dose (MIRD) Committee at the annual SNM meeting, held in San Diego, CA. The award was established in 1999 in honor of Robert Loevinger, PhD, and Mones Berman, PhD, who formulated the MIRD schema for internal dose calculations. The award is given in recognition of excellence pertaining to the field of internal dosimetry as it relates to nuclear medicine through research and/or development, significant publication contributions, or advancement of the understanding of internal dosimetry in relationship to risk and therapeutic efficacy.
Clinical cancer research : an official journal of the American Association for Cancer Research, 1999
The purpose of this study was to validate an analytical expression for the absorbed-dose calculat... more The purpose of this study was to validate an analytical expression for the absorbed-dose calculation from the spherical source of beta-emitting radionuclides and to apply it to micrometastases treated with radiolabeled monoclonal antibodies. The self-absorbed fractions from I-131 and P-32 uniform spherical sources were calculated using the analytical expression introduced by P. K. Leichner (J. Nucl. Med., 35: 1721-1729, 1994). The calculated absorbed fractions were compared with previously reported values and were found to be in reasonable agreement, with a maximum difference of 15% for smaller masses and a long-range beta emitter. The expression was subsequently applied to estimate the absorbed dose within spheroid models with nonuniform penetration of radiolabeled antibody. The corresponding absorbed dose for I-131 was compared with reported micro-thermoluminescence dosimeter measurements and found to be in good agreement. This work has independently substantiated the methodology ...
Cancer research, 1995
Thresholding is the most widely used organ or tumor segmentation technique used in single photon ... more Thresholding is the most widely used organ or tumor segmentation technique used in single photon emission computed tomography (SPECT) and planar imaging for monoclonal antibodies. Selecting the optimal threshold requires a priori knowledge (volumes from CT or magnetic resonance) for the size and contrast level of the organ in question. Failure to select an optimal threshold leads to overestimation or underestimation of the volume and, subsequently, the organ-absorbed dose value in radio-immunotherapy. To investigate this threshold selection problem, we performed a phantom experiment using six lucite spheres ranging from 1 to 117 ml and filled with a uniform activity of 1 microCi/ml Tc-99m. These spheres were placed at the center and off-center locations of a Jasczsak phantom and scanned with a three-headed gamma camera in SPECT and planar modes. Target-nontarget (T:NT) ratios were changed by adding the appropriate activity to the background. A threshold search algorithm with an inte...
International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1991
Implantable miniature thermoluminescent dosimeters and conventional biodistribution analysis were... more Implantable miniature thermoluminescent dosimeters and conventional biodistribution analysis were used to determine the locally absorbed radiation dose delivered to three morphologically distinct human renal cell carcinoma xenografts (TK-39, TK-82 and TK-177C; N = 87) following a 50 microCi infusion of 131iodine-labeled monoclonal antibody A6H. Xenografts were clearly detected by radioimmuno-scintigraphy. Pronounced differences were noted among the three xenografts in MAb pharmacokinetics and in the locally absorbed irradiation doses which ranged from 2 to 5 cGy per injected microCi of 131iodine-labelled A6H.
International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology, 1986
Rhenium-186 has been theoretically determined to be among the best therapy radiolabels due to its... more Rhenium-186 has been theoretically determined to be among the best therapy radiolabels due to its unique half-life, particulate and gamma emissions and chelation properties. Traditionally, rhenium chelates have been synthesized by the tin reduction method at low pH which frequently produces denaturation of acid labile proteins. A comparative study has been carried out to assess three techniques of reducing 186ReO-4 in order to label biologically active macromolecules (i.e. human serum albumin (HSA), anti-human serum albumin antibody (HSA-Ab) and a monoclonal antibody to T-cells [T-101]). These experiments showed that stannous and dithionite reduction methods provide for an overall labeling yield of between 5 and 18% with an associated immunoreactivity of 12-40%. The hypophosphorous acid (H3PO2) reduction method, however, yielded no usable radiolabeled product. The preparation of 186Re-DTPA-HSA produced an 18.2% radiochemical yield (7.4 X 10(6) Bq/mg) and 40% retention of binding affinity. Using the stannous or dithionite reduction methods for the radiolabeling of HSA-Ab and T-101 resulted in a relatively low yield (9%), but the labeled product retained binding affinity of 12.25% with Protein A.
Seminars in Radiation Oncology, 2000
As more radionuclide therapies move from laboratory feasibility studies into clinical reality, it... more As more radionuclide therapies move from laboratory feasibility studies into clinical reality, it becomes increasingly important for the labeling chemistry to produce consistently a stable radiopharmaceutical that remains intact under the challenge of human catabolism. Similarly, once proof of principle is established to bring a radionuclide conjugate into clinical therapy trials, dosimetric estimates should be made to select the appropriate radionuclide properties, which are based on animalspecific or patient-specific pharmacokinetics and match a set of specific clinical endpoints. These properties may include the radionuclide physical half-life, radiolabeled conjugate biological uptake and clearance, productspecific activity, range and type of emissions, and resultant effects on tumor and normal tissue cellular survival. The immunologist and labeling chemist have now produced a variety of strategies that have potential to increase the therapeutic ratio (tumor-to-normal tissue dose ratio). The advent of normal tissue clearing agents, fragmented or chimerized carriers to improve targeting, and the method of bispecific or two-step and three-step targeting agents has increased the need for realistic modeling of the carrier in vivo to guide prospectively the competitive development of these radiopharmaceuticals. In this article, examples have been taken from the literature to elucidate the benchmark of success that careful experimental design has fostered to bring these agents into clinical practice by creative and logical methodologies.
Neurosurgery, 2005
We report the safety and feasibility of using convection-enhanced delivery to administer Cotara (... more We report the safety and feasibility of using convection-enhanced delivery to administer Cotara (Peregrine Pharmaceuticals, Inc., Tustin, CA), a novel radioimmunotherapeutic agent, to patients with malignant glioma. Between April 1998 and November 2002, 51 patients with histologically confirmed malignant glioma received Cotara by convection-enhanced delivery. Most patients (88%) were treated with Cotara targeting tumor volume-dependent, single or multiple administrations of activity ranging from 0.5 to 3.0 mCi/cm3 of baseline clinical target volume. Two weeks after infusion, single-photon emission computed tomographic imaging determined the spatial distribution of Cotara. Patients were followed for as long as 41 months (average follow-up, 5 mo). Safety was evaluated on the basis of incidence of procedure-related, neurological, and systemic adverse events. Feasibility was evaluated in a subset of patients on the basis of the correlation between the prescribed activity and the actual activity administered to the targeted region. Fifty-one patients, 37 with recurrent glioblastoma multiforme, 8 with newly diagnosed glioblastoma multiforme, and 6 with recurrent anaplastic astrocytomas, were treated. Average tumor volume was 36 +/- 27.6 cm3 (range, 5-168 cm3). Of the 67 infusions, 13 (19%), 52 (78%), and 2 (3%) delivered less than 90%, 100 +/- 10%, and more than 110%, respectively, of the prescribed administered activity to the targeted region. Treatment-emergent, drug-related central nervous system adverse events included brain edema (16%), hemiparesis (14%), and headache (14%). Systemic adverse events were mild. Several patients had objective responses to Cotara. The majority of Cotara infusions delivered between 90 and 110% of the prescribed administered activity to the targeted region. This method of administration has an acceptable safety profile compared with literature reports of other therapeutics delivered by convection-enhanced delivery.
Medical Physics, 1984
An absorbed dose calculation comparison has been computed for radiolabeled tumor associated antib... more An absorbed dose calculation comparison has been computed for radiolabeled tumor associated antibodies distributed over a standard geometry and tumor location. Half-life data, maximum specific activities, and relative organ doses of nine radionuclides, Cu-67, Br-77, Br-82, Y-90, Tc-99m, In-111, I-131, Re-186, and At-211, have been compiled in which the radionuclides were assumed to be coupled with antibody. These nuclides were chosen on the basis of physical characteristics that warranted their inclusion as either imaging or therapy radiolabels. Radionuclide biodistribution data based on current available estimates for antibody uptake and clearance in humans has been adopted. Re-186 and Y-90 have been determined to be among the best therapy radiolabels since they possess sufficiently long half lives necessary for tumor localization, little or no gamma radiation, intermediate beta energy, stable daughter products, and have a reasonable chance to form a stable chelate with an antibody system.
Medical Physics, 1993
Radiolabeled monoclonal antibodies have been used for radioimmunotherapy studies with human tumor... more Radiolabeled monoclonal antibodies have been used for radioimmunotherapy studies with human tumor spheroids and murine and human tumor xenografts in experimental animals. This paper reviews the work that has been performed in these models with different types of cancer, and highlights those papers that have presented dosimetry estimates and attempts to correlate the findings. Radioimmunotherapy studies in multicell spheroids, as a model for micrometastases, have been performed in human neuroblastoma, colon cancer, and melanoma cell lines using 131I-, 125I-, 186Re-, and 212Bi-labeled antibodies. The uniform geometry of the spheroid has allowed radiation dose estimates to be made. Up to three logs of cell kill have been achieved with 131I- and 186Re-specific antibody with minimal toxicity from labeled nonspecific antibody, but 212Bi-antibody had little effect because of its short half-life as shown by Langmuir. It appears that the two most important factors for therapeutic efficacy in this model are good penetration of the radiolabeled antibody and an adequate radionuclide half-life to allow penetration of the immunoconjugate prior to significant radionuclide decay. Radioimmunotherapy studies in animals bearing transplants of colon cancer, leukemia, lymphoma, hepatoma, renal cell carcinoma, neuroblastoma, glioma, mammary carcinoma, small cell lung carcinoma, cervical carcinoma, ovarian carcinoma, and bladder cancer have been performed with 131I, 90Y, 186Re, 153Sm, and 177Lu beta emitting, and 212Bi alpha emitting radionuclides conjugated to monoclonal antibodies. A few studies compared different radionuclides in the same model system. The approaches that have been used in these studies to estimate tumor dosimetry include the MIRD approach, thermoluminescent dosimetry, autoradiography, and comparison to external irradiation. The majority of investigators have estimated the dose to tumor and normal organs using MIRD-based calculations (time-activity curve and equilibrium dose constant method). The range of tumor doses has been between 17 and 11 171 mGy/MBq of administered radioactivity. The effectiveness of radiolabeled monoclonal antibody therapy depends on a number of factors relating to the antibody such as specificity, affinity, and immunoreactivity. The density, location, and heterogeneity of expression of tumor-associated antigen within tumors will affect the localization and therapeutic efficacy of radiolabeled antibodies, as will physiological factors such as the tumor vascularity, blood flow, and permeability. These factors are discussed and examples are presented.(ABSTRACT TRUNCATED AT 400 WORDS)
Journal of Immunotherapy, 1994
International Journal of Radiation Oncology*Biology*Physics, 1989
Growth delay was measured in TK-82 renal cell carcinoma (RCC) xenografts implanted in nude mice r... more Growth delay was measured in TK-82 renal cell carcinoma (RCC) xenografts implanted in nude mice receiving single fraction external beam irradiation (SF-XRT), multifraction external beam irradiation (MF-XRT), or radioimmunotherapy (RIT). Thermoluminescent dosimeter(s) (TLD) and autoradiography were used to ascertain the average absorbed dose delivered and the degree of heterogeneous uptake of radiolabeled antibody for the RIT irradiations. For intravenous administered activities of 100, 200,400, and 600 &i of I-131 labeled A6H antibody, volume doubling times (VDT) and TLD absorbed dose measurements for each administered activity were 7 days (341 cGy), 38 days (383 cGy), 85 days (886 cGy) and no regrowth (1034 cGy), respectively. For SF-XRT irradiations of 500,1000, and 1500 cGy, VDT times were 11,62, and 103 days, respectively. MF-XRT of 4 X 250 cGy over a 2-week period yielded a VDT of 25 days. Marked peripheral activity deposition was noted on most autoradiographs from multiple tumor samples. These data suggest that an equivalent to superior tumor growth delay is obtained for absorbed doses delivered by exponentially decaying low dose rate radioimmunotherapy RIT compared to similar doses of acute dose rate XRT as quantitated by the TLD method.
International Journal of Radiation Oncology*Biology*Physics, 1980
ABSTRACT
Cancer Research, Feb 1, 1990
Progress in animal radioimmunotherapy has been reviewed by high lighting 22 successful experiment... more Progress in animal radioimmunotherapy has been reviewed by high lighting 22 successful experiments using human \enografts in rodent models. Significant tumor growth delay has been observed in all experi ments with five groups reporting tumor control 100 days post-tumor implantation. The radiobiological significance of these experiments is analyzed through a proposed framework for the comparison of radioim munotherapy to external beam therapy in both animals and humans. The limits of applicability of animal modeling to the clinical setting are evaluated in terms of intrinsic radiosensitivity, tumor volume effects, tumor bed effects, and the host defense mechanism. A generalized strat egy for the development of clinical radioimmunotherapy is proposed based on utilization of radioimmunotherapy as a boost therapy in com bination with external beam radiation.
International Journal of Radiation Applications and Instrumentation Part B Nuclear Medicine and Biology, 1986
Rhenium-186 has been theoretically determined to be among the best therapy radiolabels due to its... more Rhenium-186 has been theoretically determined to be among the best therapy radiolabels due to its unique half-life, particulate and gamma emissions and chelation properties. Traditionally, rhenium chelates have been synthesized by the tin reduction method at low pH which frequently produces denaturation of acid labile proteins. A comparative study has been carried out to assess three techniques of reducing 186ReO-4 in order to label biologically active macromolecules (i.e. human serum albumin (HSA), anti-human serum albumin antibody (HSA-Ab) and a monoclonal antibody to T-cells [T-101]). These experiments showed that stannous and dithionite reduction methods provide for an overall labeling yield of between 5 and 18% with an associated immunoreactivity of 12-40%. The hypophosphorous acid (H3PO2) reduction method, however, yielded no usable radiolabeled product. The preparation of 186Re-DTPA-HSA produced an 18.2% radiochemical yield (7.4 X 10(6) Bq/mg) and 40% retention of binding affinity. Using the stannous or dithionite reduction methods for the radiolabeling of HSA-Ab and T-101 resulted in a relatively low yield (9%), but the labeled product retained binding affinity of 12.25% with Protein A.
Int J Radiat Oncol Biol Phys, 1980
ABSTRACT
Thesis University of Notre Dame 1975 Source Dissertation Abstracts International Volume 35 12 Section B Page 6033, 1975
Cancer, 1998
As a direct result of the use of the absorbed dose unit the 'Gray&#39... more As a direct result of the use of the absorbed dose unit the 'Gray' as the gold standard for predicting response in external beam radiotherapy, the physicist role has been essential to clinical practice for many decades. However, although the dosimetry for internal emitters has proven useful in managing health physics concerns and diagnostic nuclear medicine, the relative success of correlating absorbed dose with response from radionuclide therapy has been limited. This overview presents the relative success and/or failure of model-based dosimetry for radionuclide therapy in comparison to results quoted for external beam therapy dosimetry. Using the standard MIRD formalism for macroscopic dosimetry, the marked non-uniform distribution of radionuclide in both tumor and normal tissue has resulted in limited correlation between computed absorbed dose and biological response in clinical trials. Several efforts are underway aimed at improving this dose-response correlation which include individualized patient specific dosimetry and selected biological parameters. The physicist role in helping the clinician determining which patients will succeed on given radionuclide therapy has been improved with simplified methods such as the assessment of tracer whole body absorbed dose on a per patient basis. The dose-response correlations are now in the moderate range of significance when individualized patient dosimetry is included. These correlations are expected to improve as unified treatment planning programs are instituted and standard methods of clinically based dosimetry are widely accepted and practiced universally.
Journal of Nuclear Medicine, Sep 1, 2006
Loevinger-Berman Award for Excellence in Internal Dosimetry, presented June 4 by the Medical Inte... more Loevinger-Berman Award for Excellence in Internal Dosimetry, presented June 4 by the Medical Internal Radiation Dose (MIRD) Committee at the annual SNM meeting, held in San Diego, CA. The award was established in 1999 in honor of Robert Loevinger, PhD, and Mones Berman, PhD, who formulated the MIRD schema for internal dose calculations. The award is given in recognition of excellence pertaining to the field of internal dosimetry as it relates to nuclear medicine through research and/or development, significant publication contributions, or advancement of the understanding of internal dosimetry in relationship to risk and therapeutic efficacy.
Clinical cancer research : an official journal of the American Association for Cancer Research, 1999
The purpose of this study was to validate an analytical expression for the absorbed-dose calculat... more The purpose of this study was to validate an analytical expression for the absorbed-dose calculation from the spherical source of beta-emitting radionuclides and to apply it to micrometastases treated with radiolabeled monoclonal antibodies. The self-absorbed fractions from I-131 and P-32 uniform spherical sources were calculated using the analytical expression introduced by P. K. Leichner (J. Nucl. Med., 35: 1721-1729, 1994). The calculated absorbed fractions were compared with previously reported values and were found to be in reasonable agreement, with a maximum difference of 15% for smaller masses and a long-range beta emitter. The expression was subsequently applied to estimate the absorbed dose within spheroid models with nonuniform penetration of radiolabeled antibody. The corresponding absorbed dose for I-131 was compared with reported micro-thermoluminescence dosimeter measurements and found to be in good agreement. This work has independently substantiated the methodology ...
Cancer research, 1995
Thresholding is the most widely used organ or tumor segmentation technique used in single photon ... more Thresholding is the most widely used organ or tumor segmentation technique used in single photon emission computed tomography (SPECT) and planar imaging for monoclonal antibodies. Selecting the optimal threshold requires a priori knowledge (volumes from CT or magnetic resonance) for the size and contrast level of the organ in question. Failure to select an optimal threshold leads to overestimation or underestimation of the volume and, subsequently, the organ-absorbed dose value in radio-immunotherapy. To investigate this threshold selection problem, we performed a phantom experiment using six lucite spheres ranging from 1 to 117 ml and filled with a uniform activity of 1 microCi/ml Tc-99m. These spheres were placed at the center and off-center locations of a Jasczsak phantom and scanned with a three-headed gamma camera in SPECT and planar modes. Target-nontarget (T:NT) ratios were changed by adding the appropriate activity to the background. A threshold search algorithm with an inte...
International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1991
Implantable miniature thermoluminescent dosimeters and conventional biodistribution analysis were... more Implantable miniature thermoluminescent dosimeters and conventional biodistribution analysis were used to determine the locally absorbed radiation dose delivered to three morphologically distinct human renal cell carcinoma xenografts (TK-39, TK-82 and TK-177C; N = 87) following a 50 microCi infusion of 131iodine-labeled monoclonal antibody A6H. Xenografts were clearly detected by radioimmuno-scintigraphy. Pronounced differences were noted among the three xenografts in MAb pharmacokinetics and in the locally absorbed irradiation doses which ranged from 2 to 5 cGy per injected microCi of 131iodine-labelled A6H.
International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology, 1986
Rhenium-186 has been theoretically determined to be among the best therapy radiolabels due to its... more Rhenium-186 has been theoretically determined to be among the best therapy radiolabels due to its unique half-life, particulate and gamma emissions and chelation properties. Traditionally, rhenium chelates have been synthesized by the tin reduction method at low pH which frequently produces denaturation of acid labile proteins. A comparative study has been carried out to assess three techniques of reducing 186ReO-4 in order to label biologically active macromolecules (i.e. human serum albumin (HSA), anti-human serum albumin antibody (HSA-Ab) and a monoclonal antibody to T-cells [T-101]). These experiments showed that stannous and dithionite reduction methods provide for an overall labeling yield of between 5 and 18% with an associated immunoreactivity of 12-40%. The hypophosphorous acid (H3PO2) reduction method, however, yielded no usable radiolabeled product. The preparation of 186Re-DTPA-HSA produced an 18.2% radiochemical yield (7.4 X 10(6) Bq/mg) and 40% retention of binding affinity. Using the stannous or dithionite reduction methods for the radiolabeling of HSA-Ab and T-101 resulted in a relatively low yield (9%), but the labeled product retained binding affinity of 12.25% with Protein A.
Seminars in Radiation Oncology, 2000
As more radionuclide therapies move from laboratory feasibility studies into clinical reality, it... more As more radionuclide therapies move from laboratory feasibility studies into clinical reality, it becomes increasingly important for the labeling chemistry to produce consistently a stable radiopharmaceutical that remains intact under the challenge of human catabolism. Similarly, once proof of principle is established to bring a radionuclide conjugate into clinical therapy trials, dosimetric estimates should be made to select the appropriate radionuclide properties, which are based on animalspecific or patient-specific pharmacokinetics and match a set of specific clinical endpoints. These properties may include the radionuclide physical half-life, radiolabeled conjugate biological uptake and clearance, productspecific activity, range and type of emissions, and resultant effects on tumor and normal tissue cellular survival. The immunologist and labeling chemist have now produced a variety of strategies that have potential to increase the therapeutic ratio (tumor-to-normal tissue dose ratio). The advent of normal tissue clearing agents, fragmented or chimerized carriers to improve targeting, and the method of bispecific or two-step and three-step targeting agents has increased the need for realistic modeling of the carrier in vivo to guide prospectively the competitive development of these radiopharmaceuticals. In this article, examples have been taken from the literature to elucidate the benchmark of success that careful experimental design has fostered to bring these agents into clinical practice by creative and logical methodologies.
Neurosurgery, 2005
We report the safety and feasibility of using convection-enhanced delivery to administer Cotara (... more We report the safety and feasibility of using convection-enhanced delivery to administer Cotara (Peregrine Pharmaceuticals, Inc., Tustin, CA), a novel radioimmunotherapeutic agent, to patients with malignant glioma. Between April 1998 and November 2002, 51 patients with histologically confirmed malignant glioma received Cotara by convection-enhanced delivery. Most patients (88%) were treated with Cotara targeting tumor volume-dependent, single or multiple administrations of activity ranging from 0.5 to 3.0 mCi/cm3 of baseline clinical target volume. Two weeks after infusion, single-photon emission computed tomographic imaging determined the spatial distribution of Cotara. Patients were followed for as long as 41 months (average follow-up, 5 mo). Safety was evaluated on the basis of incidence of procedure-related, neurological, and systemic adverse events. Feasibility was evaluated in a subset of patients on the basis of the correlation between the prescribed activity and the actual activity administered to the targeted region. Fifty-one patients, 37 with recurrent glioblastoma multiforme, 8 with newly diagnosed glioblastoma multiforme, and 6 with recurrent anaplastic astrocytomas, were treated. Average tumor volume was 36 +/- 27.6 cm3 (range, 5-168 cm3). Of the 67 infusions, 13 (19%), 52 (78%), and 2 (3%) delivered less than 90%, 100 +/- 10%, and more than 110%, respectively, of the prescribed administered activity to the targeted region. Treatment-emergent, drug-related central nervous system adverse events included brain edema (16%), hemiparesis (14%), and headache (14%). Systemic adverse events were mild. Several patients had objective responses to Cotara. The majority of Cotara infusions delivered between 90 and 110% of the prescribed administered activity to the targeted region. This method of administration has an acceptable safety profile compared with literature reports of other therapeutics delivered by convection-enhanced delivery.
Medical Physics, 1984
An absorbed dose calculation comparison has been computed for radiolabeled tumor associated antib... more An absorbed dose calculation comparison has been computed for radiolabeled tumor associated antibodies distributed over a standard geometry and tumor location. Half-life data, maximum specific activities, and relative organ doses of nine radionuclides, Cu-67, Br-77, Br-82, Y-90, Tc-99m, In-111, I-131, Re-186, and At-211, have been compiled in which the radionuclides were assumed to be coupled with antibody. These nuclides were chosen on the basis of physical characteristics that warranted their inclusion as either imaging or therapy radiolabels. Radionuclide biodistribution data based on current available estimates for antibody uptake and clearance in humans has been adopted. Re-186 and Y-90 have been determined to be among the best therapy radiolabels since they possess sufficiently long half lives necessary for tumor localization, little or no gamma radiation, intermediate beta energy, stable daughter products, and have a reasonable chance to form a stable chelate with an antibody system.
Medical Physics, 1993
Radiolabeled monoclonal antibodies have been used for radioimmunotherapy studies with human tumor... more Radiolabeled monoclonal antibodies have been used for radioimmunotherapy studies with human tumor spheroids and murine and human tumor xenografts in experimental animals. This paper reviews the work that has been performed in these models with different types of cancer, and highlights those papers that have presented dosimetry estimates and attempts to correlate the findings. Radioimmunotherapy studies in multicell spheroids, as a model for micrometastases, have been performed in human neuroblastoma, colon cancer, and melanoma cell lines using 131I-, 125I-, 186Re-, and 212Bi-labeled antibodies. The uniform geometry of the spheroid has allowed radiation dose estimates to be made. Up to three logs of cell kill have been achieved with 131I- and 186Re-specific antibody with minimal toxicity from labeled nonspecific antibody, but 212Bi-antibody had little effect because of its short half-life as shown by Langmuir. It appears that the two most important factors for therapeutic efficacy in this model are good penetration of the radiolabeled antibody and an adequate radionuclide half-life to allow penetration of the immunoconjugate prior to significant radionuclide decay. Radioimmunotherapy studies in animals bearing transplants of colon cancer, leukemia, lymphoma, hepatoma, renal cell carcinoma, neuroblastoma, glioma, mammary carcinoma, small cell lung carcinoma, cervical carcinoma, ovarian carcinoma, and bladder cancer have been performed with 131I, 90Y, 186Re, 153Sm, and 177Lu beta emitting, and 212Bi alpha emitting radionuclides conjugated to monoclonal antibodies. A few studies compared different radionuclides in the same model system. The approaches that have been used in these studies to estimate tumor dosimetry include the MIRD approach, thermoluminescent dosimetry, autoradiography, and comparison to external irradiation. The majority of investigators have estimated the dose to tumor and normal organs using MIRD-based calculations (time-activity curve and equilibrium dose constant method). The range of tumor doses has been between 17 and 11 171 mGy/MBq of administered radioactivity. The effectiveness of radiolabeled monoclonal antibody therapy depends on a number of factors relating to the antibody such as specificity, affinity, and immunoreactivity. The density, location, and heterogeneity of expression of tumor-associated antigen within tumors will affect the localization and therapeutic efficacy of radiolabeled antibodies, as will physiological factors such as the tumor vascularity, blood flow, and permeability. These factors are discussed and examples are presented.(ABSTRACT TRUNCATED AT 400 WORDS)
Journal of Immunotherapy, 1994
International Journal of Radiation Oncology*Biology*Physics, 1989
Growth delay was measured in TK-82 renal cell carcinoma (RCC) xenografts implanted in nude mice r... more Growth delay was measured in TK-82 renal cell carcinoma (RCC) xenografts implanted in nude mice receiving single fraction external beam irradiation (SF-XRT), multifraction external beam irradiation (MF-XRT), or radioimmunotherapy (RIT). Thermoluminescent dosimeter(s) (TLD) and autoradiography were used to ascertain the average absorbed dose delivered and the degree of heterogeneous uptake of radiolabeled antibody for the RIT irradiations. For intravenous administered activities of 100, 200,400, and 600 &i of I-131 labeled A6H antibody, volume doubling times (VDT) and TLD absorbed dose measurements for each administered activity were 7 days (341 cGy), 38 days (383 cGy), 85 days (886 cGy) and no regrowth (1034 cGy), respectively. For SF-XRT irradiations of 500,1000, and 1500 cGy, VDT times were 11,62, and 103 days, respectively. MF-XRT of 4 X 250 cGy over a 2-week period yielded a VDT of 25 days. Marked peripheral activity deposition was noted on most autoradiographs from multiple tumor samples. These data suggest that an equivalent to superior tumor growth delay is obtained for absorbed doses delivered by exponentially decaying low dose rate radioimmunotherapy RIT compared to similar doses of acute dose rate XRT as quantitated by the TLD method.
International Journal of Radiation Oncology*Biology*Physics, 1980
ABSTRACT