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Background-Evaluation of novel cellular therapies in large-animal models and patients is currently hampered by the lack of imaging approaches that allow for long-term monitoring of viable transplanted cells. In this study, sodium iodide symporter (NIS) transgene imaging was evaluated as an approach to follow in vivo survival, engraftment, and distribution of human-induced pluripotent stem cell (hiPSC) derivatives in a pig model of myocardial infarction. Methods and Results-Transgenic hiPSC lines stably expressing a fluorescent reporter and NIS (NIS pos -hiPSCs) were established. Iodide uptake, efflux, and viability of NIS pos -hiPSCs were assessed in vitro. Ten (Ϯ2) days after induction of myocardial infarction by transient occlusion of the left anterior descending artery, catheter-based intramyocardial injection of NIS pos -hiPSCs guided by 3-dimensional NOGA mapping was performed. Dual-isotope single photon emission computed tomographic/computed tomographic imaging was applied with the use of 123 I to follow donor cell survival and distribution and with the use of 99m TC-tetrofosmin for perfusion imaging. In vitro, iodide uptake in NIS pos -hiPSCs was increased 100-fold above that of nontransgenic controls. In vivo, viable NIS pos -hiPSCs could be visualized for up to 15 weeks. Immunohistochemistry demonstrated that hiPSC-derived endothelial cells contributed to vascularization. Up to 12 to 15 weeks after transplantation, no teratomas were detected. S tem cell-based therapies are being actively explored as a potentially innovative therapeutic strategy for various genetic and acquired diseases. Recently, the possibility of reprogramming human somatic cells into human-induced pluripotent stem cells (hiPSCs) that are able to differentiate into all cell lineages present in the heart 1-4 has opened novel opportunities for myocardial repair. With respect to the potential therapeutic application of pluripotent stem cell derivatives, major progress Conclusions-This Editorial see p 388 Clinical Perspective on p 439However, there are still major hurdles and risks to overcome with regard to PSC-based heart repair. These include safety risks, especially the potential of teratoma and tumor formation, 2 low cell retention and engraftment rates, 8 -11 and the general question of whether engraftment of hiPSCs after simple intramyocardial cell injection leads to formation of functional tissue, such as de novo vasculature or myocardium, and results in significant clinical benefits. 12 Although some of these issues can be addressed in vitro or in appropriate small-animal models, others will require exploration in large-animal models, which are more similar to humans. 13 Transplanted human cardiomyocytes, for example, are unlikely to fully functionally integrate with rodent myocardium because of highly dissimilar beating rates. 11 Therefore, meaningful assessment of human cells for heart repair must be demonstrated in large-animal models such as dogs, pigs, or monkeys. 13 Clearly, advanced imaging technologies allowing for l...

Purpose: We examined the tumor-targeting and therapeutic effects of 67 Cu-labeled single amino acid mutant forms of anti-L1 monoclonal antibody chCE7 in nude mice with orthotopically implanted SKOV3ip human ovarian carcinoma cells. Experimental Design: For radioimmunotherapy, chCE7 antibodies with a mutation of histidine 310 to alanine (chCE7H310A) and a mutation of asparagine 297 to glutamine (chCE7agl) were generated to achieve more rapid blood clearance. Biodistributions of Cu-chCE7agl alone on tumor reduction and survival were investigated. In addition, a combination of low-dose 67 Cu-radioimmunotherapy with unlabeled anti-L1 antibody L1-11A on survival was investigated. Results:67 Cu-CPTA-chCE7agl showed high (up to 49% ID/g) and persistent (up to 168 h) uptake in SKOV3ip metastases, with low levels in normal tissues. Cu-radioimmunotherapy, thereby increasing the efficiency of antibody treatment of metastatic ovarian carcinoma.

The folate receptor alpha (FR) is expressed in a variety of gynecological cancer types. It has been widely used for tumor targeting with folic acid conjugates of diagnostic and therapeutic probes. The cervical KB tumor cells have evolved as the standard model for preclinical investigations of folate-based (radio) conjugates. In this study, a panel of FR-expressing human cancer cell lines—including cervical (HeLa, KB, KB-V1), ovarian (IGROV-1, SKOV-3, SKOV-3.ip), choriocarcinoma (JAR, BeWo) and endometrial (EFE-184) tumor cells—was investigated in vitro and for their ability to grow as xenografts in mice. FR-expression levels were compared in vitro and in vivo and the cell lines were characterized by determination of the sensitivity towards commonly-used chemotherapeutics and the expression of two additional, relevant tumor markers, HER2 and L1-CAM. It was found that, besides KB cells, its multiresistant KB-V1 subclone as well as the ovarian cancer cell lines, IGROV-1 and SKOV-3.ip, could be used as potentially more relevant preclinical models. They would allow addressing specific questions such as the therapeutic efficacy of FR-targeting agents in tumor (mouse) models of multi-resistance and in mouse models of metastases formation.

Our study is the first to show that anti-L1CAM (161)Tb RIT is more effective compared to (177)Lu RIT in ovarian cancer xenografts. These results suggest that (161)Tb is a promising candidate for future clinical applications in combination with internalising antibodies.

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The L1‐cell adhesion molecule (L1‐CAM) is highly expressed in various cancer types including ovarian carcinoma but is absent from most normal tissue. A chimeric monoclonal antibody, chCE7, specifically binds to human L1‐CAM and exhibits anti‐proliferative effects on L1‐CAM‐expressing tumor cells. The goal of this study was to evaluate the efficacy of a novel 177Lu‐chCE7 radioimmunotherapeutic agent and to compare it to a treatment protocol with unlabeled, growth‐inhibiting chCE7 in a mouse xenograft model of disseminated ovarian cancer. chCE7agl, an aglycosylated IgG1 variant with improved pharmacokinetics, was conjugated with 1,4,7,10‐tetraazacyclododecane‐N‐N′‐N′‐N‴‐tetraacetic acid (DOTA) and labeled with the low‐energy β‐emitter 177Lu. Tumor growth and survival were assessed after a single i.v. dose of 8 MBq (60 μg) radioimmunoconjugate in nude mice bearing either subcutaneous or intraperitoneal SKOV3.ip1 human ovarian cancer tumors. Therapeutic efficacy was compared with three times weekly i.p. administration of 10 mg/kg unconjugated chCE7. In vivo analysis of 177Lu‐chCE7agl biodistribution demonstrated high and specific accumulation of radioactivity at the tumor site with maximal tumor uptake of up to 48.0 ± 8.1% ID/g at 168 h postinjection. A single treatment with 177Lu‐DOTA‐chCE7agl caused significant retardation of tumor growth and prolonged median survival from 33 to 71 days, while administration of a nontargeted 177Lu‐immunoconjugate had no beneficial effect. Three times weekly i.p. application of unlabeled chCE7 10 mg/kg similarly increased survival from 44 to 72 days. We conclude that a single dose of 177Lu‐DOTA‐chCE7agl is as effective as repeated administration of nonradioactive chCE7 for treatment of small intraperitoneal tumors expressing L1‐CAM.