BME PhD Proposal Presentation

Date: June 10th, 2019

Time: 2:00-3:00pm

Location: IBB Suddath Room 1128

Committee Members:

Gabe Kwong, PhD (Georgia Institute of Technology, Biomedical Engineering) (Advisor)

Andrés García, PhD (Georgia Institute of Technology, School of Mechanical Engineering)

James Dahlman, PhD (Georgia Institute of Technology, Biomedical Engineering)

Costas Arvanitis, PhD (Georgia Institute of Technology, School of Mechanical Engineering)

Haydn Kissick, PhD (Emory University School of Medicine)

Title: Remote control of antitumor immunity against intracranial tumors

Abstract:

Cytotoxic T lymphocytes (CTL) have tremendous curative potential as cell-based therapies for cancer and have proven effective across a range of tumor types, yet intracranial malignancies, such as glioblastomas (GBM), remain a significant challenge. Despite significant advances in the treatment of hematological cancers with T cells bearing chimeric antigen receptors (CARs), brain tumors escape engineered T cell recognition by employing a number of antigen escape strategies and by harboring immunosuppressive microenvironments that impede T cell function. These include antigen mutation or antigen loss and inhibition through immune checkpoint pathways PD-1 and CTLA-4. Moreover, biologics designed to enhance T cell activity (e.g., IL-2) or block inhibitory signals (e.g., αPD-1) affect both antitumor and endogenous T cell populations, resulting in widespread systemic toxicities that include off-target cell killing. Thus, methods that can enable spatially-defined control of T cell effector function and promote recognition of synthetic antigens by CAR T cells could convert immunologically “cold” tumors to “hot” and make aggressive malignancies, such as GBM, more vulnerable to effective antitumor T cell responses.

Inspired by the precision by which thermal cues can be delivered noninvasively by various approaches such as high-intensity focused ultrasound (FUS), we propose to engineer bioswitches (Aim 1) that allow for thermal control of T cell effector function in vivo (Aim 2). We will test our thermal control system in the setting of adoptive T cell transfer in preclinical models of GBM and breast cancer brain metastasis. Additionally, we propose to deliver synthetic antigens to render immune evasive GBM tumors vulnerable to CAR T cell recognition (Aim 3). This framework may improve the efficacy of engineered T cell responses against refractory malignant brain tumors.