Project 2: Adoptive Cell Therapies for Chordomas

PROJECT 2: ABSTRACT 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 >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.