Our long-term goal is to cure metastatic solid tumors in children. In most cases, these cancers are initially treated with dose-intensive therapies. Although efficacious for bulk disease, the damage caused by these therapies on immune competence requires months or even years to repair. Meanwhile, minimal residual disease (MRD) remains the obstacle to cure.
T cell immunity is widely recognized as the best effector arm against most tumors and should be most effective at the time of MRD. However, it has been difficult to develop effective protocols in patients to stimulate the development of immune T cells. Even after successful vaccination with professional antigen-presenting cells (APC), many tumors lose major histocompatibility complex (MHC) expression, rendering them invisible to immune T cells. In addition, tumor heterogeneity of T cell epitopes and inhibition of T cell signaling by cancer cells continue to hamper meaningful clinical responses.
Passive immunotherapy using monoclonal antibodies (MoAb) has recently shown efficacy against a variety of human solid tumors. If tumor to blood area-under-the-curve (AUC) ratio can be increased and their tumoricidal signals multiplied, antitumor effect may be improved substantially. Single chain V-fragment (scFv)-streptavidin separates the administration of the antibody from the cytotoxic moiety, decoupling the "slow" blood clearance from the "fast" kinetics of the small ligands. By means of biotin conjugation, the repertoire of drugs and biologics that can be targeted to tumor sites has vastly expanded. We propose to use scFv-chimeric immune receptors (CIR) to create artificial clonal populations from blood T cells without the need of preexisting immunity, such that they can target to novel tumor antigens including carbohydrates and lipids.
We have successfully exploited anti-idiotypic reagents to optimize the CIR technology and are developing sensitive tracking methods to study their homing properties. While developing scFv-chimeric genes and proteins in preclinical models, we continue to study the tumor itself. Neuroblastoma is our clinical focus, and we use expression arrays on fresh tumors and tumor stem lines to define novel targets and pathways. Based on these arrays we have identified highly sensitive markers for monitoring MRD in patients. We now take advantage of the CR3 receptor on human white cells to enhance their FcR-mediated tumor cytotoxicity. Strategies to enhance CR3 function include the use of รข-glucans and other polysaccharides. These various approaches are currently being tested in clinical trials.
