ChE PhD Dissertation Defense: Victoria Duback

Name:
Victoria Duback

Title:
Pharmacokinetic and Pharmacodynamic Assessment of a T Cell-Targeted Vector for In Vivo Car-T Cell Therapy

Date:
06/05/2024

Time:
10:00:00 AM

Committee Members:
Prof. Abigail Koppes (Advisor)
Prof. Ryan Koppes
Prof. Debra Auguste
Dr. Kutlu Elpek

Location:
Kariotis 309

Abstract:
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated transformative efficacy in the treatment of B-cell malignancies, particularly through autologous approaches. However, the clinical utility of autologous CAR-T therapy is limited by complex manufacturing processes, patient-specific variability, and the requirement for lymphodepletion, which can delay or prevent treatment for critically ill patients. In vivo-generated CAR-T cell therapy offers a promising alternative by enabling the direct genetic engineering of T cells within the patient, potentially streamlining treatment and expanding access.

This dissertation focuses on the preclinical characterization of a CD8-targeted lentiviral fusosome designed to deliver a CD19-specific CAR transgene in vivo. The overarching objective of this work is to understand the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of in vivo CAR-T cell generation to inform the development and clinical translation of nextgeneration gene therapy products. In vitro experiments demonstrated efficient and selective transduction of both resting and pre-activated CD8⁺ T cells, with enhanced CAR expression and function in pre-activated populations. A humanized mouse model was optimized to evaluate vector performance in vivo, incorporating engraftment of human PBMCs and CD19⁺ tumor cells to assess efficacy, biodistribution, and dose-response relationships.

Pharmacokinetic studies revealed rapid clearance of the vector in naïve mice, while the presence of target T cells significantly prolonged vector persistence, likely through cellular binding and internalization. Dose-dependent CAR-T cell generation and tumor suppression were observed, with no signs of fusosome-related toxicity. Importantly, donor-to-donor variability was noted, emphasizing the need for robust model systems in predicting clinical outcomes. To further enhance the fusosome potency, novel constructs incorporating CD3-mediated activation signals were engineered, resulting in improved gene integration and functional CAR-T activity in vitro. Together, these studies provide critical insight into the PK/PD relationship of in vivo CAR-T cell therapies and establish a strong preclinical foundation for the continued development of clinically viable, targeted lentiviral vectors for the treatment of B cell malignancies.

Victoria (Tori) Duback is a third-year doctoral candidate in the Chemical Engineering department at Northeastern University, pursuing a Ph.D. in Engineering with a focus on viral vector gene delivery. She is expected to graduate in June 2025. Her research focuses on characterizing targeted gene delivery systems, and her thesis examines the pharmacokinetics and pharmacodynamics of a T-cell-targeted vector for the treatment of B-cell malignancies. In parallel with her academic pursuits, Tori is a seasoned industry professional, serving as a Senior Scientist at Sana Biotechnology in the T-cell therapeutics group. Over the past several years, she has played a pivotal role in the design and evaluation of cutting-edge immunotherapies. She leads a team of scientists dedicated to assessing the safety and efficacy of in vivo generated CAR-T cells and allogeneic CAR-T cell therapies, conducting studies both in vivo and in vitro. Beyond the lab, Tori is a passionate advocate for STEM education and community engagement. She has mentored high school students across the Boston Public Schools, promoting early exposure to careers in science and engineering. Her commitment to mentoring and education reflects her belief in creating more inclusive and accessible pathways into scientific research. Looking ahead, she aims to continue growing as a scientist in industry, with a focus on developing safe, effective, and accessible therapies for patients in need. In her free time, Tori enjoys traveling, outdoor activities, and spending time at the beach.