DOI

10.17077/etd.8qr21tr2

Document Type

Dissertation

Date of Degree

Fall 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Immunology

First Advisor

Craig T. Morita

First Committee Member

Craig T Morita

Second Committee Member

Vladimir P Badovinac

Third Committee Member

George J Weiner

Fourth Committee Member

Zuhair K Ballas

Fifth Committee Member

David M Lubaroff

Abstract

Human γδ T cells expressing Vγ2Vδ2 TCRs monitor foreign- and self-prenyl pyrophosphate metabolites in isoprenoid biosynthesis to mediate immunity to microbes and tumors. Vγ2Vδ2 cells have been used for adoptive cancer immunotherapy with some partial and complete remissions. Most trials have used continuous zoledronate exposure to expand Vγ2Vδ2 cells. Zoledronate inhibits farnesyl pyrophosphate synthase causing isopentenyl pyrophosphate to accumulate that then stimulates Vγ2Vδ2 cells. Because zoledronate exposure is toxic, we hypothesized that a short period of exposure would reduce T cell toxicity but still be sufficient for monocytes uptake. Supporting this hypothesis, pulse zoledronate exposure with IL-2 resulted in more uniform expansion of Vγ2Vδ2 cells with higher purity and cell numbers as compared with continuous exposure. These Vγ2Vδ2 cells also had higher levels of CD107a and perforin and slightly increased tumor cytotoxicity. Importantly, adoptive immunotherapy with Vγ2Vδ2 cells derived by pulse stimulation controlled human PC-3 prostate cancer cells in immunodeficient NSG mice significantly better than those derived by continuous stimulation. Pulse zoledronate stimulation of Vγ2Vδ2 cells with IL-15 also resulted in higher purity and cell numbers. Like with CD8 αβ T cells, IL-15 preserved early memory Vγ2Vδ2 T cell subsets better than IL-2. However, despite this fact, adoptive immunotherapy with Vγ2Vδ2 cells derived with IL-15 showed similar inhibition of PC-3 tumor growth as those derived with IL-2. Thus, pulse zoledronate stimulation maximizes the purity, quantity, and quality of expanded Vγ2Vδ2 cells. This simple modification to existing protocols would likely enhance the effectiveness of adoptively transferred Vγ2Vδ2 T cells.

Public Abstract

Cancer is the second leading cause of death worldwide. In 2015, cancer killed more than 600,000 people in US alone. Besides its impact on health, cancer has a huge economical impact with billions of dollars spent every year to provide health care for cancer patients. Today, there are 14 million cancer patients who live with the disease and hope that one day a cure for such a fatal disease can be a possibility. One of the most recent and promising advancement in the field of cancer treatment is using immune system to fight and kill cancer cells. Immune system consists of immune cells that are responsible of killing cancer cells once get activated. Among those cells, a group of cells called gamma delta (γδ) T cells that show a strong killing activity against wide range of cancer. Based on these results, γδ T cells have been used clinically to treat patients with various types of cancer. γδ T cell treatment has been shown to be safe with few major toxicities and has resulted in rare complete remissions, some partial remissions, and stabilization of disease. The clinical trials have established the safety of the treatment but also showed that the response rate has to be increased before its widespread use. In our studies, we have focused on enhancing the activity of γδ T cell cancer treatment by modifying current treatment protocols. By making a simple modification to existing protocols used to grow γδ T cells, we were able to significantly increase the number of γδ T cells generated and their killing of human cancer cells in laboratory studies. Furthermore, the γδ T cells showed improved ability to control human prostate cancer tumors in a pre-clinical mouse model as compared with γδ T cells grown conventionally. We expect that a similar improvement in efficacy would be observed in the treatment of cancer patients. We also discuss other potential ways to increase the effectiveness of γδ T cell therapy. Improving the effectiveness of γδ T cells could a major advance in the treatment of a variety of cancer types.

Keywords

Cancer Immunotherapy, IL-15, Prostate cancer, Vγ2Vδ2 T CELLS, Zoledronate, γδ T cells

Pages

xvi, 134 pages

Bibliography

Includes bibliographical references (pages 105-134).

Comments

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Copyright

Copyright © 2016 Mohanad Hameed Nada

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