Thesis defense Marjolein Stip

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The thesis of Marjolein Stip discusses the potential of IgA anti-GD2 antibody therapy as a treatment for neuroblastoma. Neuroblastoma is one of the most common tumors in children. It arises during embryonic development, usually in the adrenal glands or nervous system in the belly. Low- and intermediate-risk patients can get better spontaneously and otherwise respond well to surgical removal. However, high-risk patients face a grim prognosis with a 5-year survival rate of only 45%.

Standard treatments for high-risk neuroblastoma include chemotherapy, surgery, stem cell transplantation and radiotherapy. Additionally, patients can receive immunotherapy. This immunotherapy consists of IgG antibodies against GD2 - a sugar-lipid molecule - expressed by neuroblastoma cells. When these antibodies bind GD2 on neuroblastoma cells, they activate immune cells, most importantly NK cells, which then attack the tumor. However, this therapy can cause severe neuropathic pain, since it is also recognizing GD2 that is expressed on nerves. When IgG anti-GD2 antibodies bind to these nerves, they activate the complement system, causing severe pain.

In this thesis the development of IgA as an alternative to IgG antibodies for immunotherapy is discussed. IgA antibodies activate so-called myeloid immune cells via the FcαRI receptor, such as neutrophils, monocytes and macrophages. This offers advantages, since experiments in mouse models showed that IgA antibodies do not activate the complement system and therefore do not induce neuropathic pain. This could be a great improvement in patient care.

Next to that, experiments demonstrated that IgA antibodies effectively target neuroblastoma cells by activating myeloid cells, mostly neutrophils. Neutrophils are very numerous and they are ‘the kamikaze fighters of the immune system’, as prof. Jeanette Leusen named them during her oration. In both neuroblastoma cell lines and mouse models, IgA antibody therapy induced tumor cell death mediated by neutrophils.

The final chapter of the thesis explores a combination therapy with agents that block the CD47-SIRPα pathway to enhance the efficacy of IgA immunotherapy. This CD47-SIRPα pathway inhibits the activation of myeloid cells, and is often hijacked by neuroblastoma to protect itself from destruction. Blocking the CD47-SIRPα axis supports IgA antibody therapy by improving tumor cell killing by neutrophils and macrophages. Altogether, this thesis describes a viable alternative for IgG anti-GD2 antibody therapy with IgA antibodies and has propelled it towards clinical application.