ZIA BC 011073 (ZIA) | |||
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Title | Immunobiology and Immunotherapy of Pediatric Cancer | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Mackall, Crystal | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,033,813 | Project Dates | 01/01/2007 - 00/00/0000 |
Fiscal Year | 2015 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Childhood Cancers (100.0%) |
Childhood Leukemia (40.0%) Leukemia (40.0%) Nervous System (10.0%) Neuroblastoma (10.0%) Sarcoma (50.0%) |
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Research Type | |||
Cancer Progression & Metastasis Systemic Therapies - Discovery and Development |
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Abstract | |||
Immunotherapy has demonstrated increasing success in the treatment of cancer, and emerging clinical studies illustrate the potential for immunotherapy to provide a fourth pillar for treatment of childhood cancer (surgery, radiation therapy, chemotherapy and immunotherapy). Several new classes and types of immunotherapeutics are emerging that open up the possibility of applying immunotherapy to an ever-increasing array of targets and cancers. This project leverages this explosion of technologies and insights in the immunotherapy domain to bear on the problem childhood cancer. We seek to answer fundamental questions about similarities and differences between childhood vs adult cancers as it relates to immune based therapies and to extend our understanding of specific factors that limit the effectiveness of immune based therapies for solid tumors compared to liquid tumors. A major accomplishment was publication of a report that defined myeloid derived suppressor cells as the basis for immune escape in murine rhabdomyosarcoma following treatment with the immune checkpoint inhibitor anti-PD1. Anti-PD1 is part of a new class of immunotherapeutics that circumvent immunosuppressive mechanisms used by cancer and allow natural, endogenous antitumor immune responses to emerge. Response rate of approximately 10-30% have been reported in malignant melanoma, lung cancer and renal cell carcinoma. This work used anti-PD1 in a model of a pediatric solid tumor, namely rhabdomyosarcoma. Briefly, treatment of mice with anti-PD1 prior to tumor inoculation completely prevented development of cancer, but delaying anti-PD1 treatment for even 7 days after tumor inoculation resulted in minimal benefit. We identified that rhabdomyosarcoma-induced expansion of myeloid derived suppressor cells that traffic to tumors via a CXCL1/CXCR1 axis. We therefore hypothesized that interruption of trafficking of myeloid derived suppressor cells to rhabdomyosarcomas could enhance the efficacy of anti-PD1 therapy. To do this, we created chimeras lacking CXCR2 on hematopoietic cells and we also treated animals with anti-CXCR2 blocking antibodies. In both cases, we observed regression of established rhabdomyosarcoma with anti-PD1 therapy. This work establishes MDSC as important mediators of immune escape in pediatric solid tumors and identified distinctions between the cells induced in adult tumors vs those induced in tumors of childhood. We also sought to determine whether the CXCL/CXCR axis was likely to play a role in human pediatric sarcomas. We first demonstrated that human sarcoma cell lines produce several CXCR ligands and furthermore, discovered that serum from patients treated on trials of immunotherapy had elevated levels of CXCL1 and CXCL8. Moreover, among patients with metastatic sarcoma, elevated CXCL8 levels were associated with poor prognosis. We therefore believe that the CXCL/CXCR chemokine axis represents a potential basis for developing therapies that could be used to augment the efficacy of immunotherapy for childhood cancer. This work was published as the cover article in Science Translational Medicine in 2014 and was also highlighted in Nature Reviews Cancer. A second accomplishment is completion of a study demonstrating that T cells genetically engineered to recognize a self antigen expressed in the thymus develop T cell leukemia through a process whereby the T cell receptor itself serves as an oncogene. We developed a T cell transgenic mouse in which the vast majority of T cells have specificity for ""survivin"" an anti-apoptotic molecule considered to be a universal tumor antigen. We hypothesized that survivin TCR transgenic mice would be immune to tumor growth as most tumors express high levels of survivin. Unfortunately and remarkably, these mice did not resist growth of implanted tumors, but rather T cell lymphoblastic leukemia developed in essentially all mice. This was not due to insertional mutagenesis. Rather, self-reactivity with survivin a |