Impact of HACA on Immunomodulation and Treatment Toxicity Following ch14.18/CHO Long-Term Infusion with Interleukin-2: Results from a SIOPEN Phase 2 Trial

Siebert, Nikolai; Troschke-Meurer, Sascha; Marx, Marlies; Zumpe, Maxi; Ehlert, Karoline; Gray, Juliet; Garaventa, Alberto; Manzitti, Carla; Ash, Susan; Klingebiel, Thomas; Beck, James D.; Castel, Victoria; Valteau‐Couanet, Dominique; Loibner, Hans; Ladenstein, Ruth; Lode, Holger N.

doi:10.3390/cancers10100387

Cited by 13 publications

(19 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Patients with disease progression, relapse or residual disease had significantly lower total leukocyte counts, as well as a lower absolute lymphocyte-, neutrophil-, and CD16+ cell counts compared to disease-and progression-free patients observed three months after therapy. Siebert and colleagues found that presence of human anti-chimeric antibodies against chimeric anti-GD2 resulted in significant reduction in peripheral anti-GD2 levels, as well as significant abrogation in ADCC and CDC [62]. However, in this study, it is not clear if such immune responses are a disadvantage for survival of the treated patients.…”

Section: Monoclonal Antibody Therapymentioning

confidence: 57%

Monitoring Immune Responses in Neuroblastoma Patients during Therapy

Szanto

Cornel

Vijver

et al. 2020

Cancers

View full text Add to dashboard Cite

Neuroblastoma (NBL) is the most common extracranial solid tumor in childhood. Despite intense treatment, children with this high-risk disease have a poor prognosis. Immunotherapy showed a significant improvement in event-free survival in high-risk NBL patients receiving chimeric anti-GD2 in combination with cytokines and isotretinoin after myeloablative consolidation therapy. However, response to immunotherapy varies widely, and often therapy is stopped due to severe toxicities. Objective markers that help to predict which patients will respond or develop toxicity to a certain treatment are lacking. Immunotherapy guided via immune monitoring protocols will help to identify responders as early as possible, to decipher the immune response at play, and to adjust or develop new treatment strategies. In this review, we summarize recent studies investigating frequency and phenotype of immune cells in NBL patients prior and during current treatment protocols and highlight how these findings are related to clinical outcome. In addition, we discuss potential targets to improve immunogenicity and strategies that may help to improve therapy efficacy. We conclude that immune monitoring during therapy of NBL patients is essential to identify predictive biomarkers to guide patients towards effective treatment, with limited toxicities and optimal quality of life.

show abstract

Section: Monoclonal Antibody Therapymentioning

confidence: 57%

Monitoring Immune Responses in Neuroblastoma Patients during Therapy

Szanto

Cornel

Vijver

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…A clinical trial with Ch14.18, a chimeric, in combination with IL-2, while showing a strong activation of antibody effector functions, did not show a better clinical outcome (30). Development of human anti-chimeric antibody (HACA) (21% of patients) did result in strong reduction of ch14.18 levels, abrogating complement dependent cytotoxicity and antibody dependent cellular cytotoxicity (31). The monoclonal studied in Cheung et al (27, 28) is of the IGVH2-9 * 02 germline while the ch14.18 variable region is derived from the IGHV1S135 * 01 germ line.…”

Section: Setting the Stage For The Idiotype Interactions In Regulamentioning

confidence: 99%

The Promise of Anti-idiotype Revisited

Köhler¹,

Pashov²,

Kieber‐Emmons³

2019

Front. Immunol.

View full text Add to dashboard Cite

The promise of idiotype-based therapeutics has been disappointing forcing a new look at the concept and its potential to generate an effective approach for immunotherapy. Here, the idiotype network theory is revisited with regard to the development of efficacious anti-idiotype vaccines. The experience of polyclonal anti-Idiotype reagents in animal models as well as an understanding of the immune response in humans lends to the proposition that polyclonal anti-Idiotype vaccines will be more effective compared to monoclonal-based anti-Idiotype vaccines. This novel strategy can be adapted in Biotech-standard production of therapeutic antibodies.

show abstract

“…To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14. 18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment.…”

mentioning

confidence: 99%

Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment

et al. 2021

Self Cite

View full text Add to dashboard Cite

Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor–ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The ex vivo testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.

show abstract

Impact of HACA on Immunomodulation and Treatment Toxicity Following ch14.18/CHO Long-Term Infusion with Interleukin-2: Results from a SIOPEN Phase 2 Trial

Cited by 13 publications

References 37 publications

Monitoring Immune Responses in Neuroblastoma Patients during Therapy

Monitoring Immune Responses in Neuroblastoma Patients during Therapy

The Promise of Anti-idiotype Revisited

Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment

Contact Info

Product

Resources

About