Claire McClain
BME PhD Proposal Presentation

Date: 2022-10-25
Time: 10:00am -11:00am
Location / Meeting Link: https://gatech.zoom.us/j/92755620190

Committee Members:
Susan Thomas PhD (Advisor) ; Melissa Kemp, PhD ; Krishnendu Roy PhD ; Erik Dreaden PhD ; Chrystal Paulos PhD


Title: Mobilizing lymph node-harbored lymphocytes to potentiate immunotherapy

Abstract:
Immunotherapies that modulate a patient’s endogenous adaptive immune response to elicit their effects that range from adoptive cell therapies (ACT) to immune checkpoint blockade (ICB) are now mainstays of clinical management of most malignancies. However, rates of patient response to immunotherapeutic regimens remain disappointingly low, a result thought to reflect a lack of a robust tumor antigen-specific lymphocyte pool in the patient. To overcome this, the potential of vaccination approaches as well as the ex vivo engineering of therapeutic cells to express a synthetic antigen receptor are being explored. Yet both require laborious patient haplotyping and antigen sequencing or cell manufacturing practices that are not only time intense and startingly cost prohibitive, but also do not result in a diverse pool of antigen-specificities required to induce long term cures. Recent studies have suggested that ACT products that contain a higher percentage of a specialized subset of CD8+ T cells termed stem-like CD8+ T cells are more effective in tumor control. These stem-like CD8+ T cells have self-renewal capacity and thus preserve a pool of tumor reactive T cells that can differentiate into effector cells with anti-tumor functions. Stem-like CD8+ T cells are also now recognized as maintaining the tumor antigen-specific CD8+ T cell reservoir associated with therapeutic response to ICB in cancer. These cells largely reside in secondary lymphoid tissues such as lymph nodes (LNs), of which there are 300-500 in humans but are difficult to access with conventional drug delivery approaches. Eliciting the functions of tumor-specific stem-like CD8+ T cells harbored within LNs therefore represents a critical hurdle to more effective immunotherapy. My objective is to engineer the mobilization of a polyclonal stem-like CD8+ T lymphocyte pool into the circulation that can be therapeutically leveraged to improve cancer treatment. My central hypothesis is that T cell receptor (TCR) agonists directed to LNs in vivo will activate in an antigen-independent manner LN resident T cells to result in the mobilization of lymphocytes enriched for stem-like phenotypes into the circulation that can be modulated in situ using ICB or harvest by blood draw for ex vivo expansion to improve tumor control.