Progress has been made against childhood cancer but 3 of 4 children diagnosed with cancer in 2012 will die of their disease, and survival rates are lower for adolescents and young adults. Current standard treatments are toxic, leaving many childhood cancer survivors with long-term side effects, some of which are life threatening themselves. The Immunology Section of the Pediatric Oncology Branch seeks to develop new, targeted therapies that harness the power of the immune system to treat childhood cancers. Immune based therapies seem capable of eradicating pediatric cancers that are resistant to current standard therapies, can potentially provide long term protection against tumor recurrence, and are less likely to cause long term life threatening toxicities.
Using a bench-to-bedside-to-bench approach to research, we conduct basic science, preclinical models and clinical trials aimed at amplifying antitumor immune responses in patients with pediatric cancer.
Our studies focus on three primary projects: I. Biology and Therapy of Lymphopenia II. Immunobiology and Immunotherapy of Pediatric Tumors and III. Clinical Immunotherapy Program in Childhood Cancer.
Project I seeks to improve understanding of the biology of T cell depletion and to develop new approaches to enhance immune reconstitution or to exploit changes in physiology induced by lymphopenia. Previously we elucidated an essential role for thymic pathways of T cell regeneration in the recovery from lymphopenia and described the limitations of this pathway present in cancer patients. We also discovered that interleukin-7, a cytokine produced by non-lymphoid stromal cells, augments thymic-independent immune reconstitution. In order to take these fundamental discoveries to the next level, we have devoted considerable effort to clinical development of rhIL7, as we posited that treatment with this agent would overcome the limitations present in patients with cancer. We undertook the first-in-human trials of this agent, demonstrating safety and biologic activity and we are currently conducting a trial of rhIL7, administered to children and young adults after treatment with dose intensive chemotherapy for high-risk pediatric solid tumors. Results thus far show that IL7 is well tolerated and potently hastens the pace of immune reconstitution following cytotoxic chemotherapy. Preliminary results also demonstrate that rhIL7 augments responses to a tumor vaccine. More recent studies have focused on increasing our understanding of soluble IL7R, which circulates in humans at high molar excess compared to IL-7, but has not been well studied. We were compelled to study this molecule because of recently published genetic data demonstrating that polymorphisms in IL7R predispose to autoimmunity. Our studies demonstrate that soluble IL7R is an important modulator of the bioactivity of IL-7 in vivo, such that increased IL7R levels potentiate the activity IL-7, and therefore predispose to autoimmunity. Future studies will determine whether soluble IL7R can be used to augment the potency of rhIL7 therapy.
Project II focuses on furthering our understanding of tumor immunology as it relates to the embryonal tumors that occur in children and on inventing and developing new immune agents to target pediatric tumors. Much energy is currently focused on developing chimeric antigen receptors to target pediatric tumors, given the exciting preliminary data in clinical trials targeting tumors in adults with chimeric antigen receptors. We posit that chimeric antigen receptors are likely to be highly effective at targeting pediatric tumors and that the ability to target cell surface antigens, irrespective of HLA type, makes the clinical development of these agents for pediatric tumors a real possibility. We currently have active preclinical studies underway using several chimeric antigen receptors, including those targeting CD19, CD22, GD2, FGFR4, ALK and B7-H3. T cells expressing these receptors are generated in the laboratory, then tested in vitro for activity against cell lines and in xenograft models. Those with high level potency and a favorable predicted safety profile are prioritized for clinical development. We currently have one open clinical trial of CAR therapy targeting CD19+ acute lymphoblastic leukemia, and plan to open trials targeting GD2+ solid tumors and CD22+ acute lymphoblastic leukemia within the next 12 months.
Project III is an active clinical trials program of immunotherapies in pediatric cancer. As discussed above, we are conducting the first in children trial of rhIL7 administered in the context of dendritic cell based tumor vaccines. We have also initiated a novel trial of activated NK cell therapy administered in patients with very high-risk solid tumors following allogeneic stem cell transplantation. This work builds on a previous study conducted by our group (Baird et al, Bio Blood and Marrow Transplant, 2011) wherein a non-myeloablative allogeneic peripheral blood stem cell transplant was administered to patients with ultra high-risk pediatric solid tumors. This study demonstrated a high level of safety and promising survival in this very high-risk population. In order to improve potency and to diminish the risk of GVHD, our current trial uses a T cell depletion platform followed by administration of activated NK cells generated using 4-1BB expressing artificial antigen presenting cells plus IL15. This is highly novel and represents the first such use of 4-1BB/IL15 activated NK cells in humans. We also completed the first in children trial of anti-TRAIL receptor 2 therapies in pediatric solid tumors that was recently published in the Journal of Clinical Oncology (Merchant et al, J Clin Onc, 2012, In Press). Results demonstrate good tolerability, and some evidence for antitumor effects as well as intriguing data suggesting an interaction between irradiation and TRAIL-receptor 2 agonists. We are hopeful that this Phase I experience will provide the basis for future Phase II trials of TRAIL-Receptor 2 agonists in pediatric solid tumors. Finally, we are also conducting the first in children study of an immune checkpoint inhibitor, anti-CTLA4, which has demonstrated activity in adults with malignant melanoma.
In summary, we believe that many immunotherapies for childhood cancer show promise for improving long term outcomes and we seek to leverage the recent dramatic progress in the field of immunotherapy for the treatment of pediatric cancer. We envision immunotherapy as a modality that can be added to lessen the doses of standard cytotoxic therapy needed to cure cancer and we believe that the most effective immunotherapy regimens are likely to be multimodal, including combinations of cell based therapies, monoclonal antibodies (or their derivatives), immunomodulators and/or cytokines.