Neil A. Petry

Radioimmunotherapy of B-Cell Lymphoma with [131I]Anti-B1 (Anti-CD20) Antibody

BACKGROUND Many patients with non-Hodgkins lymphomas are not cured by current therapies, and new approaches to treatment are needed. As part of an ongoing phase 1 study, we examined the effect of radioimmunotherapy with 131I-labeled B-cell-specific anti-CD20 monoclonal antibody in 10 patients with CD20-positive B-cell lymphomas in whom primary chemotherapy had failed. METHODS AND RESULTS Anti-B1 (anti-CD20) mouse monoclonal antibody trace-labeled with 131I (15 mg containing 5 mCi) was given intravenously at approximately one-week intervals: first, without pretreatment with unlabeled anti-B1 antibody, to all 10 patients; then, with pretreatment with 135 mg of unlabeled antibody, to 8 patients; and then, with pretreatment with 685 mg, to 2 patients. Serial quantitative gamma-camera images and measures of whole-body radioactivity were obtained after each tracer dose. All known disease sites larger than 2 cm could be imaged. The effect of a pretreatment dose of unlabeled anti-B1 antibody on targeting of the tumor with the radiolabeled antibody was variable. The pretreatment dose of unlabeled antibody that produced the highest ratio of the tumor dose to the whole-body dose in tracer studies was then used to deliver higher doses of radioactivity for radioimmunotherapy in nine patients. Three patients received doses designed to deliver 25 cGy to the whole body (two patients treated twice, six to eight weeks apart), four patients received 35 cGy (one patient treated twice), and two patients received 45 cGy (one patient treated twice); each dose contained 34 to 66 mCi of activity. Six of the nine treated patients had tumor responses, including patients with bulky or chemotherapy-resistant disease: four patients had complete remissions, and two had partial responses. Three patients had objective responses to tracer infusions before they received radioimmunotherapeutic doses. Of the four patients with complete remissions, one remained in remission for eight months and the other three continue to have no disease progression (for 11, 9, and 8 months). There was mild or no myelosuppression. CONCLUSIONS Radioimmunotherapy with [131I]anti-B1 antibody is a promising new treatment for lymphoma.

Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors

The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused (123)I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses <or=100 ng/ml. CED has significant potential for enhancing delivery of therapeutic macromolecules throughout the human brain. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients.

Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: Descriptive effects of target anatomy and catheter positioning

OBJECTIVE Convection-enhanced delivery (CED) holds tremendous potential for drug delivery to the brain. However, little is known about the volume of distribution achieved within human brain tissue or how target anatomy and catheter positioning influence drug distribution. The primary objective of this study was to quantitatively describe the distribution of a high molecular weight agent by CED relative to target anatomy and catheter position in patients with malignant gliomas. METHODS Seven adult patients with recurrent malignant gliomas underwent intracerebral infusion of the tumor-targeted cytotoxin, cintredekin besudotox, concurrently with 123I-labeled human serum albumin. High-resolution single-photon emission computed tomographic images were obtained at 24 and 48 hours and were coregistered with magnetic resonance imaging scans. The distribution of 123I-labeled human serum albumin relative to target anatomy and catheter position was analyzed. RESULTS Intracerebral CED infusions were well-tolerated and some resulted in a broad distribution of 123I-labeled human serum albumin, but target anatomy and catheter positioning had a significant influence on infusate distribution even within non-contrast-enhancing areas of brain. Intratumoral infusions were anisotropic and resulted in limited coverage of the enhancing tumor area and adjacent peritumoral regions. CONCLUSIONS CED has the potential to deliver high molecular weight agents into tumor-infiltrated brain parenchyma with volumes of distribution that are clinically relevant. Target tissue anatomy and catheter position are critical parameters in optimizing drug delivery.

First-in-Man Evaluation of 2 High-Affinity PSMA-Avid Small Molecules for Imaging Prostate Cancer

This phase 1 study was performed to determine the pharmacokinetics and ability to visualize prostate cancer in bone, soft-tissue, and the prostate gland using 123I-MIP-1072 and 123I-MIP-1095, novel radiolabeled small molecules targeting prostate-specific membrane antigen. Methods: Seven patients with a documented history of prostate cancer by histopathology or radiologic evidence of metastatic disease were intravenously administered 370 MBq (10 mCi) of 123I-MIP-1072 and 123I-MIP-1095 2 wk apart in a crossover trial design. 123I-MIP-1072 was also studied in 6 healthy volunteers. Whole-body planar and SPECT/CT imaging was performed and pharmacokinetics studied over 2–3 d. Target-to-background ratios were calculated. Absorbed radiation doses were estimated using OLINDA/EXM. Results: 123I-MIP-1072 and 123I-MIP-1095 visualized lesions in soft tissue, bone, and the prostate gland within 0.5–1 h after injection, with retention beyond 48 h. Target-to-background ratios from planar images averaged 2:1 at 1 h, 3:1 at 4–24 h, and greater than 10:1 at 4 and 24 h for SPECT/CT. Both agents cleared the blood in a biphasic manner; clearance of 123I-MIP-1072 was approximately 5 times faster. 123I-MIP-1072 was excreted in the urine, with 54% and 74% present by 24 and 72 h, respectively. In contrast, only 7% and 20% of 123I-MIP-1095 had been renally excreted by 24 and 72 h, respectively. Estimated absorbed radiation doses were 0.054 versus 0.110 mGy/MBq for the kidneys and 0.024 versus 0.058 mGy/MBq for the liver, for 123I-MIP-1072 and 123I-MIP-1095, respectively. Conclusion: 123I-MIP-1072 and 123I-MIP-1095 detect lesions in soft tissue, bone, and the prostate gland at as early as 1–4 h. These novel radiolabeled small molecules have excellent pharmacokinetic and pharmacodynamic profiles and warrant further development as diagnostic and potentially when labeled with 131I therapeutic radiopharmaceuticals.

Colocalization of Gadolinium-Diethylene Triamine Pentaacetic Acid With High-Molecular-Weight Molecules After Intracerebral Convection-Enhanced Delivery in Humans

BACKGROUND:Convection-enhanced delivery (CED) permits site-specific therapeutic drug delivery within interstitial spaces at increased dosages through circumvention of the blood-brain barrier. CED is currently limited by suboptimal methodologies for monitoring the delivery of therapeutic agents that would permit technical optimization and enhanced therapeutic efficacy. OBJECTIVE:To determine whether a readily available small-molecule MRI contrast agent, gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA), could effectively track the distribution of larger therapeutic agents. METHODS:Gd-DTPA was coinfused with the larger molecular tracer, 124I-labeled human serum albumin (124I-HSA), during CED of an EGFRvIII-specific immunotoxin as part of treatment for a patient with glioblastoma. RESULTS:Infusion of both tracers was safe in this patient. Analysis of both Gd-DTPA and 124I-HSA during and after infusion revealed a high degree of anatomical and volumetric overlap. CONCLUSION:Gd-DTPA may be able to accurately demonstrate the anatomic and volumetric distribution of large molecules used for antitumor therapy with high resolution and in combination with fluid-attenuated inversion recovery (FLAIR) imaging, and provide additional information about leaks into cerebrospinal fluid spaces and resection cavities. Similar studies should be performed in additional patients to validate our findings and help refine the methodologies we used.

Comparison of technetium-99m sestamibi and thallium-201 retention characteristics in canine myocardium

OBJECTIVES The aim of this study was to compare the myocardial retention of technetium-99m (Tc-99m) sestamibi and thallium-201 over a wide range of blood flow at different time points after tracer injection. BACKGROUND Technetium-99m sestamibi has been proposed as a new perfusion tracer with better physical characteristics than those of thallium-201 for scintigraphic imaging. However, no studies have simultaneously compared the ability of both tracers to assess myocardial blood flow during pharmacologic vasodilation. METHODS The myocardial retention of Tc-99m sestamibi and thallium-201 were compared over a wide range of blood flow induced by regional coronary occlusion and dipyridamole infusion in an open chest dog model. Myocardial retention of both tracers was determined by in vitro tissue counting at 2, 5, and 20 min after tracer injection and was correlated with microsphere-determined blood flow. RESULTS Thallium-201 demonstrated greater absolute tissue retention than did Tc-99m sestamibi. At 2 min after tracer injection, there was an almost linear relation between the retention of both tracers and myocardial blood flow over a wide flow range. However, this relation was not maintained over time. At 20 min after injection, the retention of both tracers underestimated myocardial blood flow at higher flow rates. At 2, 5 and 20 min after injection, increments of relative tracer retention between the different levels of flow were always greater for thallium-201 than for Tc-99m sestamibi. CONCLUSIONS Thallium-201 displays more suitable physiologic characteristics as a flow tracer and may allow better differentiation of myocardial regions with different levels of coronary flow reserve. For both tracers, early cardiac imaging may minimize underestimation of blood flow at higher flow rates.

The relationship between myocardial retention of technetium-99m teboroxime and myocardial blood flow

OBJECTIVES The aim of this study was to define the temporal changes in the relationship between technetium-99m teboroxime tissue retention and myocardial blood flow in a canine model. BACKGROUND Technetium-99m teboroxime is a new neutral lipophilic myocardial perfusion agent. It is known to be highly extracted by the myocardium but to have a rapid clearance rate. METHODS A wide range of myocardial blood flow was induced in each experiment by regional coronary occlusion and dipyridamole infusion. Myocardial retention of technetium-99m teboroxime was determined by in vitro tissue counting at 1, 2 or 5 min after injection of the tracer. Tracer retention was correlated with microsphere-determined blood flow and the data were fitted to nonlinear functions. RESULTS Correlation coefficients for these functions were 0.92, 0.95 and 0.95 at 1, 2, and 5 min, respectively. At 1 min after injection, the relationship of technetium-99m teboroxime retention to blood flow was linear over a wide flow range, becoming nonlinear at flow rates greater than 4.5 ml/min per g. After 5 min the retention-flow relationship was linear only to 2.5 ml/min per g, above which little change in retention was noted. Normalized myocardial retention, expressed as a percent of the retention at 1 ml/min per g, was also calculated. At flow rates of 1, 2, 3, 4 and 5 ml/min per g, normalized retention was 100, 169, 228, 277 and 317% at 1 min and 100, 171, 217, 239 and 237% at 5 min after injection. CONCLUSIONS At 1 min after injection, the relationship of technetium-99m teboroxime myocardial retention to blood flow is well maintained over a wide range of flow. However, after only 5 min, tracer retention underestimates flow changes at moderate and high flow rates. Thus, rapid acquisition protocols are necessary to fully exploit the potential of this promising new tracer in the evaluation of myocardial perfusion.

PET of hypoxia and perfusion with 62Cu-ATSM and 62Cu-PTSM using a 62Zn/62Cu generator.

OBJECTIVE Copper-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) and copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) are being studied as potential markers of hypoxia and perfusion, respectively. The use of short-lived radionuclides (e.g., 62Cu) has advantages for clinical PET, including a lower radiation dose than long-lived radionuclides and serial imaging capability. A 62Zn/62Cu microgenerator and rapid synthesis kits now provide a practical means of producing 62Cu-PTSM and 62Cu-ATSM on-site. Tumors can be characterized with 62Cu-PTSM, 62Cu-ATSM, and 18F-FDG PET scans during one session. We present the initial clinical data in two patients with lung neoplasms. CONCLUSION Hypoxia and perfusion are important parameters in tumor physiology and can have major implications in diagnosis, prognosis, treatment planning, and response to therapy. We have shown the feasibility of performing 62Cu-ATSM and 62Cu-PTSM PET together with FDG PET/CT during a single imaging session to provide information on both perfusion and hypoxia and tumor anatomy and metabolism.

A Tracer Dose of Technetium-99m–Labeled Liposomes Can Estimate the Effect of Hyperthermia on Intratumoral Doxil Extravasation

Purpose: A noninvasive method to monitor intratumoral Doxil delivery in individual patients during targeted tumor therapy is important to predict treatment response. The purpose of this study was to determine if a small tracer dose of technetium-99m (99mTc)–labeled liposomes could be used to quantify the effect of local hyperthermia on intratumoral Doxil extravasation. Experimental Design: Experiments were carried out in a rat fibrosarcoma model with transplanted thigh tumors. Liposomes of approximately same size and composition as Doxil were radiolabeled using [technetium-99m (99mTc)]exametazime. Eight treatment groups received either Doxil, a tracer dose or a large dose of 99mTc-labeled liposomes, or a combination of tracer and Doxil, with or without hyperthermia. This design was chosen to assure that coadministration of both liposomal formulations did not influence their intratumoral distribution. Hyperthermia was done for 45 minutes. Scintigraphic images were obtained at 5 and 18 hours. At 18 hours, tumors were removed and gamma counts as well as doxorubicin concentrations were measured. Results: Intratumoral extravasation of the 99mTc-labeled tracer could be imaged scintigraphically under normothermic and hyperthermic conditions. The thermal enhancement ratio was slightly higher for radiolabeled liposomes than for doxorubicin concentration. However, there was a significant positive correlation of intratumoral doxorubicin concentration and intratumoral uptake of the radiolabeled tracer (expressed as percentage of the injected dose per gram of tissue). Coadministration of radiolabeled liposomes did not negatively influence the amount of drug delivered with Doxil. Conclusions: The use of a radiolabeled tracer has potential value to monitor drug delivery and estimate the effect of an intervention aimed to increase liposomal accumulation, such as local hyperthermia.

Platelet reactivity in human aortic grafts: A prospective, randomized midterm study of platelet adherence and release products in Dacron and polytetrafluoroethylene conduits

Platelet-related phenomena at the blood-surface interface of randomly placed knitted Dacron (n = 6) and polytetrafluoroethylene (ePTFE) (n = 6) interposition aortic grafts were studied in patients undergoing abdominal aortic aneurysmectomy. Luminal accumulation of platelets was assessed by infusing indium-111-oxine (400 microCi) labeled autologous platelets and imaging grafts at 1 week, 3 months, and 6 months after surgery. Image analysis included an indium ratio technique (comparing aortic graft radioactivity to that of an iliac artery) and a red blood cell technetium subtraction technique (excluding blood pool radioactivity from graft radioactivity, with the heart or iliac artery serving as reference regions). Plasma levels of beta-thromboglobulin and platelet factor 4 were correlated with platelet accumulations on the aortic prostheses. Differences in graft radioactivity or platelet-release products were not evident 1 week after surgery. Three months after implantation, Dacron and ePTFE conduits exhibited 87% and 47% (p less than 0.05) more radioactivity with the indium ratio technique than the iliac artery. Similarly, increased Dacron compared with ePTFE graft radioactivity was noted using technetium subtraction techniques: 71% vs 30% with a heart reference and 26% vs 11% with an iliac artery reference, respectively. Increases in graft radioactivity correlated with increases in both plasma beta-thromboglobulin and platelet factor 4 at 3 months (r = 0.6 to 0.9; p less than 0.05 to 0.001 depending on the imaging technique used). At 6 months, differences did not persist. In fact, technetium subtraction techniques suggested less Dacron conduit reactivity. It is speculated that differences in platelet accumulation and activation associated with different graft substrates may prove clinically important.