The Next Generation of Antigen-Specific T cells for Sarcoma Therapies for Sarcoma
Outcomes remain poor for patients with metastatic Synovial Sarcoma (SS) and Myxoid/ round cell liposarcoma (MRCL). Immunotherapeutic approaches may be well suited to SS and MRCL because both of these sarcoma subtypes characteristically express high levels of cancer testis antigens (CT Antigens). These immunogenic proteins are typically seen in some cancers and the germ cells of testis, but not other adult tissues. Several CT Antigens, including NY-ESO-1, are strongly expressed by both SS and MRCL. We have developed a methodology to make antigen specific T cells from the peripheral blood of patients that can target NY-ESO-1 and other CT antigens; we have demonstrated clinical activity in vivo. While our tetramer-guided methodology is well suited to target numerous antigens in patients with multiple HLA types, there are several important hurdles that need to be overcome in order to optimize this therapy. First, tetramer-selected T cells take a long time to culture and there is considerable variability in the potency of the T-cell products. Secondly, particularly in these tumors where there may be inhibitory signaling in the tumor microenvironment, we need to assure consistently high T-cell activation. T cell therapy has resulted in durable responses for many cancer patients and we believe with the right cells, we can bring these results to patients with sarcoma. The specific aims of this proposal are: Specific Aim 1: To develop a library of high affinity, sarcoma-specific T-cell receptors for “off-the-shelf” individualized T-cell therapy. In this Aim, we will use single cell RT-PCR to sequence T-cell receptors (TCR) from tumor specific T cells targeting multiple antigens in patients with multiple HLA types. These T-cell receptors will be incorporated into a library for “off-the-shelf” individualized T cell therapy for patients with SS and MRCL. Specific Aim 2: To enhance the function of sarcoma specific T-cell receptors using a “co-stim” chimeric antigen receptor. In this aim, we will develop a new type of TCR engineered T cell that also carries a co-stimulatory chimeric antigen receptor (CAR). We have identified a target, B7-H3 that is highly expressed by soft tissue sarcomas. We will test whether the a B7-H3 targeting “co-stim” CAR can be inserted into cells with natural or engineered tumor specificity (such as those from Aim 1), causing increased tumor-specific T-cell activation.