Metastatic solid tumors in children are typically treated upfront with intensive therapies. Although efficacious for bulk disease, these treatments do damage to the immune system that takes months, if not years, to repair. It is unacceptable that many patients, despite having achieved clinical remission after grueling chemotherapy, will have their tumors recur soon after completion of treatment. Adjuvant therapy using immunotherapy has helped control minimal residual disease in the bone marrow, slowing down the likelihood of marrow relapse. For metastatic neuroblastoma, we have focused on passive immunity, whereby patients are not asked to develop immunity on their own, but where antibodies or antibody-based therapies are given to them. Monoclonal antibodies (MoAb) can destroy tumor cells by inducing cell death, complement-mediated cytotoxicity (CMC), and antibody-dependent cellular cytotoxicity (ADCC). Following treatment with first generation mouse antibodies, patients with metastatic neuroblastoma have maintained their remission for years. More recently, MoAb conjugated with radioisotopes administered into the cerebral spinal fluid (CSF) has changed the natural history of recurrent relapses in the brain or leptomeninges, with many of these children being alive and well. Since passive immunity for 12 to 24 months following chemotherapy will permit adequate time for the complete repair of the damaged immune system, vaccines can be successfully applied after that time frame. To that end, we are actively pursuing a vaccine program to engage both the humoral as well as cell-mediated immunities to benefit these children afflicted with neuroblastoma.
Our second generation MoAb now consist of chimeric and humanized antibodies directed at GD2, B7-H3, CSPG4 and L1CAM. It has been known for some time that affinity of antibodies for Fc receptors and for the tumor can have major influence on clinical efficacy. Hence, our third generation MoAb have focused on novel Fc glycoforms with greatly improved affinity for the Fc receptors, which in turn translate into considerable improvements in ADCC properties against tumors. Using X-ray crystallography, the structures of these antibodies are now known, allowing docking of antigens to map the contact residues accurately and to design mutations in order to optimize binding. These energy-optimized sequences provide the blueprints for our fourth generation MoAb.
By using these antibodies as vehicles, novel isotopes including those that emit positrons, beta particles and alpha particles, can now be delivered to the tumor cells. Utilizing these antibodies, bispecific reagents are made to direct T cells and NK cells to tumor sites. Going beyond the known tumor-associated antigens, MoAb can now be derived from large phage display libraries against peptide-HLA complexes. All of these new generations of MoAb can be reshaped into single chain fragment (scFv) for building chimeric antigen receptors (CAR) to redirect T cells and NK cells. These antibody-based reagents are rapidly going through GMP-compliant production and into phase I/II clinical trials, with potential broad applications to a variety of pediatric solid tumors, to help control MRD in various body compartments, such as CNS and peritoneal cavity.
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Since metastases and treatment resistance are two major causes of death, we are concurrently performing SNP, transcriptome, exome, and whole genome sequencing analyses to define the genetic aberrations that drive CNS metastases, marrow metastases, and tumor resistance. This is the result of decades of carefully annotated and archived serial frozen tumor samples with the accompanying remission marrow or blood from individual patients at Memorial Sloan-Kettering Cancer Center. While individual genes and pathways are being unraveled, we have also focused on p53 pathway in resistant tumors, taking advantage of recently developed small molecules to overcome their defects. In addition, using high-throughput drug screening we have identified several classes of potent compounds for chemo-resistant cell lines. These agents are being tested further for their in vitro and in vivo antitumor effects, with the ultimate goal of identifying optimal doses and schedules that can substantially enhance the efficacy of standard agents to prevent or overcome resistant disease.
Integration of these strategies into clinical trials will help our patients to survive this devastating cancer and improve their quality of life. The best chance of success is when therapy is applied at the time of MRD, and applied in the appropriate compartments. A sensitive and accurate measurement of MRD becomes critical in order to quantify the magnitude of tumor response and to detect early relapses. Using genomic wide screens, we have identified highly sensitive novel markers for a number of solid tumors. Panels of these markers have been successful in predicting patient outcome. The ability to use them in the future for treatment decisions as part of a coordinated effort of rationally prioritized clinical trials will be critical if we want to rapidly accomplish our treatment goals. We strongly believe that the optimal use of antibody-based therapies, vaccines, and pathway-specific inhibitors will complement what chemoradiotherapy and surgery have already achieved to give our patients the best chance of cure.