One of the most promising approaches in immunotherapy is activating antitumor immunity in patients by 'checkpoint blockade' referring to the use of antibodies that block immuno-inhibitory pathways switched on by cancer cells. A growing number of cancers that respond to these checkpoint blockades have now been described in patients. Antibodies that block CTLA-4 (ipilimumab) and PD-1 (pembrolizumab) have been approved to treat patients with melanoma, renal-cell carcinoma and non-small-cell lung carcinoma with durable clinical responses. However as checkpoint blockade becomes a promising therapeutic avenue for cancer therapy, current preclinical models are not able to recapitulate the antitumor immune responses mediated by checkpoint blockade therapies. This is partly because of the inherent differences between the mouse and the human immune systems. HuMurine Technologies was founded in 2008 as a CRO to standardize and optimize the construction of 'humanized' mice (Hu-M(tm) platform) stably engrafted with a human immune system. The Hu-M(tm) platform has been successfully implemented for evaluating therapies that specifically target the human immune system in a wide range of diseases models. In order to address the high unmet need for a robust preclinical platform for testing the efficacy and safety of novel immunotherapies HuMurine has partnered with Champions' Oncology to develop and validate the PDX/ Hu-M(tm) platform using the approved immune- checkpoint modulators Ipilimumab and Pembrolizumab. This development process will also included consultation with potential end users of the platform including major pharmaceutical companies and biotech's which demonstrates a strong commercialization plan for the platform post-validation. This proposal aims to address a part of "NCI's provocative questions initiative" about the development of appropriate model systems to understand the human immune responses within the tumor microenvironment. Validated of this novel PDX/Hu-M(tm) platform would significantly reduce the high attrition rates of immunotherapeutics in clinical trials. The Specific Aims of this proposal are: Aim 1: Determine if Ipilimumab treated HLA-A2- matched melanoma PDX/ Hu-M(tm) mice generates a tumor- specific T cell response. Aim 2: Determine antitumor efficacy of combinational checkpoint blockade of CTLA-4 and PD-1 in HLA-A2 matched melanoma and NSCLC PDX/ Hu-M(tm) mice.
Public Health Relevance Statement: Public Health Relevance: Patient Derived Xenograft (PDX) in Humanized NOG Mice: Evaluation and Validation of Immuno- oncology Agents Targeting immune checkpoints using monoclonal antibodies are a novel and highly effective strategy to combat a variety of cancers by activating the antitumor immune response. "Humanized" (Hu-MTM) mice, stably engrafted with a human immune system, will be engrafted with patient derived xenotransplant (PDX) melanoma and non-small-cell-lung-carcinoma (NSCLC), representing tumors that are derived from patients without being passaged in culture. Ipilimumab and Pembrolizumab, two clinically approved immunotherapies, will be tested in this novel mouse model (PDX/ Hu-M(tm)) to establish whether this platform can be used to screen the anticancer effects and preclinical safety of new and upcoming immune checkpoint therapies.
NIH Spending Category: Biotechnology; Cancer
Project Terms: Address; Adverse effects; Adverse event; Aftercare; Allogenic; Animal Model; Antibodies; B-Lymphocytes; base; Biological Models; biomarker identification; Biotechnology; Blocking Antibodies; cancer cell; cancer immunotherapy; cancer therapy; CD14 gene; CD19 gene; CD34 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Maturation; Cells; Characteristics; Checkpoint therapy; Clinical; Clinical Research; Clinical Trials; cohort; combat; Combined Modality Therapy; commercialization; Consultations; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Development; Disease model; Drug Kinetics; Effectiveness; efficacy testing; Engraftment; Evaluation; Face; Generations; Genetic; Genetic Drift; Hematopoiesis; Hematopoietic stem cells; HLA-A2 Antigen; Human; humanized mouse; Immune; immune activation; Immune response; Immune system; Immune Targeting; Immunity; Immunotherapeutic agent; Immunotherapy; implantation; In Vitro; Individual; Injection of therapeutic agent; Lymphangiogenesis; macrophage; Malignant Neoplasms; Mediating; melanoma; Molecular Profiling; Monoclonal Antibodies; mouse model; Mus; Natural Killer Cells; NCAM1 gene; Neoplasms; Newborn Infant; Non-Small-Cell Lung Carcinoma; novel; novel strategies; oncology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Phase; pre-clinical; Pre-Clinical Model; preclinical safety; Prevention; Process; public health relevance; Publishing; Qualifying; Renal Cell Carcinoma; Reporting; response; Safety; screening; Signal Transduction; Small Business Innovation Research Grant; Specificity; Stromal Cells; success; T cell response; T-Lymphocyte; targeted agent; Technology; Testing; Therapeutic; treatment group; tumor; tumor growth; tumor microenvironment; tumor xenograft; Tumor-Derived; Validation; Xenograft Model; Xenograft procedure
