Neuroblastoma Therapy - A New HopeDate:07 April 2016
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for approximately 8% of childhood cancers. Nearly 40% of NB tumors are classified as high-risk (HR) using current risk stratification criteria. The prognosis for high-risk and relapsed high-risk neuroblastoma patients (HR-NB) remains poor with conventional treatment. There is, therefore, a compelling need to develop a safe and effective targeted therapy that increases long-term survival for this population of patients.
Immunotherapy for Neuroblastoma
Immunotherapy is an attractive cancer treatment option in which tumor markers that are not widely shared by normal cells are targeted. In the context of NB, the surface antigen that has been the primary target of antibody targeting is GD2. GD2 is expressed by ca. 98% of NB tumors and several other HR-tumors.
Since 1985, the specificity of several antibodies to GD2 has been explored, resulting in the selection of 3F8, a murine antibody, as a primary candidate. It was subsequently demonstrated that 3F8 was effective in eradicating neuroblastoma cells from bone marrow.
Capitalizing on the effectiveness of targeting GD2 for neuroblastoma immunotherapy, a chimeric human-mouse antibody based on 14.18, a murine GD2-targeting antibody not derived from 3F8, was developed. This chimeric antibody, ch14.18, demonstrated specificity for GD2 and induction of cell-mediated lysis of neuroblastoma cells. Since that time, ch14.18 has shown promise through several phase I trials as a stand-alone treatment and in conjunction with cytokines to increase the immune response, for neuroblastoma.
Recently, a study by the Children’s Oncology Group (COG) demonstrated an increase of 20% in 2-y event-free survival and an 11% increase in overall survival using a maintenance therapy of 13-cis-retinoic acid and the anti-GD2 antibody ch14.18 in conjunction with a cytokine regimen versus cis-retinoic acid alone. The hu14.18K322A variant of the GD2-targeting antibody hu14.18 has been shown to elicit antibody-dependent cell-mediated cytotoxicity (ADCC) toward human neuroblastoma cells similar to that of the parent antibody while exhibiting decreased complement activation and decreased associated pain, the dose-limiting toxicity in neuroblastoma immunotherapy. On the basis of these results, hu14.18.K322A-based anti-GD2 immunotherapy is now becoming the standard of care for NB patients.
Radioimmunotherapy (RIT), the use of an antibody to selectively deliver a therapeutic radionuclide to a tumor, remains in its infancy for pediatric tumors, despite its potential as an attractive therapeutic modality. Most childhood tumors are radiation sensitive, but the side effects of external beam radiation are well recognized. In comparison to external beam radiation, RIT may reduce the non-target organ toxicity such as growth impairment and asymmetry, learning difficulties, and other neurologic effects, that are associated with external beam radiation and are of particular significance in children.
Furthermore, radiolabeling the mAb with an imaging radionuclide (e.g., 89Zr) may increase the sensitivity and specificity of detecting the disease through imaging. More importantly, it provides vital pharmacokinetic information and biodistribution data that can used to estimate the radiation dose for RIT; data that is not available using anatomic imaging modalities such has CT or MRI.
Radioimmunotherapy for Neuroblastoma
Despite achieving apparently complete remissions with sophisticated combination therapies, treatment failure in NB is common, primarily because of the inability to eradicate minimal residual disease (MRD), microscopic metastases that are typically distant and occult. Over time, these sites result in disease reoccurrence, frequently with lethal results. RIT, however, has the potential to target MRD and thus improve patient outcome. Additionally, because intensive chemotherapy regimens used in most childhood cancers are highly immunosuppressive, repeated administration of radiolabeled monoclonal antibodies (mAbs) is possible without the immediate induction of human antimouse or human antichimeric antibody responses.
The development of new, more specific, radioimmunoconjugates (RIC) is essential to applying RIT to the treatment of childhood solid tumors, and research to improve targeting while simultaneously reducing toxicity is currently underway. The largest number of children undergoing RIT has been patients with NB treated with the anti-GD2 mAb 131I-3F8. This antibody has been used in patients since 1986, and the therapeutic efficacy and safety of unlabeled 3F8 as well as of 131I-3F8 have been carefully studied. The safety of 131I-3F8 was evaluated in a phase I dose escalation study performed at Memorial Sloan–Kettering Cancer Center where it showed some success. However, an important limitation to 131I-3F8 is the 131I radiolabel; which, among other limitations, emits high-energy gamma rays that irradiate non-target tissue and care-givers as well as the tumor and undergoes in vivo deiodination, which leads to a significant radiation dose to the thyroid that may compromise thyroid function.
Personalized Radioimmunotherapy Treatment for High-Risk and Relapsed High-Risk Neuroblastoma Patients
In an effort to combine the radiation sensitive characteristics of HR NB tumors with the use of anti-GD2 antibodies, researchers at Boston Children’s Hospital, are developing a radioimmunotherapy (RIT) strategy for HR and relapsed HR NB patients that obviates these limitations.
Prof. Alan B. Packard and Dr. Jason L. Dearling, both located at Boston Children’s Hospital, are working on generating a novel radioimmunoconjugate (RIC) by radiolabelling the established anti-GD2 antibody, hu14.18K322A, with a pair of radionuclides, 89Zr and 177Lu, where the 89Zr-labeled RIC will be used for PET imaging of NB and the 177Lu-labeled RIC will be used for RIT. By doing so they hypothesize that they will be able to:
(1) Confirm that the target GD2 antigen is expressed by the tumors prior to the start of radioimmunotherapy,
(2) Define the extent of metastases for each patient,
(3) Estimate the appropriate 177Lu dose based on the extent of individual metastatic disease as well as uptake in non-target tissue, and
(4) Monitor response to this personalized RIT.
This innovative therapeutic approach is expected to significantly increase the overall survival of patients with HR and relapsed HR-NB while decreasing treatment-associated morbidity.
Prof. Packard and Dr. Dearling can be contacted at:
Boston Children’s Hospital
Department of Radiology
300 Longwood Ave
Boston MA 02115