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Harnassing natural killer cell receptors for tumor immunotherapy / by Ming-Ru Wu

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Author	Wu, Ming-Ru
Title	Harnassing natural killer cell receptors for tumor immunotherapy / by Ming-Ru Wu
Date	2015
Abstract	Despite all the efforts and progress in cancer research, cancer remains a devastating disease. After more than 120 years of research, immunotherapy provides a realistic hope to cure cancer. Several formats of immunotherapy, such as immune-checkpoint-blockade antibodies and a bispecific T cell engager (BiTE) have been approved by the FDA. Immunotherapies that harness T cell effector functions will likely be the mainstream of cancer therapy in the near future. Chimeric antigen receptor (CAR) T cell therapies and BiTE therapies have shown curative and potential durable clinical efficacy in several clinical trials. However, the majority of pre-clinical and clinical development of CARs and BiTEs focuses on targeting hematological malignancies. CARs and BiTEs that can target solid tumors and have the potential to target multiple tumor types are rare. Furthermore, these pan-tumor targeting CARs and BiTEs in preclinical and clinical development generally target tumor associated antigens, which are also expressed by normal tissues and can potentially cause side effects. This thesis aims to describe studies of new CARs and BiTEs that can target multiple tumor types, including hematological malignancies and solid tumors, with high anti-tumor specificity. We aim to accomplish this goal by harnessing the pan-tumor recognition ability of natural killer (NK) cell receptors. Our data demonstrate that NK cell receptors can be harnessed for creating CARs and BiTEs. NKp30 based-, DNAM-1 based-, and B7H6-specific single-chain variable-fragment (scFv) based-CARs all exhibit the ability to recognize and kill multiple ligand+ tumor types in vitro and provide therapeutic efficacy in murine tumor models in vivo. A B7H6-specific BiTE also triggers T cells to kill multiple B7H6+ tumor types and mediates therapeutic efficacy in murine tumor models in vivo, including models of lymphoma, melanoma, and ovarian cancer. Harnessing NK cell receptors for creating CAR and BiTE therapies enables us to combine the best features of the two cell types, which are pan-tumor recognition of NK cells and potent effector functions of T cells, for designing effective immunotherapies. These approaches also demonstrate that bio-inspired engineering is efficient and effective. The CARs and BiTEs developed in this thesis have high translational values and have the potential to be further developed into clinical usage. In the future, by further harnessing the advances in genome engineering and synthetic biology, we will further enhance our ability to improve tumor immunotherapy and eventually unleash the full power of immunotherapy
Description	1 online resource (xiv, 155 leaves) : illustrations (some color)
Format	application/pdf
College	Dartmouth College -- Department of Microbiology and Immunology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1600

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