Elsevier

Seminars in Oncology

Volume 41, Issue 5, October 2014, Pages 589-612
Seminars in Oncology

GD2-Targeted Immunotherapy and Radioimmunotherapy,☆☆

https://doi.org/10.1053/j.seminoncol.2014.07.003Get rights and content

Ganglioside GD2 is a tumor-associated surface antigen found in a broad spectrum of human cancers and stem cells. They include pediatric embryonal tumors (neuroblastoma, retinoblastoma, brain tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma), as well as adult cancers (small cell lung cancer, melanoma, soft tissue sarcomas). Because of its restricted normal tissue distribution, GD2 has been proven safe for antibody targeting. Anti-GD2 antibody is now incorporated into the standard of care for the treatment of high-risk metastatic neuroblastoma. Building on this experience, novel combinations of antibodies, cytokines, cells, and genetically engineered products all directed at GD2 are rapidly moving into the clinic. In this review, past and present immunotherapy trials directed at GD2 will be summarized, highlighting the lessons learned and the future directions.

Section snippets

Murine Antibodies: IgG3 Antibody 3F8

In the first-in-human phase I study of anti-GD2 monoclonal antibody (MAb), toxicity of murine IgG3 antibody 3F8 was assessed in 17 patients with neuroblastoma and malignant melanoma (Table 1).24 Tumor response by using International Neuroblastoma Response Criteria (INRC)25 was observed in two of 17 patients with neuroblastoma.26 Importantly, this study demonstrated specific binding of 3F8 antibodies to tumor using in vitro immunostaining and in vivo radioimaging with 131I-3F8. Toxicities

Gd2 Vaccines

Building on the success of anti-GD2 antibodies, active vaccination against GD2 is a logical next step.60 HAMA, an indirect measure of the host anti-idiotype network, was consistently correlated with long term survival.34, 60 Because of these observations, anti-idiotypic antibody vaccines such as mouse IgG1 antibody 1A7 specific for ch14.1861 and rat IgG1 antibody A1G4 specific for 3F862 were tested in phase I trials (NCT00003023). The GD2 peptide mimotope63 and its DNA vaccine64 can induce

Immunocytokines

Fusion of cytokines to GD2-specific antibody has the potential to improve tumor delivery and help achieve a higher local concentration and reduce systemic toxicity of the cytokines. In phase I study of hu14.18/IL-2 immunocytokine in 28 children with refractory neuroblastoma and melanoma, no objective responses were observed. DLTs included hypersensitivity, hypotension, and myelosuppression.67 Phase II study included 39 children with refractory neuroblastoma. Of 13 patients with measurable

Importance of NK Cells and the Role of Inhibitory Killer Cell Immunoglobulin-Like Receptor

Anti-GD2 MAb is more than a passive linker of tumors to NK cells; they rescue NK cells from suppression by neuroblastoma. FcγRIII (CD16)-mediated signaling removes the inhibition by inhibitory killer cell immunoglobulin-like receptors (KIRs).74 Since 60% of patients have KIRs on their NK cells with no corresponding KIR ligands during cellular maturation,75 these NK cells are “uneducated” and hyporeactive until their CD16 is activated during ADCC. On the other hand, while “educated” NK cells are

Antibody Drug Conjugates

Antibody immunoconjugates can selectively deliver the cytotoxic payload to the tumor.97 Such conjugates could be a drug (antibody drug conjugates [ADCs]) with known anti-tumor activity, a radionuclide, or a toxin. There are several factors that can affect clinical use of immunoconjugates negatively. The conjugation chemistry can damage immunoreactivity, interfering with antibody binding to the target. Instability of the conjugate in serum can diminish its effect on the target sometimes

Radionuclide Immunoconjugates For Radioimmunotherapy

Radionuclides can exert anti-tumor effect not just on antigen(+) but also on surrounding antigen(-) tumor cells via a “cross-fire” effect and radiation-induced intercellular signaling.99

Choice of Radioisotope and Immunoreactivity

Most clinical applications of RIT utilize β-emitting radioimmunoconjugates. β-particles have a relatively long range (0.8–5 mm) and low linear energy transfer (approximately 0.2 keV/µm). This long range results in the delivery of radiation not only to the antigen-positive, but also to antigen-negative tumor cells, as well as to the surrounding normal tissues. Thus, β-emitters can treat bulky diseases effectively, but they are not optimal for eradicating single cells or micrometastasis. Most

Nanoparticles

Inorganic nanoparticles are delivery systems built to precise specifications for medical applications.98 They represent small particles (3–200 nm) made up of inert scaffolds. As therapeutics, they are built for their superior pharmacokinetics, thereby enhancing intracellular concentration of drugs in cancer cells while minimizing their systemic side effects. In neuroblastoma-bearing mice, fenretinide, a synthetic retinoic acid derivative,114 or doxorubin115 could be encapsulated in

Future Directions

Anti-GD2 antibodies have been extensively evaluated in preclinical and clinical studies in the past two decades. Therapeutic efficacy and acceptable safety profile have made them an integral part of the current treatment of neuroblastoma. Curing high-risk metastatic neuroblastoma diagnosed≥18 months of age or with MYCN amplification was unthinkable 25 years ago. The addition of GD2-targeted treatments has greatly improved their outlook, where>50% PFS beyond 5 years is now possible. Several key

Acknowledgments

The authors thank Drs Irene Cheung, Brian H. Kushner, Kim Kramer, and Shakeel Modak for their critical review of the manuscript and valuable suggestions.

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    Supported in part by grants from the Department of Defense (PR111043), the National Cancer Institute (CA106450 and CA161978), Enid A Haupt Endowed Chair, Kids Walk for Kids with Cancer NYC, Katie’s Find a Cure Foundation, Catie Hoch Foundation and the Robert Steel Foundation.

    ☆☆

    Financial disclosure: N.-K. Cheung was named as an inventor on patents filed by MSKCC on beta-glucan, hu3F8 and 8H9. Beta-glucan was licensed by MSKCC to Biotec Pharmacon.

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