Improving Cellular Therapy for Solid Tumors – a Three-Pronged Approach Restricted; Files Only
Wittling, Megen (Spring 2026)
Abstract
T cell therapies have undoubtedly revolutionized cancer treatment. CAR T cell therapies are now standard of care for certain leukemias and lymphomas in the relapsed setting, and TCR and TIL therapies have recently emerged as FDA-approved options for patients with solid tumors. Despite these advances, there remains substantial room to improve the efficacy of adoptive cellular therapy (ACT), particularly for patients with hard-to-treat solid tumors such as melanoma and gastrointestinal malignancies.
Many barriers to successful ACT have been identified, including hostile tumor microenvironments, inefficient trafficking to tumors, limited T cell persistence, and challenges in selecting optimal target antigens. The body of work presented here directly addresses these obstacles with the goal of improving ACT for patients with solid tumors. Specifically, it focuses on enhancing T cell persistence, defining how antigen selection shapes T cell biology, and determining how costimulatory pathways influence the often underappreciated T helper 17 (Th17) cell subset.
First, this thesis reviews the current literature to define strategies being pursued to improve both CD8 and CD4 T cell persistence in adoptive immunotherapy. Approaches such as cytokine modulation, CAR T cell design, reduced ex vivo expansion time, lymphodepletion, and gene editing are discussed. Building on this framework, we then examine how chemotherapy and total body irradiation (TBI) as lymphodepletion strategies impact adoptively transferred, antigen-specific Th17 cells. While both approaches enhance antitumor immunity when combined with ACT, they differentially promote cytokine production and engraftment of transferred cells, revealing distinct biological consequences of these commonly used conditioning regimens.
Next, we address antigen selection as a critical determinant of ACT efficacy. We show that antigen-specific T cells more effectively target and eradicate tumors expressing high-avidity mutated antigens compared to tumors expressing low-avidity, tumor-associated or wild-type antigens. These transferred T cells gave rise to potent effector populations characterized by enhanced cytokine production and long-term persistence across multiple tissues. Successful antitumor responses by CD8 T cells also required effective trafficking through lymph nodes in established melanoma models. We extended these findings to tumor-infiltrating lymphocyte (TIL) therapy by developing the first murine TIL model for cholangiocarcinoma, a malignancy arising from epithelial cells of the biliary tract. Incorporation of tumor antigens during TIL expansion improved in vitro cytotoxicity, and these TILs mediated measurable antitumor responses when combined with anti-PD-L1 therapy. TIL therapy for colon cancer, another gastrointestinal malignancy, was also explored in murine systems, with a focus on how the tissue of origin and cytokine composition during expansion influence therapeutic efficacy.
Finally, we investigated mechanisms underlying the curative capacity of Th17 cells in melanoma models. These studies reveal a critical role for costimulatory signaling both during ex vivo expansion and following adoptive transfer. In particular, ICOS emerged as a key regulator of Th17-mediated antitumor immunity. Our findings demonstrate that costimulatory pathways can be strategically leveraged during T cell manufacturing and after transfer to enhance therapeutic outcomes. Collectively, this work defines how lymphodepletion promotes Th17 cell persistence, how antigen avidity and antigen exposure during expansion shape adoptively transferred T cells and TIL products, and how ICOS signaling can be exploited to improve current ACT and CAR T cell therapies.
Table of Contents
Chapter 1: Introduction
1.1 Immunotherapy for Cancer Over the Years
1.2 Origins of T Cell Therapies and Their Emerging Use in Solid Tumors
1.3 T Cell Therapies – How They Work
1.4 Barriers for T Cell Therapies in Solid Tumors
1.5 Goals for This Dissertation
Chapter 2: Strategies for Improving CAR T Cell Persistence in Solid Tumors
2.1 Abstract
2.2 Introduction
2.3 Discussion
2.4 Conclusions
Chapter 3: Distinct host preconditioning regimens differentially impact the antitumor potency of adoptively transferred Th17 cells.
3.1 Abstract
3.2 Introduction
3.3 Results
3.4 Discussion
3.5 Materials and Methods
Chapter 4: T cell priming by high-avidity neoantigens in lymph nodes augments adoptive immunotherapy
4.1 Abstract
4.2 Introduction
4.3 Results
4.4 Discussion
4.5 Materials and Methods
Chapter 5: Development of a murine tumor infiltrating lymphocyte (TIL) therapy model for cholangiocarcinoma
5.1 Abstract
5.2 Introduction
5.3 Results
5.4 Discussion
5.5 Conclusions
5.6 Materials and Methods
Chapter 6: T Cell Therapies from Lymph Nodes versus Tumors in Colon Cancer Models
6.1 Abstract
6.2 Introduction
6.3 Results
6.4 Discussion
6.5 Materials and Methods
Chapter 7: Early ICOS signaling programs antitumor Th17 cell fitness in adoptive immunotherapy
7.1 Abstract
7.2 Introduction
7.3 Results
7.4 Discussion
7.5 Materials and Methods
Chapter 8: Conclusions and Closing Remarks
8.1 Summary
8.2 Limitations and Future Directions
Chapter 9: References
About this Dissertation
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File download under embargo until 27 May 2032 | 2026-04-08 10:59:05 -0400 | File download under embargo until 27 May 2032 |
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