Author ORCID Identifier

0000-0003-4648-7830

Date of Graduation

12-2021

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dr. Anirban Maitra

Committee Member

Dr. Chantale Bernatchez

Committee Member

Dr. Cara Haymaker

Committee Member

Dr. Qing Ma

Committee Member

Dr. Gregory Lizee

Committee Member

Dr. Pamela Wenzel

Abstract

The success of immune checkpoint inhibitors (ICIs) has established the importance of cancer immunotherapy in solid cancers, where it has been adopted as one of the standards of care for advanced melanoma and lung cancer. It is currently being investigated to treat other solid cancers. However, a large fraction of patients do not respond to ICIs and relapse. ICI therapy offers an in vivo approach to activate tumor-specific T cells, albeit in some cases, this modality does not create a sufficiently robust anti-tumor response. Thus, ex vivo approaches employing manipulation of immune cells, such as Adoptive Cell Therapy (ACT) using autologous Tumor-infiltrating lymphocytes (TILs), might be able to provide therapeutic benefit. TILs are selective tumor antigen-targeted T cells that can be expanded from freshly resected tumor tissue and reinfused to the patient through ACT as an anti-tumor therapeutic modality. At MD Anderson, we have observed a response rate of approximately 42% to autologous TIL therapy treatment for Metastatic Melanoma (MM) patients. Learning from MM, we implemented and improved on our ex vivo TIL expansion method for Non-small Cell Lung Cancer (NSCLC), employing a three-way stimulatory approach using an agonistic CD3 (TCR stimulation), 4-1BB (co-stimulation) antibodies and IL-2 (cytokine support), an approach referred to as “TIL 3.0”. We demonstrated the feasibility of robustly expanding a T-cell repertoire recapitulating the clonal hierarchy of the T cells in the NSCLC tumor, including a large number of putative tumor-specific TIL clones, using this TIL 3.0 methodology.

Success of TIL-ACT also depends on the capacity of infused TIL to thrive and elicit anti-tumor activity after re-infusion. Infused TILs can migrate to the tumor milieu, but long-term persistence and efficient tumor killing are essential to eradicate tumor. Multiple solid cancers create a hostile tumor microenvironment (TME) for optimal T-cell persistence through various mechanisms. One such mechanism involves TGFβ, a pleiotropic cytokine secreted by the majority of solid tumors that has been shown to suppress TIL functionality and is associated to resistance to immunotherapy. Additionally, TILs can face a deficit of essential co-stimulatory and cytokine growth signaling in the TME, which may limit their effector function in vivo. My work demonstrated that TILs engineered to express a TGFβ-chimeric antigen receptor (TGFβ-CAR) can not only block inhibitory TGFβ signals, but also convert it to stimulatory signals for TIL persistence and activation. Here, TGFβ-CAR is designed to support and enhance the natural TCR activity of the TILs, while capitalizing on the multitude of tumor antigens recognized by TILs to prevent tumor immune escape, as opposed to the typical single-antigen targeted CARs. Therefore, these innovative approaches can consistently generate a TIL-ACT product with enhanced tumor specificity and provide the required co-stimulation and cytokine support at the TME to achieve a potent anti-tumor immunity.

Keywords

TIL-ACT, CAR-Therapy, Immunotherapy, NSCLC, TGFb

Available for download on Tuesday, December 13, 2022

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