ganglioside--gd2 and Bone-Neoplasms

Novel therapies to treat patients with solid cancers that have developed resistance to chemotherapy represent unmet needs of considerable dimensions. In the present review, we will address the attempts to develop chimeric antigen receptor (CAR) targeted immunotherapy against osteosarcoma (OS). This aggressive cancer displays its peak incidence in children and young adults. The main cause of patient death is lung metastases with a 5-year survival as low as 5%-10% in the primary metastatic setting and 30% in the relapse situation, respectively. Effective adjuvant combination chemotherapy introduced more than 40 years ago improved the survival rates from below 20% to around 60% in patients; however, since then, no major breakthroughs have been made. The use of immune checkpoint inhibitors has been disappointing in OS, while other types of immunotherapies such as CAR T cells remain largely unexplored. Indeed, for CAR T-cell therapy to be efficacious, two main criteria need to be fulfilled: (a) CAR T cells should target an epitope selectively expressed on the cell surface of OS in order to prevent toxicities in normal tissues and (b) the target should also be widely expressed on OS metastases. These challenges have already been undertaken in OS and illustrate the difficulties in developing tomorrow's CAR-T treatment in a solid tumour. We will discuss the experiences with CAR-T therapy development and efficacy to combat the clinical challenges in OS.

Topics: Bone Neoplasms; Cancer-Associated Fibroblasts; Endopeptidases; Gangliosides; Gelatinases; Humans; Immunotherapy, Adoptive; Membrane Proteins; Osteosarcoma; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Interleukin-11; Serine Endopeptidases; Tumor Microenvironment

Anti-G(D2) murine antibody 3F8 plus subcutaneously (sc) administered granulocyte-macrophage colony-stimulating factor (GM-CSF) was used against primary refractory neuroblastoma in metastatic osteomedullary sites. Large study size and long follow-up allowed assessment of prognostic factors in a multivariate analysis not reported with other anti-G(D2) antibodies. In a phase II trial, 79 patients without prior progressive disease were treated for persistent osteomedullary neuroblastoma documented by histology and/or metaiodobenzyl-guanidine (MIBG) scan. In the absence of human antimouse antibody, 3F8 + scGM-CSF cycles were repeated up to 24 months. Minimal residual disease (MRD) in bone marrow was measured by quantitative reverse transcription-polymerase chain reaction pre-enrollment and post-cycle #2, before initiation of 13-cis-retinoic acid. Study endpoints were: (i) progression-free survival (PFS) compared with the predecessor trial of 3F8 plus intravenously administered (iv) GM-CSF (26 patients) and (ii) impact of MRD on PFS. Using all 105 patients from the two consecutive 3F8 + GM-CSF trials, prognostic factors were analyzed by multivariate Cox regression model. Complete response rates to 3F8 + scGM-CSF were 87% by histology and 38% by MIBG. Five-year PFS was 24 ± 6%, which was significantly superior to 11 ± 7% with 3F8 + ivGM-CSF (p = 0.002). In the multivariate analysis, significantly better PFS was associated with R/R or H/R FCGR2A polymorphism, sc route of GM-CSF and early MRD response. MYCN amplification was not prognostic. Complement consumption was similar with either route of GM-CSF. Toxicities were manageable, allowing outpatient treatment. 3F8 + scGM-CSF is highly active against chemoresistant osteomedullary neuroblastoma. MRD response may be an indicator of tumor sensitivity to anti-G(D2) immunotherapy. Correlative studies highlight the antineoplastic potency of myeloid effectors.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Gangliosides; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunoglobulin G; Infant; Isotretinoin; Male; Myeloid Cells; Neoplasm Staging; Neoplasm, Residual; Neuroblastoma; Prognosis; Survival Rate; Young Adult

Pain can hinder immunotherapy with anti-G(D2) monoclonal antibodies (MoAbs) like 3F8. Heat-modified 3F8 (HM3F8) lacks effector functions and could mask G(D2) or cross-reactive epitopes on nerves, thereby preventing a subsequent dose of unmodified 3F8 from activating pain fibers. We hypothesized that 3F8 dose escalation is possible without increased analgesic requirements in patients pretreated with HM3F8.. Thirty patients with resistant neuroblastoma (NB) received one to two cycles of 3F8 plus granulocyte-macrophage colony-stimulating factor. 3F8 dosing began at 20 mg/m(2)/d and increased by 20 mg/m(2)/d in the absence of dose-limiting toxicity (DLT). Premedication included analgesics, antihistamines, and 5-minute infusions of HM3F8. On the basis of experience with 3F8 10 mg/m(2)/d in prior protocols, the DLT of pain was defined as more than seven doses of opioids administered within 2 hours. Opioid use was compared with a contemporary control group treated with 3F8 20 mg/m(2)/d but no HM3F8. Disease response was assessed.. Treatment was administered in the outpatient setting. Dose escalation stopped at 160 mg/m(2)/d because of drug supply limitations; even through this dosage level, analgesic requirements were similar to historical controls, and there were no DLTs. Analgesic requirements at 3F8 dosage levels through 80 mg/m(2)/d were significantly less compared with controls. Anti-NB activity occurred at all dosages.. Multifold dose escalation of 3F8 is feasible. The findings can be interpreted as compatible with the possibility that HM3F8 can modify toxicity without blunting anti-NB activity. This pain control strategy may help achieve dose escalation with other anti-G(D2) MoAbs.

Topics: Adolescent; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Bone Marrow Neoplasms; Bone Neoplasms; Child; Child, Preschool; Dose-Response Relationship, Immunologic; Female; Gangliosides; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunotherapy; Infant; Male; Maximum Tolerated Dose; Neuroblastoma; Prospective Studies; Survival Rate; Treatment Outcome

We generated MHC-independent chimeric antigen receptors (CARs) directed to the GD2 antigen expressed by neuroblastoma tumor cells and treated patients with this disease. Two distinguishable forms of this CAR were expressed in EBV-specific cytotoxic T lymphocytes (EBV-CTLs) and activated T cells (ATCs). We have previously shown that EBV-CTLs expressing GD2-CARs (CAR-CTLs) circulated at higher levels than GD2-CAR ATCs (CAR-ATCs) early after infusion, but by 6 weeks, both subsets became low or undetectable. We now report the long-term clinical and immunologic consequences of infusions in 19 patients with high-risk neuroblastoma: 8 in remission at infusion and 11 with active disease. Three of 11 patients with active disease achieved complete remission, and persistence of either CAR-ATCs or CAR-CTLs beyond 6 weeks was associated with superior clinical outcome. We observed persistence for up to 192 weeks for CAR-ATCs and 96 weeks for CAR-CTLs, and duration of persistence was highly concordant with the percentage of CD4(+) cells and central memory cells (CD45RO(+)CD62L(+)) in the infused product. In conclusion, GD2-CAR T cells can induce complete tumor responses in patients with active neuroblastoma; these CAR T cells may have extended, low-level persistence in patients, and such persistence was associated with longer survival. This study is registered at www.clinialtrials.gov as #NCT00085930.

Topics: Adolescent; Adoptive Transfer; Antigens, Tumor-Associated, Carbohydrate; Bone Marrow Neoplasms; Bone Neoplasms; Cell Line, Tumor; Child; Child, Preschool; Female; Follow-Up Studies; Gangliosides; Genetic Therapy; Humans; Immunologic Memory; Male; Neoplasm, Residual; Neuroblastoma; Receptors, Antigen, T-Cell; Recombinant Fusion Proteins; T-Lymphocytes, Cytotoxic; Young Adult

To describe oncolytic effects of treatment with anti-G(D2) monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with neuroblastoma (NB).. Patients were eligible for 3F8/GM-CSF if intensive therapy had not eradicated potentially lethal NB. One cycle consisted of GM-CSF (subcutaneous bolus) on days 1 through 5, 11, and 12, and GM-CSF (2-hour intravenous [IV] infusion) followed after a 1-hour interval by 3F8 (1.5-hour IV infusion) on days 6 through 10 and 13 through 17. GM-CSF was dosed at 250 microg/m(2)/d on days 1 through 7 and at 500 microg/m(2)/d on days 8 through 17. 3F8 was dosed at 10 mg/m(2)/d (100 mg/m(2)/cycle). 3F8 was given with an opiate and an antihistamine. Patients without progressive disease (PD) or elevated human antimouse antibody titers could be treated again beginning 3 weeks after completion of a cycle.. Among 19 patients treated for NB resistant to induction therapy, 12 of 15 had complete remission (CR) of bone marrow (BM) disease, and three others who had less than partial responses achieved prolonged progression-free survival (one remains on study at 21+ months, two had PD at 12 and 17 months). Among patients treated for recurrent NB resistant to retrieval therapy, five of 10 had CR in BM. The 15 patients treated for PD fared poorly, although two had scintigraphic findings suggestive of a short-term response. Side effects were limited to readily manageable pain and, less commonly, rash of short duration; hence, patients were treated as outpatients.. 3F8/GM-CSF is well tolerated and shows promise for treatment of minimal residual NB in BM.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antibody-Dependent Cell Cytotoxicity; Bone Marrow Neoplasms; Bone Neoplasms; Child; Child, Preschool; Disease Progression; Drug Therapy, Combination; Female; Gangliosides; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunoglobulin G; Infusions, Intravenous; Male; Neuroblastoma

To eradicate minimal residual disease with anti-G(D2) monoclonal antibody 3F8 in stage 4 neuroblastoma (NB) diagnosed at more than 1 year of age.. Thirty-four patients were treated with 3F8 at the end of chemotherapy. Most had either bone marrow (n=31) or distant bony metastases (n=29). Thirteen patients were treated at second or subsequent remission (group I) and 12 patients in this group had a history of progressive/persistent disease after bone marrow transplantation (BMT); 21 patients were treated in first remission following N6 chemotherapy (group II).. Before 3F8 treatment, 23 patients were in complete remission CR, eight in very good partial remission (VGPR), one in partial remission (PR), and two had microscopic foci in marrow. Twenty-five had evidence of NB by at least one measurement of occult/minimal tumor (iodine 131[(131)I]-3F8 imaging, marrow immunocytology, or marrow reverse-transcriptase polymerase chain reaction [RT-PCR]). Acute self-limited toxicities of 3F8 treatment were severe pain, fever, urticaria, and reversible decreases in blood counts and serum complement levels. There was evidence of response by immunocytology (six of nine), by GAGE RT-PCR (seven of 12), and by (131)I-3F8 scans (six of six). Fourteen patients are alive and 13 (age 1.8 to 7.4 years at diagnosis) are progression-free (40 to 130 months from the initiation of 3F8 treatment) without further systemic therapy, none with late neurologic complications. A transient anti-mouse response or the completion of four 3F8 cycles was associated with significantly better survival.. Despite high-risk nature of stage 4 NB, long-term remission without autologous (A)BMT can be achieved with 3F8 treatment. Its side effects were short-lived and manageable. The potential benefits of 3F8 in consolidating remission warrant further investigations.

Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Bone Marrow Neoplasms; Bone Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Female; Gangliosides; Humans; Immunotherapy; Infant; Male; Neoplasm Staging; Neoplasm, Residual; Neuroblastoma; Treatment Outcome

Chimeric antigen receptor (CAR) T-cell therapy of pediatric sarcomas is challenged by the paucity of targetable cell surface antigens. A candidate target in osteosarcoma (OS) is the ganglioside G. We aimed to identify mechanisms that upregulate G. G. Expression of G

Topics: Benzamides; Biphenyl Compounds; Bone Neoplasms; Brefeldin A; Cell Culture Techniques; Cytotoxicity, Immunologic; Enhancer of Zeste Homolog 2 Protein; Gangliosides; Humans; Morpholines; Osteosarcoma; Protein Synthesis Inhibitors; Pyridones; Surface Properties; T-Lymphocytes; Tumor Cells, Cultured

The cure rate for metastatic osteosarcoma has not substantially improved over the past decades. Clinical trials of anti-HER2 trastuzumab or anti-GD2 dinutuximab for metastatic or refractory osteosarcoma were not successful, and neither was immune checkpoint inhibitors (ICIs).. We tested various target antigen expressions on osteosarcoma cell lines using flow cytometry and analyzed in vitro T cell engaging BsAb (T-BsAb)-dependent T cell-mediated cytotoxicity using 4-h. GD2 and HER2 were chosen from a panel of surface markers on osteosarcoma cell lines and PDXs. Anti-GD2 BsAb or anti-HER2 BsAb exerted potent anti-tumor effect against osteosarcoma tumors in vitro and in vivo. T cells armed with anti-GD2-BsAb (GD2-EATs) or anti-HER2-BsAb (HER2-EATs) showed significant anti-tumor activities as well. Anti-PD-L1 combination treatment enhanced BsAb-armed T cell function in vivo and improved tumor control and survival of the mice, when given sequentially and continuously.. Anti-GD2 and anti-HER2 BsAbs were effective in controlling osteosarcoma. These data support the clinical investigation of GD2 and HER2 targeted T-BsAb treatment in combination with immune checkpoint inhibitors, particularly anti-PD-L1, in patients with osteosarcoma to improve their treatment outcome.

Topics: Animals; Antibodies, Bispecific; Antineoplastic Agents, Immunological; Bone Neoplasms; Cell Line, Tumor; Gangliosides; Humans; Male; Mice, Inbred BALB C; Osteosarcoma; Receptor, ErbB-2; T-Lymphocytes

The cell membrane glycolipid GD2 is expressed by multiple solid tumors, including 88% of osteosarcomas and 98% of neuroblastomas. However, osteosarcomas are highly heterogeneous, with many tumors exhibiting GD2 expression on <50% of the individual cells, while some tumors are essentially GD2-negative. Anti-GD2 immunotherapy is the current standard of care for high-risk neuroblastoma, but its application to recurrent osteosarcomas, for which no effective therapies exist, has been extremely limited. This is, in part, because the standard assays to measure GD2 expression in these heterogeneous tumors are not quantitative and are subject to tissue availability and sampling bias. To address these limitations, we evaluated a novel, sensitive radiotracer [

Topics: Animals; Antibodies, Monoclonal; Apoptosis; Bone Neoplasms; Cell Proliferation; Gangliosides; Humans; Immunotherapy; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Recurrence, Local; Osteosarcoma; Positron-Emission Tomography; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Cisplatin is an effective chemotherapeutic agent for osteosarcoma (OS) and has been shown to induce endoplasmic reticulum (ER) stress-associated apoptosis in human cancer cells. Ganglioside GD2-specific antibodies can inhibit tumor cell viability without involvement of the immune system. A recent study has shown that antiGD2 monoclonal antibody (mAb) 14G2a effectively inhibits the viability and invasiveness of human OS cells. In this study, we explored the effect of anti-GD2 mAb and cisplatin alone and in combination on ER stress-associated apoptosis in osteosarcoma cells. MG-63 and Saos-2 human OS cells were treated with cisplatin and/or an-GD2 mAb 14G2a for 48 hours. Cisplatin and 14G2a dose-dependently induced apoptosis in MG-63 and Saos-2 cells. They in combination induced 70%-77% of apoptosis in MG-63 cells and 79%-85% of apoptosis in Saos-2 cells, exhibiting a synergistic effect stronger than addition of their individual effects over the control level. Showing no significant effect on the expression of protein kinase RNA-like ER kinase (PERK), cisplatin and 14G2a exhibited a marked synergistic effect on inducing phosphorylation/activation of PERK, phosphorylation/inactivation of eukaryotic translation initiation factor 2α (eIF2α), expression of CHOP, in parallel to inducing the caspase-3 activity and apoptosis in MG-63 and Saos-2 cells. The effects were abolished by lentivirus-mediated knockdown of PERK. Particularly, PERK knockdown abolished 63% and 65% of the combined apoptotic effect of cisplatin and 14G2a on MG-63 and Saos-2 cells, respectively. In conclusion, this study provides the first evidence supporting that cisplatin and 14G2a synergize to induce ER stress-associated apoptosis in human OS cells through activating the PERK ER stress pathway by synergistically inducing phosphorylation/activation of PERK. Our findings add new insights into the pharmacologic effects of anti-GD2 mAb in anticancer treatment and suggest that cisplatin plus anti-GD2 mAb could be a new effective therapeutic strategy for OS.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Cisplatin; Drug Synergism; eIF-2 Kinase; Endoplasmic Reticulum Stress; Enzyme Activation; Gangliosides; Gene Knockdown Techniques; Humans; Osteosarcoma; Phosphorylation; Signal Transduction

Survival outcomes for patients with osteosarcoma have remained stagnant over the past 30 years. Targeting of ganglioside GD2, a glycosphingolipid on the cell surface of some tumors, with immunotherapy has resulted in improved outcomes for patients with neuroblastoma. In the current study, the expression pattern of GD2 was examined in osteosarcoma.. Immunohistochemistry was performed on osteosarcoma samples from patients at the time of initial biopsy, definitive surgery, and disease recurrence. The intensity and location of staining were scored. Cell-based enzyme-linked immunoadsorbent assay was performed on osteosarcoma cell lines to quantitate the level of GD2 expression.. Forty-four osteosarcoma samples were evaluated by immunohistochemistry, including 8 samples from the initial biopsy, 28 samples from the definitive surgery, and 8 samples from the time of disease recurrence. GD2 was expressed on all 44 osteosarcoma samples. Osteosarcoma tissue obtained at the time of disease recurrence demonstrated a higher intensity of staining compared with samples obtained at initial biopsy and definitive surgery (P = .016). The majority of osteosarcoma cell lines expressed GD2 at higher levels than the neuroblastoma cell line BE(2)-C.. Ganglioside GD2 is highly expressed on osteosarcomas. Clinical trials are needed to assess the efficacy of targeting GD2 in patients with osteosarcoma.

Topics: Antibodies, Monoclonal; Biopsy; Bone Neoplasms; Gangliosides; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Recurrence, Local; Neuroblastoma; Osteosarcoma; Primary Cell Culture; Radioimmunotherapy

Novel treatment strategies in Ewing sarcoma include targeted cellular therapies. Preclinical in vivo models are needed that reflect their activity against systemic (micro)metastatic disease.. Whole-body magnetic resonance imaging (WB-MRI) was used to monitor the engraftment and dissemination of human Ewing sarcoma xenografts in mice. In this model, we evaluated the therapeutic efficacy of T cells redirected against the Ewing sarcoma-associated antigen GD2 by chimeric receptor engineering.. Of 18 mice receiving intravenous injections of VH-64 Ewing sarcoma cells, all developed disseminated tumour growth detectable by WB-MRI. All mice had lung tumours, and the majority had additional manifestations in the bone, soft tissues, and/or kidney. Sequential scans revealed in vivo growth of tumours. Diffusion-weighted whole-body imaging with background signal suppression effectively visualised Ewing sarcoma growth in extrapulmonary sites. Animals receiving GD2-targeted T-cell therapy had lower numbers of pulmonary tumours than controls, and the median volume of soft tissue tumours at first detection was lower, with a tumour growth delay over time.. Magnetic resonance imaging reliably visualises disseminated Ewing sarcoma growth in mice. GD2-retargeted T cells can noticeably delay tumour growth and reduce pulmonary Ewing sarcoma manifestations in this aggressive disease model.

Topics: Animals; Bone Neoplasms; Cell Line, Tumor; Diffusion Magnetic Resonance Imaging; Female; Gangliosides; Humans; Immunotherapy, Adoptive; Male; Mice; Mice, Inbred NOD; Mice, SCID; Sarcoma, Ewing; T-Lymphocytes; Whole Body Imaging; Xenograft Model Antitumor Assays

Novel treatment strategies are needed to cure disseminated Ewing sarcoma. Primitive neuroectodermal features and a mesenchymal stem cell origin are both compatible with aberrant expression of the ganglioside antigen G(D2) and led us to explore G(D2) immune targeting in this cancer.. We investigated G(D2) expression in Ewing sarcoma by immunofluorescence staining. We then assessed the antitumour activity of T cells expressing a chimeric antigen receptor specific for G(D2) against Ewing sarcoma in vitro and in vivo.. Surface G(D2) was detected in 10 out of 10 Ewing sarcoma cell lines and 3 out of 3 primary cell cultures. Moreover, diagnostic biopsies from 12 of 14 patients had uniform G(D2) expression. T cells specifically modified to express the G(D2)-specific chimeric receptor 14. G2a-28ζ efficiently interacted with Ewing sarcoma cells, resulting in antigen-specific secretion of cytokines. Moreover, chimeric receptor gene-modified T cells from healthy donors and from a patient exerted potent, G(D2)-specific cytolytic responses to allogeneic and autologous Ewing sarcoma, including tumour cells grown as multicellular, anchorage-independent spheres. G(D2)-specific T cells further had activity against Ewing sarcoma xenografts.. G(D2) surface expression is a characteristic of Ewing sarcomas and provides a suitable target antigen for immunotherapeutic strategies to eradicate micrometastatic cells and prevent relapse in high-risk disease.

Topics: Adolescent; Adult; Animals; Antigens, Surface; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Child; Coculture Techniques; Cytotoxicity, Immunologic; Female; Gangliosides; Granzymes; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Receptors, Antigen, T-Cell; Recombinant Fusion Proteins; Sarcoma, Ewing; Single-Chain Antibodies; Spheroids, Cellular; T-Lymphocytes; Young Adult

The expression and implications of gangliosides in human osteosarcomas have not been systematically analyzed. In this study, we showed that gangliosides GD3 and GD2 are highly expressed in the majority of human osteosarcoma cell lines derived from oral cavity regions. Introduction of GD3 synthase cDNA into a GD3/GD2-negative (GD3/GD2-) human osteosarcoma subline resulted in the establishment of GD3/GD2+ transfectant cells. They showed increased cell migration and invasion activities in wound healing and Boyden chamber invasion assays, respectively, compared to the control cells. When treated with serum, GD3/GD2+ cells showed stronger tyrosine phosphorylation of p130Cas, focal adhesion kinase, and paxillin than GD3/GD2- cells. In particular, paxillin underwent much stronger phosphorylation, suggesting its role in cell motility. Furthermore, we tried to dissect the roles of GD3 and GD2 in the malignant properties of the transfectant cells by establishing single ganglioside-expressing cells, that is, either GD3 or GD2. Although GD3/GD2+ cells showed the most malignant properties, GD2+ cells showed almost equivalent levels to GD3/GD2+ cells in invasion and migration activities, and in the intensities of tyrosine phosphorylation of paxillin. Among Src family kinases, Lyn was expressed predominantly, and was involved in the invasion and motility of GD3- and/or GD2-expressing transfectants. Furthermore, it was elucidated by gene silencing that Lyn was located in a different pathway from that of FAK to eventually lead paxillin activation. These results suggested that GD2/GD3 are responsible for the enhancement of the malignant features of osteosarcomas, and might be candidate targets in molecular-targeted therapy.

Topics: Bone Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Crk-Associated Substrate Protein; Focal Adhesion Kinase 1; Gangliosides; Gene Expression; Gene Silencing; Humans; Osteosarcoma; Paxillin; Phosphorylation; Sialyltransferases; Signal Transduction; src-Family Kinases; Tyrosine

Early and correct diagnosis of local tumor recurrence, occurrence of metastases, and therapy response are essential in patients with neuroblastoma stage IV. The aim of the study was to evaluate the diagnostic value of metaiodobenzylguanidine (mIBG) and a chimeric GD2 antibody in the follow-up of patients with neuroblastoma. In a prospective study, mIBG (N = 31 scans) and immunoscintigraphy were compared with a chimeric antiganglioside antibody, ch14.18 (MAb) (N = 31 scans), labeled with technetium Tc 99m in the follow-up of 18 patients with stage IV neuroblastoma. The findings were compared with histologic findings, other imaging examinations, and clinical changes over the course of 4 to 6 years. For the diagnosis of local tumor recurrences, sensitivity was 80% for MAb and 70% for mIBG. Specificity was 93% for MAb and 72% for mIBG. The MAb was superior for the detection of skeletal metastases, with a sensitivity of 82% compared with 72% for mIBG. Specificity was 100% for both techniques. Also, for soft tissue/lymph node metastases, sensitivity for MAb was higher (50%) than for mIBG (31%). Specificity was 100% for each technique. In sequential studies, metastases were detected earlier with MAb (mean: 2.3 m for skeletal metastases, 3.6 m for soft tissue metastases) than with mIBG. After therapy, tumor uptake was visualized longer with mIBG (mean 6.3 m) than with MAb. The chimeric antibody ch14.18 is likely to be valuable for follow-up examinations and for assessment of therapy response because of earlier detection of new metastases.

Topics: 3-Iodobenzylguanidine; Adolescent; Antibodies, Monoclonal; Bone Neoplasms; Child; Child, Preschool; False Negative Reactions; Female; Fluorescent Antibody Technique; Follow-Up Studies; Gangliosides; Humans; Liver Neoplasms; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Neuroblastoma; Radionuclide Imaging; Radiopharmaceuticals; Recombinant Fusion Proteins; Soft Tissue Neoplasms; Technetium

A case of recurrent, disseminated retinoblastoma is presented. The primary intraocular tumor, a metastatic mass at recurrence, and the tumor cells infiltrating bone marrow were all positive for the anti-GD2 monoclonal antibody (Mab) 3A7. Indirect immunofluorescence using the monoclonal antibody 3A7 was an effective method of detecting residual disease in the marrow. After remission was achieved by conventional therapy, the patient underwent autologous bone marrow transplantation (ABMT). The preparative regimen consisted of VP-16, cisplatinum, high-dose melphalan, and total body irradiation. The autologous marrow inoculum was clean of tumor cells at the detection level of 1:10,000. The transplant course was uneventful, and the patient is well and disease-free 17 months after ABMT. We conclude that high-dose chemotherapy and total body irradiation in an ABMT setting is feasible and a potentially curative approach to disseminated retinoblastoma.

Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow; Bone Marrow Purging; Bone Marrow Transplantation; Bone Neoplasms; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Etoposide; Eye Enucleation; Eye Neoplasms; Female; Gangliosides; Humans; Mandibular Neoplasms; Methotrexate; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Remission Induction; Retinoblastoma; Transplantation, Autologous; Vincristine; Whole-Body Irradiation