The Pediatric Osteosarcoma Research Program (POSRP) at The University of Texas MD Anderson Cancer Center will focus on identifying targets for developing novel therapeutics for the bone cancer, osteosarcoma (OS). OS is the most common bone cancer in children, adolescents, and young adults. OS can quickly spread to other parts of the body, and for patients with tumors that have spread to other parts of the body or tumors that have recurred, the survival rate drops to less than 30% at 5 years after initial diagnosis. After diagnosis, OS is treated with surgery and intensive systemic chemotherapy, and this therapeutic regimen has not changed in decades, despite dismal and stagnant outcomes for ...

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The Pediatric Osteosarcoma Research Program (POSRP) at The University of Texas MD Anderson Cancer Center will focus on identifying targets for developing novel therapeutics for the bone cancer, osteosarcoma (OS). OS is the most common bone cancer in children, adolescents, and young adults. OS can quickly spread to other parts of the body, and for patients with tumors that have spread to other parts of the body or tumors that have recurred, the survival rate drops to less than 30% at 5 years after initial diagnosis. After diagnosis, OS is treated with surgery and intensive systemic chemotherapy, and this therapeutic regimen has not changed in decades, despite dismal and stagnant outcomes for patients with metastatic, malignant disease. Furthermore, no rapid, minimally invasive assay methods have been developed to detect potential biomarkers to determine which patients will or which patients will not respond to therapy. Recent biomarker studies have shown that exosomes, which are nano-sized particles shed from tumor cells into the blood circulation, contain proteins, lipids, nucleotides, etc. that reflect their cell of origin as well as surface proteins that target recipient cells and can be immunomodulatory. Exosomes can provide useful information on tumor evolution, metastasis, and risk for cancer recurrence and/or relapse. Exosomes can be safely obtained from serial blood samples obtained throughout the duration of treatment with a routine blood test, unlike conventional biopsy-based monitoring methods that cannot usually be repeated due to prohibitive risk or expense. Project 1 will analyze exosomes, both exosome cargo inside and exosome cell surface proteins, from the blood of OS patients as potential, predictive biomarkers of disease progression or recurrence. Data from Project 1 will be analyzed by investigators in Core 2 (i.e., Biostatistics and Bioinformatics Core), who have much experience in biomarker-integrated translational research. Project 1 has identified and will continue to identify cell surface proteins on OS tumors, themselves, to be used by Project 2 in developing new therapies: antibody-drug conjugates (ADCs) as well as ADCs comprising bi-specific antibodies (BsADCs) that bind to more than one target simultaneously. Project 1 will also uncover cell surface protein modifications, such as sugar and peptide moieties on proteins, as to their ability to be targeted by drug and immune-based therapies. Project 2 has already developed a tool ADC that has shown remarkable anti-tumor efficacy and low toxicity in preclinical models. Preclinical efficacy and toxicity and optimization of ADCs and BsADCs will be supported by Core 2, which will provide statistical design, sample size and power calculations. Core 1 (i.e., OS Model/Cell Core) will supply these preclinical models, treatment-sensitive and treatment-resistant preclinical models, as well as OS tumor cells and non-tumor cells to Project 1 to identify cell surface proteins and cell surface protein modifications, Project 2 for testing novel ADCs comprising one or more different cell surface protein targets and circumventing resistance to these ADCs, as well as to Project 3 for preclinical testing immune cell-based therapies. Core 2 will provide innovative, semi-mechanistic early phase clinical trial designs to Project 3 that systematically incorporate pharmacokinetic (PK) and/or pharmacodynamic (PD) information. Core 1 will also provide cells that are barcoded to trace the genealogies and/or lineage trees of the cells in Project 2 and Project 3. These barcoded OS tumor cell lines and non-tumor cells lines will serve as tumor progression models and help to overcome any resource limitations of other preclinical models, allowing for large-scale, high-throughput screening of therapies. These barcoded OS cell lines will help distinguish between an intrinsic lack of response to therapy and therapeutic resistance, which will inform on how combination therapies may be optimally leveraged. Project 3 will develop the next generation of immune cell-based therapy, wherein these immune cells are collected from the individual patient and re-engineered in the laboratory into chimeric antigen receptor (CAR) T cells. CARs recognize and bind to specific proteins, called antigens, on the surface of cancer cells, and these CAR T cells kill the cancer cells. CAR T cells have been a cure for some blood cancer patients, leading to the patients' long-term survival. The synergistic research projects and cores of the POSRP have the potential to significantly impact the long-term survival of pediatric cancer patients with OS by offering new treatment options, which may produce less side effects with the potential to cure those with recurrent and/or relapsed, metastatic disease. Metastatic OS patients have a poor overall survival, and the immune-based therapies representing immune checkpoint inhibitors have not been successful in all patients and have been associated with severe side effects. Although immune checkpoint inhibitors are considered a breakthrough in cancer treatment and have successfully treated dozens of tumor types by removing the "brakes" from the patient's own immune system, allowing anti-tumor immune responses, the reasons that immune checkpoint inhibitors are not effective in OS patients have been postulated to be due to immune inhibitory cells and molecules in tumors that facilitate immune escape of OS cells. Whereas immune checkpoint inhibitors are not specific to tumors, but rather block molecules on immune cells, CAR T cells are attracted to and migrate directly into tumors due to tumor antigen recognition by CAR T cells. Successful use of CAR T cells in treating solid tumors has remained a challenge, because of the physical barriers of the tissue surrounding tumors (i.e., stroma) and the immunosuppressive tumor microenvironment. The tumor microenvironment contains a variety of non-cancer cells, including cancer-associated fibroblasts (CAFs). CAFs generate extracellular matrix proteins, such as collagen, which help to create a physical barrier in the tumor microenvironment against therapies. To overcome this physical barrier and the immunosuppressive tumor microenvironment, the POSRP will re-engineer, in the laboratory, T cells that have already infiltrated into OS tumors (i.e., tumor-infiltrating lymphocytes [TILs]). These TILs are considered more reactive to tumors and are already primed to detect many other antigens within tumors than T cells circulating in the blood, from which CAR T cells have already been generated and are currently being clinically tested by POSRP investigators for the treatment of sarcomas. Within the POSRP, investigators will harvest TILs for engineering these cells to bind to a specific cell surface protein and will take advantage of the innate ability of TILs to detect many other tumor antigens. TILs will also be re-engineered to express and secrete a specific cytokine: interleukin-12 (IL-12). Human IL-12 administration to patients in clinical studies have shown remarkable results, but repeat administration is needed, which can lead to patient toxicities. Thus, the POSRP investigators have designed CAR T cells that release IL-12 at the tumor site; thus, capitalizing on the true anti-tumor potential of IL-12 without the risk of harm to patients. Furthermore, these IL-12-secreting CAR T cells do not induce dangerous cytokine release syndrome in patients, an adverse effect of administration of conventional CAR T cell therapy, and these cells, derived from TILs, seem to disrupt and penetrate the CAF-rich and collagen-rich stroma of OS. The POSRP will also perform cell surfaceome profiling of CAFs, which has never before been done in the field of OS research, and this profiling is anticipated to result in the identification of novel, non-tumor therapeutic targets for disrupting tumor stroma. Along with non-tumor targets, the POSRP will perform tumor cell target profiling from hundreds of OS tumors of known molecular subtypes, and these targets will be selected for targeted therapy development based on the minimal expression of these targets on normal cells. To guide the scientific direction and oversee the programmatic activities of the POSRP, an External Advisory Board (EAB) comprising members who are experts in the POSRP-relevant focus areas will be organized by the Administrative Core (AC). The AC will be established as part of the POSRP infrastructure to support, coordinate, and facilitate all POSRP activities aimed at achieving and evaluating the goals of the POSRP: 1) identify OS-specific therapeutic targets and immune epitopes, based on tumor cell and stromal cell (e.g., CAFs) surface proteins and their post-translational modifications; 2) utilize these targets in designing OS-specific therapies, such as ADCs, BsADCs, and adoptive T-cell therapies; and 3) test these therapies in preclinical models for efficacy and toxicity as well as for Investigational New Drug (IND)-enabling studies for applications to the United States Food and Drug Administration (FDA) for launching a Phase 1 clinical trial. The POSRP will have a significant scientific and societal impact because: 1) OS patients, with metastasis or recurrence, have poor survival; (2) OS patient survival has not improved and no new therapies have been FDA approved for OS in four decades; and (3) Bone cancers are rare, difficult to treat, and can acquire therapy resistance. The POSRP has built a foundation for success in that investigators have: (1) already established a cell surfaceome profiling workflow; (2) identified promising therapeutic targets; (3) access to barcoded cell lines and patient samples for generating patient-mimicking models for testing novel therapeutic agents; and (4) initiated a clinical trial testing a first-generation immunotherapy that will be performed in parallel to the development of a second-generation immunotherapy.

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