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Nanomaterials for Theranostics: Recent Advances and Future Challenges *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Eun-Kyung Lim, Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh, Kwangyeol Lee
Cancer-cell targeting theranostic CNTs were fabricated by conjugating antibodies. In a study by Peng et al., GD2 mAb (anti-GD2) was conjugated to SWNTs for specific targeting of disialoganglioside (GD2) overexpressed neuroblastoma stNB-V1 cells [902]. Anti-GD2-linked SWNTs were extensively internalized by neuroblastoma cells via antibody-mediated endocytosis. When SWNTs-treated neuroblastoma cells were irradiated with an 808 nm NIR laser it was clearly seen that anti-GD2-conjugated SWNTs could selectively eradicate GD2-expressing neuroblastoma cells via necrosis. Similarly, Vitetta et al. studied the targeting ability and NIR-induced photothermal ability of SWNTs conjugated by antibodies such as anti-Her2, anti-CD22 mAb, or anti-CD25 mAb [903, 904].
Clinical Studies In Oncology
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Jan Schmielau, Wolff Schmiegel
The GD2 serves as an antigen for the murine IgG2a mAb 14G2a with CDC-and ADCC-activity in vitro. Twelve patients with malignant melanoma were treated with a total dose of 10-120 mg (Saleh et al., 1992b). Apart from neurologic symptoms, including abdominal/pelvic pain and two cases of reversible motor neuropathy, one PR was observed. In patients with neuroblastoma this mAb was applied at a total dose of 100-400 mg/m2 (Handgretinger et al., 1992). Three out of nine patients were treated in an adjuvant setting with a relapse after one year or later. Among the remaining six patients two patients each revealed either CR or PR. Furthermore, all patients in both regimens where the mAb was applied in multiple infusions developed HAMA. Murray et al. (1994) treated 18 patients suffering from malignant melanoma, neuroblastoma, or osteosarcoma with continuous infusions over 5 days with a total dose of 50-200 mg/m2 mAb 14G2a. Although all but two patients had detectable tumor sites in immunoscintigraphy only two neuroblastoma patients had PR. It is noteworthy that 16 out of 18 patients developed anti-idiotypic antibodies where high levels correlated with clinical response. Side effects usually were severe abdominal pain and allergic reactions in all studies using anti-GD2 mAb.
Herpes Simplex Virus Vaccines and the Viral Strategies Used to Evade Host Immunity
Published in Marie Studahl, Paola Cinque, Tomas Bergström, Herpes Simplex Viruses, 2017
Lauren M. Hook, Harvey M. Friedman
Two clinical trials were performed using the Chiron Corporation vaccine to assess the role of therapeutic vaccination in controlling frequency and severity of genital herpes. The first used HSV-2 glycoprotein gD (100 µg) in alum as adjuvant (36). Ninety-eight subjects who reported 4–14 recurrences per year received either gD2 vaccine or placebo. Vaccine recipients had fewer virologically confirmed recurrences per month (0.18 vs. 0.28, P = 0.019), and fewer mean recurrences per year (4 vs. 6, P = 0.039). In a follow-up study, gB2 was added to the vaccine formulation and combined with gD2, each used at 10 µg, which is lower than the dose used in the first study (37). The adjuvant used was MF59 adjuvant, which was selected based on improved T-cell responses compared with alum. Two hundred and two subjects with 4–14 recurrences annually were randomized to receive either vaccine or placebo. No significant improvement was noted in monthly rate of recurrences; however, the duration and severity of the first outbreak was significantly reduced in the vaccine group. The authors commented that the lower dose of vaccine antigen used in the second study may have contributed to the less impressive protection. These studies suggest that therapeutic vaccination using gB2 or gD2 has only a modest effect on the course of genital herpes.
The yes-associated protein (YAP) is associated with resistance to anti-GD2 immunotherapy in neuroblastoma through downregulation of ST8SIA1
Published in OncoImmunology, 2023
Adeiye A. Pilgrim, Hunter C. Jonus, Andrew Ho, Anna C. Cole, Jenny Shim, Kelly C. Goldsmith
A common approach to treating patients with chemotherapy resistant, relapsed neuroblastoma uses immunotherapies targeting neuroblastoma-specific tumor antigens. The glycosphingolipid GD2 is expressed on the surface of neuroblastomas,18–21 and the introduction of humanized monoclonal antibodies targeting GD2 (i.e. dinutuximab) significantly improved survival for newly diagnosed patients with high-risk disease.22,23 Anti-GD2 antibodies have also been combined with cytotoxic chemotherapy (“chemoimmunotherapy”), which demonstrated impressive response rates for relapsed neuroblastoma and resulted in GD2 chemoimmunotherapy becoming the most widely used salvage therapy for patients with refractory or relapsed disease.3,24 Unfortunately, not all patients respond to GD2-targeting immunotherapies and robust biomarkers of response are so far lacking, leaving many to suffer toxicities with no clinical antitumor benefit.23,25,26
Methodological advances in the discovery of novel neuroblastoma therapeutics
Published in Expert Opinion on Drug Discovery, 2022
Miguel F. Segura, Aroa Soriano, Josep Roma, Olga Piskareva, Carlos Jiménez, Ariadna Boloix, Jamie I. Fletcher, Michelle Haber, Juliet C. Gray, Leonor Cerdá-Alberich, Blanca Martínez de Las Heras, Adela Cañete, Soledad Gallego, Lucas Moreno
Immunotherapy has been considered a key element of neuroblastoma therapy since the seminal study by Yu et al. (2010), demonstrating a significant improvement in survival in children with high-risk neuroblastoma receiving anti-GD2 (dinutuximab) based immunotherapy in addition to standard treatment [83]. However, a large proportion of patients still relapse and die from their disease [84] and anti-GD2 immunotherapy is associated with significant toxicity, including neuropathic pain, neurotoxicity and vascular leak syndrome. In view of this, novel anti-GD2 antibodies, such as hu14.18K322A, have been engineered and developed, with the aim of improving efficacy and reducing toxicity [85]. In addition, bi-specific antibody constructs have been engineered, with scFv moieties for both GD2 and CD3, to direct endogenous T cells (expressing CD3) to the tumor (targeting GD2) [86]. More recently, the development of anti-GD2 antibody-conjugated immunoliposomes has been reported. The latter allows direct targeting of cytotoxic drugs (CPT-11 and panobinostat), contained within the liposomes, to the GD2 expressing tumor site [87]. Finally, conjugates have been developed that link anti-GD2 to nanoparticles, encapsulating a chemotherapy drug, achieving significantly better tissue penetration in preclinical neuroblastoma models than the chemotherapy agent alone [88].
Ophthalmic Implications of Chimeric Antigen Receptor T-Cell Therapy
Published in Seminars in Ophthalmology, 2021
Kevin D Chodnicki, Sashank Prasad
Two targets have been identified for CAR T-cell treatment of retinoblastoma – GD2 ganglioside and CD171. GD2 is expressed on the cell surface of neuroectodermal tumors, including retinoblastoma, and demonstrates low levels of expression in other tissues, such as skin melanocytes and peripheral nerves. Importantly, GD2 is not expressed in normal retina. Immunotherapy with anti-GD2 antibodies has shown promise in treating patients with another neuroectodermal tumor, high-risk neuroblastoma, validating GD2 as a possible target.14 The other target focus, CD171 (also known as L1 cell adhesion molecule), is a transmembrane glycoprotein and is involved in neuronal cell proliferation and migration. In malignancies, including retinoblastoma, it is linked with poorly differentiated tumors and chemoresistance of cancer cells, which make it an attractive target for alternative therapeutics, including immunotherapy.15 CD171 is expressed on normal human tissues including peripheral nerves and kidney tubules. In pre-clinical studies in rhesus macaques, which have similar CD171 expression to humans, testing high doses of CD171 CAR T-cells showed no overt collateral toxicity.16 This furthered the interest in developing CD171 directed CAR T-cells for retinoblastoma.