Children's Research Institute (CNMC) Archives

2018

Young Investigator

Amy Houghtelin

Washington, DC

Optimizing T Cell Therapy for Patients with High Risk Solid Tumors

Many pediatric patients with high risk solid tumors (sarcomas, Wilms tumor and neuroblastoma) have a poor prognosis. Patients with primary refractory or relapsed disease not amenable to surgery, as well as patients with metastatic disease resistant to standard treatment, have an overall survival of less than 25%. Additionally, salvage treatments are often associated with significant long term sequelae. T cell based immunotherapies are promising alternatives for pediatric patients with refractory malignancies, and have been shown to be safe and effective in preliminary data for other malignancies. While T cell therapies, like chimeric antigen receptor (CAR) T cells targeting CD19 have been successfully used against hematologic malignancies, efforts to harness this same approach for solid tumors have been less robust. This is likely a result of the complex nature of the tumor and microenvironment seen with solid tumors, which employ numerous immunosuppressive strategies to evade recognition by the immune system. Many solid tumors have increased intratumoral genetic complexity, precluding the targeting of single antigens. We propose that the simultaneous targeting of multiple tumor-associated antigens (TAA) by a mixed population of T cells may be an effective way to overcome the tumor immune escape mechanism of antigen loss. However, there are other mechanisms by which tumors evade the immune system, leading to resistance to T cell immunotherapy. For example, tumors create an immune tolerant environment via the secretion of TGFbeta, which has devastating effects on T cell function and proliferation in vivo. This proposal seeks to evaluate anti-tumor immunity in patients following infusion of multi tumor-associated antigen-specific T cells (TAA-T). This includes the identification of the mechanisms underlying treatment resistance, evaluation of tumor samples for the expression of tumor associated antigens in the presence and absence of demethylating agents. Further, we will evaluate whether TAA-T cell cytolytic function can be enhanced by genetic modification with a dominant negative TGFbeta receptor (DNR-TGFbeta). These findings will contribute to the optimization of T cell immunotherapies for a broader group of patients with solid tumors, identify new therapeutic targets, and pave the way for the successful development of combination immunotherapies.