T cell immunity is widely recognized as one of the best weapons against cancers and is usually most effective when tumors are small. However, it has been difficult to develop effective protocols in patients to stimulate the development and homing of immune T cells. Even after successful vaccination with professional antigen-presenting cells (APC), many tumors are rendered invisible to T cells due to loss of major histocompatibility complex (MHC) expression. In addition, tumor heterogeneity of T cell epitopes and inhibition of T cell signaling by cancer cells or by regulatory T cells continue to hamper meaningful clinical responses. 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. At present, while innovative research continues to investigate ways to recharge the damaged immune system, many there is still a high rate of relapse and morbidity.
For years we have focused on passive immunity, whereby patients are not asked to develop immunity on their own, but antibodies or antibody-based therapies, as well as killer cells, 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). We now know that Fc receptors and their polymorphism, complement receptors, and the absence of inhibitory ligands for natural killer cells can influence patient outcome. As proof of principle, mouse MoAb directed at GD2 or cell-surface glycoproteins such as B7H3 has been highly effective in prolonging patient survival and in the safe targeting of radioisotopes to solid tumors. This is particularly promising in patients with leptomeningeal and brain metastases. Our current research efforts are concentrated on (1) humanization of MoAb, (2) MoAb genetic and biochemical modifications to enhance ADCC, (3) arming MoAb with beta- and alpha-emitters for radioimmunotherapy (RIT), (4) expanding the antibody repertoire using human single chain Fv (scFv) phage display libraries, (5) improving MoAb affinity maturation in vitro, and (6) improving their engineering into scFv-fusion proteins. We believe that passive immunity for 12 to 24 months following chemotherapy will permit adequate time for the complete repair of the damaged immune system, after which vaccines can be successfully applied. We are actively pursuing a vaccine program to engage both the humoral as well as cell-mediated immunities toward these recalcitrant metastatic solid tumors in children.
Since chemotherapy resistance is a major cause of disease progression, we are also studying pathway-specific inhibitors, some of which are highly effective in their synergy with conventional chemotherapy. 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 arriving at optimal doses and schedules that can substantially enhance the efficacy of standard agents to prevent or overcome resistant disease. We expect these combinations to complement antibody-based immunotherapies.
While we continue to explore novel agents and treatment methods, we also devote substantial resources to develop molecular markers of minimal residual disease (MRD). This is because we believe that MRD, unlike gross disease, should be easier to eradicate and is truly the final hurdle to cancer cure. Using gene expression arrays, we have identified highly sensitive and novel markers for a number of solid tumors. Retrospective and prospective validations of these markers using clinical samples have shown promise.
Finally, unless these drugs and concepts can be integrated into the total treatment schema of patients, they remain unfulfilled promises. A coordinated schema of well-prioritized clinical trials continues to be actively developed to test different MoAb, radioimmunoconjugates and molecular markers of MRD. We are particularly interested in the clinical role of beta-glucan in enhancing ADCC and the potential of adoptively transferred allogeneic natural killer cells and their activators in immunotherapy. Immune functions of cells and sera from patients enrolled in these clinical trials are being closely monitored. New information from these studies has substantially changed the directions of our research and many of our treatment strategies.
