Phase I Trial of Oral Yeast-Derived β-Glucan to Enhance Anti-GD2 Immunotherapy of Resistant High-Risk Neuroblastoma

Fiorella Iglesias Cardenas, Audrey Mauguen, Irene Y Cheung, Kim Kramer, Brian H Kushner, Govind Ragupathi, Nai-Kong V Cheung, Shakeel Modak, Fiorella Iglesias Cardenas, Audrey Mauguen, Irene Y Cheung, Kim Kramer, Brian H Kushner, Govind Ragupathi, Nai-Kong V Cheung, Shakeel Modak

Abstract

Beta glucans, complex polysaccharides, prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of complement-activating monoclonal antibodies. We conducted a phase I study (clinicaltrials.gov NCT00492167) to determine the safety of the combination of yeast-derived beta glucan (BG) and anti-GD2 murine monoclonal antibody 3F8 in patients with relapsed or refractory high-risk neuroblastoma. Patients received intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10-200 mg/kg/day × 17 days in cohorts of 3-6 patients each). Forty-four patients completed 141 cycles. One patient developed DLT: transient self-limiting hepatic transaminase elevation 5 days after starting BG (120 mg/kg/day). Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. Progression-free and overall survival at 2 years were 28% and 61%, respectively. BG lacked major toxicity. Treatment with 3F8 plus BG was associated with anti-neuroblastoma responses in patients with resistant disease. Although the maximal tolerated dose for yeast BG was not reached, considering the large volume of oral BG, we recommended 40 mg/kg/day as the phase II dose.

Keywords: anti-GD2 antibody; neuroblastoma; β-glucan.

Conflict of interest statement

N.K.C., S.M. and G.R. were named as inventors on the US patent of β-glucan filed by M.S.K.C.C. Both M.S.K. and N.K.C. have financial interest in YmAbs, Abpro-Labs and Eureka Therapeutics. N.K.C. reports receiving commercial research grants from Y-mabs Therapeutics and Abpro-Labs Inc. N.K.C. was named as inventor on multiple patents filed by M.S.K., including those licensed to YmAbs Therapeutics, Biotec Pharmacon and Abpro-labs. N.K.C. is a SAB member for Eureka Therapeutics. K.K. is a consultant for YmAbs.

Figures

Figure 1
Figure 1
Clinical response of a neuroblastoma patient to 3F8 plus yeast beta-glucan. 123MIBG scans before the start of 3F8 plus yeast β-glucan (A) and after (B) 4 cycles of 3F8 plus yeast β-glucan. The skeletal uptake of 123MIBG (seen in skull, appendicular skeleton, pelvis and vertebrae) resolved after treatment with 3F8 plus yeast BG.
Figure 2
Figure 2
Correlative studies and overall survival. (A) Overall survival post-treatment by HAMA status during treatment. (B) Overall survival by Dectin-polymorphism rs3901533 genotype.

References

    1. Irwin M.S., Park J.R. Neuroblastoma: Paradigm for Precision Medicine. Pediatric Clin. N. Am. 2015;62:225–256. doi: 10.1016/j.pcl.2014.09.015.
    1. Yu A.L., Gilman A.L., Ozkaynak M.F., London W.B., Kreissman S.G., Chen H.X., Smith M., Anderson B., Villablanca J.G., Matthay K.K., et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl. J. Med. 2010;363:1324–1334. doi: 10.1056/NEJMoa0911123.
    1. Yu A.L., Gilman A.L., Ozkaynak M.F., Naranjo A., Diccianni M.B., Gan J., Hank J.A., Batova A., London W.B., Tenney S.C., et al. Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032. Clin. Cancer Res. 2021;27:2179–2189. doi: 10.1158/1078-0432.CCR-20-3909.
    1. Ladenstein R., Potschger U., Valteau-Couanet D., Luksch R., Castel V., Yaniv I., Laureys G., Brock P., Michon J.M., Owens C., et al. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): A multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1617–1629. doi: 10.1016/S1470-2045(18)30578-3.
    1. Kushner B.H., Cheung I.Y., Modak S., Basu E.M., Roberts S.S., Cheung N.K. Humanized 3F8 Anti-GD2 Monoclonal Antibody Dosing With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Resistant Neuroblastoma: A Phase 1 Clinical Trial. JAMA Oncol. 2018;4:1729–1735. doi: 10.1001/jamaoncol.2018.4005.
    1. Mora J., Castaneda A., Gorostegui M., Santa-Maria V., Garraus M., Munoz J.P., Varo A., Perez-Jaume S., Mane S. Naxitamab combined with granulocyte-macrophage colony-stimulating factor as consolidation for high-risk neuroblastoma patients in complete remission. Pediatric Blood Cancer. 2021;68:e29121. doi: 10.1002/pbc.29121.
    1. Basta N.O., Halliday G.C., Makin G., Birch J., Feltbower R., Bown N., Elliott M., Moreno L., Barone G., Pearson A.D., et al. Factors associated with recurrence and survival length following relapse in patients with neuroblastoma. Br. J. Cancer. 2016;115:1048–1057. doi: 10.1038/bjc.2016.302.
    1. Kreitz K., Ernst A., Schmidt R., Simon T., Fischer M., Volland R., Hero B., Berthold F. A new risk score for patients after first recurrence of stage 4 neuroblastoma aged >/=18 months at first diagnosis. Cancer Med. 2019;8:7236–7243. doi: 10.1002/cam4.2562.
    1. London W.B., Bagatell R., Weigel B.J., Fox E., Guo D., Van Ryn C., Naranjo A., Park J.R. Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children’s Oncology Group early-phase trials. Cancer. 2017;123:4914–4923. doi: 10.1002/cncr.30934.
    1. Imai M., Landen C., Ohta R., Cheung N.K., Tomlinson S. Complement-mediated mechanisms in anti-GD2 monoclonal antibody therapy of murine metastatic cancer. Cancer Res. 2005;65:10562–10568. doi: 10.1158/0008-5472.CAN-05-1894.
    1. Yang R.K., Sondel P.M. Anti-GD2 Strategy in the Treatment of Neuroblastoma. Drugs Future. 2010;35:665. doi: 10.1358/dof.2010.035.08.1513490.
    1. Cheung N.K., Cheung I.Y., Kushner B.H., Ostrovnaya I., Chamberlain E., Kramer K., Modak S. Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J. Clin. Oncol. 2012;30:3264–3270. doi: 10.1200/JCO.2011.41.3807.
    1. Kushner B.H., Ostrovnaya I., Cheung I.Y., Kuk D., Kramer K., Modak S., Yataghene K., Cheung N.K. Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2 immunotherapy and isotretinoin: A prospective Phase II study. Oncoimmunology. 2015;4:e1016704. doi: 10.1080/2162402X.2015.1016704.
    1. Zhang M., Kim J.A., Huang A.Y. Optimizing Tumor Microenvironment for Cancer Immunotherapy: Beta-Glucan-Based Nanoparticles. Front. Immunol. 2018;9:341. doi: 10.3389/fimmu.2018.00341.
    1. Qi C., Cai Y., Gunn L., Ding C., Li B., Kloecker G., Qian K., Vasilakos J., Saijo S., Iwakura Y., et al. Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived beta-glucans. Blood. 2011;117:6825–6836. doi: 10.1182/blood-2011-02-339812.
    1. Brown G.D. Dectin-1: A signalling non-TLR pattern-recognition receptor. Nat. Rev. Immunol. 2006;6:33–43. doi: 10.1038/nri1745.
    1. Han B., Baruah K., Cox E., Vanrompay D., Bossier P. Structure-Functional Activity Relationship of beta-Glucans From the Perspective of Immunomodulation: A Mini-Review. Front. Immunol. 2020;11:658. doi: 10.3389/fimmu.2020.00658.
    1. Ragupathi G., Yeung K.S., Leung P.C., Lee M., Lau C.B., Vickers A., Hood C., Deng G., Cheung N.K., Cassileth B., et al. Evaluation of widely consumed botanicals as immunological adjuvants. Vaccine. 2008;26:4860–4865. doi: 10.1016/j.vaccine.2008.06.098.
    1. Hong F., Hansen R.D., Yan J., Allendorf D.J., Baran J.T., Ostroff G.R., Ross G.D. β-Glucan Functions as an Adjuvant for Monoclonal Antibody Immunotherapy by Recruiting Tumoricidal Granulocytes as Killer Cells. Cancer Res. 2003;63:9023–9031.
    1. Cheung N.K., Modak S., Vickers A., Knuckles B. Orally administered beta-glucans enhance anti-tumor effects of monoclonal antibodies. Cancer Immunol. Immunother. 2002;51:557–564. doi: 10.1007/s00262-002-0321-3.
    1. Modak S., Koehne G., Vickers A., O’Reilly R.J., Cheung N.K. Rituximab therapy of lymphoma is enhanced by orally administered (1-->3),(1-->4)-D-beta-glucan. Leuk. Res. 2005;29:679–683. doi: 10.1016/j.leukres.2004.10.008.
    1. Modak S., Kushner B.H., Kramer K., Vickers A., Cheung I.Y., Cheung N.K. Anti-GD2 antibody 3F8 and barley-derived (1 --> 3),(1 --> 4)-beta-D-glucan: A Phase I study in patients with chemoresistant neuroblastoma. Oncoimmunology. 2013;2:e23402. doi: 10.4161/onci.23402.
    1. Brodeur G.M., Pritchard J., Berthold F., Carlsen N.L., Castel V., Castelberry R.P., De Bernardi B., Evans A.E., Favrot M., Hedborg F., et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J. Clin. Oncol. 1993;11:1466–1477. doi: 10.1200/JCO.1993.11.8.1466.
    1. Cheung N.K., Cheung I.Y., Canete A., Yeh S.J., Kushner B., Bonilla M.A., Heller G., Larson S.M. Antibody response to murine anti-GD2 monoclonal antibodies: Correlation with patient survival. Cancer Res. 1994;54:2228–2233.
    1. Kushner B.H., Cheung N.K. Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity. Blood. 1992;79:1484–1490. doi: 10.1182/blood.V79.6.1484.1484.
    1. Cheung I.Y., Cheung N.V., Modak S., Mauguen A., Feng Y., Basu E., Roberts S.S., Ragupathi G., Kushner B.H. Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk Neuroblastoma With Prior Disease Progression. J. Clin. Oncol. 2021;39:215–226. doi: 10.1200/JCO.20.01892.
    1. Cheung N.K., Guo H.F., Cheung I.Y. Correlation of anti-idiotype network with survival following anti-G(D2) monoclonal antibody 3F8 therapy of stage 4 neuroblastoma. Med. Pediatric Oncol. 2000;35:635–637. doi: 10.1002/1096-911X(20001201)35:6<635::AID-MPO32>;2-W.
    1. Kalia N., Singh J., Kaur M. The role of dectin-1 in health and disease. Immunobiology. 2021;226:152071. doi: 10.1016/j.imbio.2021.152071.
    1. Zhou P., Xie Y., Yan Z., Liu X., Hua H. Association between dectin-1 gene single nucleotide polymorphisms and fungal infection: A systemic review and meta-analysis. Biosci. Rep. 2019;39 doi: 10.1042/BSR20191519.
    1. Kushner B.H., Cheung I.Y., Modak S., Kramer K., Ragupathi G., Cheung N.K. Phase I trial of a bivalent gangliosides vaccine in combination with beta-glucan for high-risk neuroblastoma in second or later remission. Clin. Cancer Res. 2014;20:1375–1382. doi: 10.1158/1078-0432.CCR-13-1012.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner