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Expand the sections below to learn more about the research projects within the SPORE.

Project Leader: Cassian Yee, M.D. (Basic Co-Leader) | Co-leader: Anthony Conley, M.D. (Clinical Co-Leader)

Chordoma in its advanced stages is refractory to conventional therapy and, thus, new and novel therapies to treat advanced disease represent a clear unmet need. Immune checkpoint therapy has seen only modest responses and adoptive cellular therapy (ACT), has been unavailable for chordoma due to a lack of an immunogenic target. In this proposal we address major challenges to advancing the use of ACT for chordomas. In that regard, we have recently identified several highly immunogenic and novel antigens and epitopes such as Brachyury, a T-box transcription factor (TBXT) overexpressed in 95% of chordomas presented by HLA-A2 and A24.

We propose to perform a first-in-human Phase IB clinical trial of ACT targeting Brachyury using a cell therapy modality developed in our lab, known as ETC (Endogenous T Cell) therapy. ETC is an ACT modality that we pioneered and refined over the last 15 years through a series of first-in-human studies using enabling technology to isolate antigen-specific CD8 memory T cells from the peripheral blood and expanding these to more than 10 billion cells of uniform specificity and phenotype. Due to the highly persistent features of ETC central memory CD8 T cells, no lymphodepletion is required. Building on this novel discovery of Brachyury antigen/epitope-specific ETC cells and our years of clinical trial expertise, we propose to evaluate the safety, in vivo persistence and anti-tumor efficacy of this adoptively transferred Brachyury-specific T cells in a Phase IB trial. This trial could be extended further by including other novel element such as immune checkpoint inhibitors (ICIs) and/or IL-7 due to the absence of serious toxicities. Second, to empower the penetration of this effective ETC cellular therapy, we propose to evaluate the next generation Brachyury ETC therapy by engineering these chordoma-specific ETC cells with our proprietary stroma/collagen destructing attIL-12, developed at MD Anderson by our co-investigators in preclinical models. The clinical trial using T cells targeting Brachyury, will serve as a platform for the future development of this preclinical asset, and enable a combination-based approach for the treatment of patients with chordoma.

Leader: Richard Gorlick, M.D. (Basic Co-Leader) | Co-leader: Andy Livingston, M.D. (Clinical Co-Leader)

Strategies to reduce the morbidity and mortality from pediatric osteosarcoma (OS) are critically needed. About 30 to 40% of OS patients recur after receiving highly toxic chemotherapy. In the past three decades, there have been no new therapies successfully developed for this cancer. Antibody drug conjugates (ADCs), designed to specifically bring cancer drugs, known as payloads, to tumor cells while leaving normal cells unharmed, represent a promising strategy.

Several ADCs have been approved by the Food and Drug Administration (FDA) for a variety of cancers, but none for osteosarcoma. Thus, this project will focus on the development and clinical translation of ADCs specific to surface proteins abundantly present in OS coupled to relevant payloads. Preliminary data provides compelling evidence that OS expresses readily available cell surface proteins which can serve as potential targets for therapies and could serve as epitopes for endogenous immune responses and immunotherapies. To clinically translate newly developed immunotherapies and targeted therapies more efficiently, determining which OS patients will or which patients will not respond to therapy is key for appropriate patient selection. Selecting which patients are likely to respond could be guided by the identification and validation of blood biomarkers. Recent biomarker studies have shown that exosomes, which are representative of and shed from tumor cells into the blood circulation, can provide useful information on tumor evolution, metastasis, and cancer recurrence and/or relapse risk.

In the first aim of this work, studies of ADCs targeting cell adhesion molecule 1 (CADM1), a protein highly expressed in OS, will be performed in OS patient derived xenograft (PDX) models for payload optimization, understanding of emerging drug resistance, and as studies to enable IND filing. In the second aim we will develop bispecific antibodies (Bs)ADCs that target two different OS surface proteins. While the terminology bispecific usually refers to antibodies which lead to T cell engagement, in this case our goal is to combine two different antigen targets on one antibody to enhance affinity and specificity. Our intent is to focus on combining CADM1 and T-cell checkpoint ligand B7-homologue (B7H3), which is also known to be a highly relevant target in OS. These bispecific antibodies will be tested for efficacy as ADCs. In the third aim a phase 1/2 trial of an already developed ADC will be conducted in patients with osteosarcoma. In addition to evaluating the safety and preliminary efficacy of an B7H3-targeting ADC, this aim will also allow the development of an OS liquid biopsy approach using circulating exosomes to identify signatures predictive of response to treatments. Biospecimens obtained in this trial as well as other acquired OS samples, will permit additional profiling of the cell surfaceome (both proteins and their post-translational modifications) to identify novel, preliminary OS surfaceome targets as well as explore drug resistance. It is expected that this work will significantly improve the lives of OS patients through the identification of effective and potentially less toxic therapies.

Expand the sections below to learn more about the cores within the SPORE.

Director: Richard Gorlick, M.D. | Co-Director: Andrew Futreal, Ph.D.

The MD Anderson Sarcoma SPORE Administrative Core will provide administrative and budgetary support to ensure the maximal success of the program. It will form the coordinating center for interactions within the MD Anderson SPORE community, as well as the community at large. The core will be co-directed by Richard Gorlick, M.D., and Andrew Futreal, Ph.D., and supported by the SPORE research program manager. The goals of the core will be to provide coordination, oversight and monitoring for the two projects, the Biostatistics and Bioinformatics Core and the Tissue and Pathology Core. In addition, it will coordinate the Developmental Research (DRP) and Career Enhancement (CEP) Programs. The overarching goals of the core are to facilitate collaboration amongst Sarcoma SPORE investigators, institutional efforts and external entities, including other SPORES and the National Cancer Institute, as well as to coordinate Sarcoma SPORE clinical trial activities. The core will support the activities of the Executive Committee, which is composed of the co-directors, project co-leaders and core co-directors.

Director: Alexander Lazar, M.D., Ph.D. | Co-Director: Wei-Lien Wang, M.P.H., M.D.

The Tissue & Pathology Core will coordinate efforts related to collection, processing, storage and distribution of annotated human and murine biospecimens for all of the MD Anderson Sarcoma SPORE projects, including the projects from the Developmental Research Program (DRP) and Career Enhancement Program (CEP) awardees. The core will be co-led by Alexander J. Lazar, M.D., Ph.D. and Wei-Lien (Billy) Wang M.P.H., M.D., two nationally reputed sarcoma pathologists with more than a decade of close collaboration. The Tissue & Pathology Core will work with all SPORE Projects (including DRP and CEP projects), CCSG Cores and collaborator laboratories and with the Administrative and Biostatistics & Bioinformatics Cores, to ensure maximum efficiency of tissue/derivatives.

The core will provide optimization of fresh tissue collection, analyte (DNA, RNA, protein) extraction from prospectively collected and archival tissue samples suitable for molecular and immunological interrogation, and the conduct of NanoString gene expression profiling. The samples and/or analytes isolated from biospecimen will be distributed to SPORE Projects and other investigators in accordance with core operating procedures. Existing sarcoma biospecimen resources available in institutional tissue banks include snap frozen tumor tissue samples from over 4,000 sarcomas, with about 30% of these directly relevant to the SPORE Projects. Formalin fixed paraffin embedded specimens are available for over 8,500 sarcoma cases over just the last 15 years, including tissue microarrays from 15+ sarcoma types (4,000+ cases arrayed). In addition, the core will provide histologic characterization, immunohistochemistry services, and interpretation guidelines for both preclinical samples from the mouse model studies in Projects 2 and 3, as well as serial human tissue biopsies obtained from the two clinical trials being conducted in Projects 2 and 3. Blood will also be processed for flow cytometry and exosome isolation in Projects 2 and 3. The core will coordinate distribution of appropriate samples to investigators funded through the SPORE CEP and DRP. Core personnel, along with the Institutional Tissue Bank, will enter detailed information related to all processes of biospecimen collection, processing, qualification, distribution and analyte extraction into the institutional biospecimen informatics platform known as Biospecimen Information Management System (BIMS?). This centralized resource will contribute significantly to the success of the multidisciplinary and translational research projects outlined in this proposal.

Director: Yisheng Li, Ph.D. | Co-Director: Xiaoping Su, Ph.D.

The primary goal of the MD Anderson SPORE in Sarcoma is to reduce the morbidity and mortality from sarcomas through innovative translational research focused on immunologic and targeted treatments, based upon the underlying genetic aberrations contributing to the pathophysiology of the disease. This is a collaborative effort that will accomplish these aims by integrating laboratory and translational research.

The Biostatistics and Bioinformatics Core will serve multiple needs for the planning and conduct of the SPORE's research. Based on a strong track record for providing biostatistical and computational support for translational research, this core will be a comprehensive, multi-lateral resource for designing clinical and basic science experiments, performing statistical analyses, developing innovative statistical methodology, and sharing the data and publishing the research results generated from this Sarcoma SPORE. The Biostatistics and Bioinformatics Core will provide guidance in the design and conduct of clinical trials and other experiments arising from the ongoing research with the SPORE Projects, Developmental Research and Career Enhancement projects, and other cores. This core will also provide biostatistical and bioinformatic modeling, simulation techniques and data analyses needed by the projects and other cores to achieve their specific aims.

The Biostatistics and Bioinformatics Core will generate statistical reports for all projects, will assist project investigators in publishing and sharing scientific results and will develop innovative statistical and bioinformatics methods pertinent to translational sarcoma studies including novel early phase adaptive clinical trial designs incorporating mechanistic, such as pharmacokinetics and pharmacodynamics information, as well as novel statistical methods for clinical trial data analysis.