Purpose:
Previously our randomized phase III trial demonstrated that immunotherapy including dinutuximab, a chimeric anti-GD2 mAb, GM-CSF, and IL2 improved survival for children with high-risk neuroblastoma that had responded to induction and consolidation therapy. These results served as the basis for FDA approval of dinutuximab. We now present long-term follow-up results and evaluation of predictive biomarkers.
Patients and Methods:
Patients recieved six cycles of isotretinoin with or without five cycles of immunotherapy which consists of dinutuximab with GM-CSF alternating with IL2. Accrual was discontinued early due to meeting the protocol-defined stopping rule for efficacy, as assessed by 2-year event-free survival (EFS). Plasma levels of dinutuximab, soluble IL2 receptor (sIL2R), and human anti-chimeric antibody (HACA) were assessed by ELISA. Fcγ receptor 2A and 3A genotypes were determined by PCR and direct sequencing.
Results:
For 226 eligible randomized patients, 5-year EFS was 56.6 ± 4.7% for patients randomized to immunotherapy (n = 114) versus 46.1 ± 5.1% for those randomized to isotretinoin only (n = 112; P = 0.042). Five-year overall survival (OS) was 73.2 ± 4.2% versus 56.6 ± 5.1% for immunotherapy and isotretinoin only patients, respectively (P = 0.045). Thirteen of 122 patients receiving dinutuximab developed HACA. Plasma levels of dinutuximab, HACA, and sIL2R did not correlate with EFS/OS, or clinically significant toxicity. Fcγ receptor 2A and 3A genotypes did not correlate with EFS/OS.
Conclusions:
Immunotherapy with dinutuximab improved outcome for patients with high-risk neuroblastoma. Early stoppage for efficacy resulted in a smaller sample size than originally planned, yet clinically significant long-term differences in survival were observed.
Natural products have been a great source of many small molecule drugs for various diseases. In spite of recent advances in biochemical engineering and fermentation technologies that allow us to explore microorganisms and the marine environment as alternative sources of drugs, more than 70% of the current small molecule therapeutics derive their structures from plants used in traditional medicine. Natural-product-based drug discovery relies heavily on advances made in the sciences of biology and chemistry. Whereas biology aims to investigate the mode of action of a natural product, chemistry aims to overcome challenges related to its supply, bioactivity, and target selectivity. This review summarizes the explorations of the caged Garcinia xanthones, a family of plant metabolites that possess a unique chemical structure, potent bioactivities, and a promising pharmacology for drug design and development.
The combination of unique structure and potent bioactivity exhibited by several family members of the caged Garcinia xanthones, led us to evaluate their pharmacophore. We have developed a Pd(0)-catalyzed method for the reverse prenylation of catechols that, together with a Claisen/ Diels-Alder reaction cascade, provides rapid and efficient access to various caged analogues. Evaluation of the growth inhibitory activity of these compounds leads to the conclusion that the intact ABC ring system containing the C-ring caged structure is essential to the bioactivity. Studies with cluvenone (7) also showed that these compounds induce apoptosis and exhibit significant cytotoxicity in multidrug-resistant leukemia cells. As such, the caged Garcinia xanthone motif represents a new and potent pharmacophore.
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