Clinical Studies In Oncology
Siegfried Matzku, Rolf A. Stahel in Antibodies in Diagnosis and Therapy, 2019
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.
Nanomaterials for Theranostics: Recent Advances and Future Challenges *
Valerio Voliani in Nanomaterials and Neoplasms, 2021
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].
Neuroblastoma
Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner in Endocrine Surgery, 2017
Immunotherapy is given along with differentiation therapy. Antibodies have been developed to target GD2, which is present on the surface of neuroblastoma cells, and targeted therapy against this receptor has been shown to have a significant effect on survival, with a 2-year EFS of 66% vs. 46% in the group that received standard therapy without immunotherapy. It is important to note that patients can have fairly significant systemic responses to the immunotherapy and should be monitored closely during infusion [26, 27].
GD2-targeted chimeric antigen receptor T cells prevent metastasis formation by elimination of breast cancer stem-like cells
Published in OncoImmunology, 2020
Christian M. Seitz, Sarah Schroeder, Philipp Knopf, Ann-Christin Krahl, Jana Hau, Sabine Schleicher, Manuela Martella, Leticia Quintanilla-Martinez, Manfred Kneilling, Bernd Pichler, Peter Lang, Daniel Atar, Karin Schilbach, Rupert Handgretinger, Patrick Schlegel
Notably, GD2 is an excellent and extensively studied target antigen for antibody-based immunotherapy.21 We and others have clinically evaluated GD2 mAbs to treat patients suffering from metastatic neuroblastoma, leading to significantly improved survival and FDA/EMA approval of ch14.18, also known as dinutuximab beta.22,23 In the present study, we used a GD2-directed immunotherapy by GD2-CAR-T to target BCSCs. CARs are synthetic receptors consisting of an extracellular binding domain, usually a scFv derived from a mAb, a transmembrane domain as well as one or multiple co-stimulatory and signaling domains.24 Expressed on T cells, CARs are capable to mediate surface antigen-dependent T-cell activation and subsequent target cell lysis. Our hypothesis was that GD2-CAR-T will circulate the body to identify and eliminate BCSC phenotypic DTCs and prevent metastasis formation.
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.
Anti-GD2 antibody and Vorinostat immunocombination therapy is highly effective in an aggressive orthotopic neuroblastoma model
Published in OncoImmunology, 2020
Renske J. E. van den Bijgaart, Michiel Kroesen, Ingrid C. Brok, Daphne Reijnen, Melissa Wassink, Louis Boon, Peter M. Hoogerbrugge, Gosse J Adema
Fc-receptor expressing immune effector cells are highly important for the clinical response following tumor-directed mAb therapy, including anti-GD2 mAb therapy. Anti-GD2 mAb alone did not significantly alter the tumor microenvironment nor inhibited tumor growth. This is in line with observations in neuroblastoma patients, where there is a need to activate the immune system with cytokines, including IL-2 and GM-CSF, to obtain effective anti-GD2 therapy.9 The combination with Vorinostat may, similarly to cytokines, enable activation of the immune system and thereby work synergistically with the anti-GD2 mAb therapy. Besides its targeting efficacy to direct immune-mediated killing, GD2 is also an ideal target for tumor-selective delivery of radioisotopes or immune stimuli. Interestingly, anti-GD2 mAb conjugates, like anti-GD2 mAb coupled to IL-2, have been generated and show clinical efficacy.30 Nevertheless, a major side effect is pain, thought to be a consequence of complement activation, which remains a clinical burden.9,31 There are efforts to optimize the efficacy of anti-GD2 mAb-based (combination) therapies while reducing its side effects, for example, by using CAR T cells or carbohydrate-based vaccines.32,33 Also, it has been suggested that O-acetyl-GD2 is specifically expressed on neuroblastoma cells, but not on peripheral nerves.34 The used 14G2a anti-GD2 mAb in this study recognizes both GD2 and the O-acetylated form of GD2. Therefore, anti-O-acetyl-GD2 antibodies might show higher tumor specificity and less adverse effects.
Related Knowledge Centers
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- Neuroblastoma
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