Engineering technologies to enrich optimal phenotypes in CAR T cells Restricted; Files Only
Lin, Heather (Spring 2025)
Abstract
Chimeric antigen receptor (CAR) T cell therapy has remarkably changed the clinical treatment landscape for hematologic malignancies. However, significant barriers remain to achieving durable responses in some hematologic malignancies and for the meaningful treatment of solid tumors. Here, we investigate several different engineering technologies to improve CAR T cell therapy to address different clinical needs. First, we developed and validated a multi-cytokine particle (MCP) platform to screen for improved manufacturing reagents that yield optimal CAR T cell phenotypes associated with durable responses in large B cell lymphoma. We show that fine-tuning the signals decorated on an MCP can generate CAR T cells that outperform those made from standard manufacturing reagents against both hematologic and solid malignancies. Secondly, we identify the novel application of mucin 16 ectodomain (Muc16CD)-targeting CAR T cells to target pancreatic cancer. We show that Muc16CD is a valuable addition to the repertoire of pancreatic tumor-associated antigen targets for CAR T cell therapy. Thirdly, we discuss in depth the current state and limitations of combining CAR T cell therapy with canonical immune checkpoint inhibitors (ICI). Lastly, we demonstrate an armored CAR T cell whose novelty lies in 1) secreting antagonistic peptides that bypass intrinsic biology and 2) targeting an emerging immune checkpoint pathway, vasoactive intestinal peptide (VIP) signaling. We show that these novel armored CAR T cells are uniquely memory-enriched, exhaustion-resistant, and metabolically fit to overcome patient-derived pancreatic tumors. Ultimately, the work presented here demonstrates several new engineering technologies that improve the phenotypes and functions of CAR T cells with the ultimate goal of translation to the clinic to improve treatments for patients.
Table of Contents
Abstract
Acknowledgments
Table of Contents
List of Figures
List of Supplementary Figures
List of Tables
List of Abbreviations
Chapter 1: Introduction
1.1. Looking Under the Hood of CAR T Cells
1.2. Touring the Clinical Eras of CAR T Cells
1.3. Summary, Scope, and Goals for This Dissertation
Chapter 2: Engineering Improved CAR T Cell Products with a Multi-Cytokine Particle Platform for Hematologic and Solid Tumors
2.1. Abstract
2.2. Introduction
2.3. Results
2.4. Discussion
2.5. Materials and Methods
Chapter 3: Muc16CD is a Novel CAR T Cell Target Antigen for Pancreatic Cancer
3.1. Abstract
3.2. Introduction
3.3. Results
3.4. Discussion
3.5. Materials and Methods
Chapter 4: Combination of CAR T Cell Therapies with Immune Checkpoint Inhibitors
4.1. Abstract
4.2. Key Points
4.3. Introduction
4.4. Rationale behind combination therapy
4.5. Clinical trials of CAR T cells and ICI combination therapy
4.6. Engineering strategies
4.7. Future directions and conclusions
Chapter 5: Modulating the VIP/VIPR pathway reprograms superior CAR T cells
5.1. Abstract
5.2. Introduction
5.3. Results
5.4. Discussion
5.5. Materials and Methods
Chapter 6: General Discussion and Closing Remarks
6.1. Clinical Translation of CAR T Cells
6.2. The Three E’s for a Successful CAR T Cell Trial in Solid Tumors
6.3. Incision to Improve Precision: The Role of Surgery with CAR T Cell Therapy
Chapter 7: References
About this Dissertation
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File download under embargo until 22 May 2031 | 2025-03-18 11:21:15 -0400 | File download under embargo until 22 May 2031 |
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