The traditional ?standard of care? for cancer over the past several decades has consisted of surgery, radiation therapy, chemotherapy, and stem cell transplantation in some cancers such as acute myeloid leukemia. In the last decade, immune therapy using monoclonal antibodies such as rituximab and traztuzumab have now been incorporated into the standard of care for lymphoma and breast cancer, respectively. Compelling data now shows that that innate immune cells, such as natural killer (NK) cells are an important component mediating the clinical effectiveness of antibody therapy. Our proposal aims to strengthen cellular innate immunity to enhance cancer therapy. Part of the challenge relates to 1) limited recognition of tumor cells by innate immune effector cells; 2) dampening of innate immune effector cell function in the tumor microenvironment; and 3) penetration of the tumor mass by innate immune effector cells. Our vision is to add activated, tumor antigen specific innate immune effector cell therapy to the existing armamentarium against both liquid and solid tumors. Strategically, this will be accomplished over the next 7 years through: 1) a more complete understanding human NK cell development, including the expression of activating and inhibitory receptors; 2) optimizing the development of human NK cells expressing chimeric antigen receptors, and 3) full development of our bi-specific NKG2D antibody that will bring human NK cells and other innate immune effector cells into the tumor bed. Our documented consistent success with basic research on NK cell development and effector function over decades, along with our successful translation of a multitude of our discoveries to the clinic in over 1,000 cancer patients both serve as a foundation for us to successfully proceed along this pathway. In the next seven years, we believe we will lead the field in: 1) enhancing NK cell tumor specificity; 2) enhancing NK cell cytolytic effector function; and 3) enhancing migration of NK and other innate immune cells into the tumor bed. The potential outcome over the next 7 years will be the completion of a series of clinical trials that first demonstrate significant anti-tumor activity in man and ultimately demonstrate significantly prolonged survival of cancer patients bearing liquid or solid tumors that express antigens to be recognized by our modified innate immune products.

Public Health Relevance

Natural killer (NK) cells serve as a crucial first line of defense against cancer. Funding of this proposal will advance our understanding of basic immunology on human NK cells as well as advance the development of NK cell-based immunotherapy to treat cancer. The knowledge and therapeutic advances obtained from this study will add a new dimension to the armamentarium against cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA210087-04
Application #
9949653
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Kuo, Lillian S
Project Start
2017-07-01
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Dai, Hong-Sheng; Caligiuri, Michael A (2018) Molecular Basis for the Recognition of Herpes Simplex Virus Type 1 Infection by Human Natural Killer Cells. Front Immunol 9:183
Chen, Luxi; Youssef, Youssef; Robinson, Cameron et al. (2018) CD56 Expression Marks Human Group 2 Innate Lymphoid Cell Divergence from a Shared NK Cell and Group 3 Innate Lymphoid Cell Developmental Pathway. Immunity 49:464-476.e4
Victor, Aaron R; Weigel, Christoph; Scoville, Steven D et al. (2018) Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development. J Immunol 200:565-572
Chan, Wing Keung; Kang, Siwen; Youssef, Youssef et al. (2018) A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma. Cancer Immunol Res 6:776-787
Park, I-K; Blum, W; Baker, S D et al. (2017) E3 ubiquitin ligase Cbl-b activates the p53 pathway by targeting Siva1, a negative regulator of ARF, in FLT3 inhibitor-resistant acute myeloid leukemia. Leukemia 31:502-505
Chen, L; Mao, H; Zhang, J et al. (2017) Targeting FLT3 by chimeric antigen receptor T cells for the treatment of acute myeloid leukemia. Leukemia 31:1830-1834
Dai, Hong-Sheng; Griffin, Nathaniel; Bolyard, Chelsea et al. (2017) The Fc Domain of Immunoglobulin Is Sufficient to Bridge NK Cells with Virally Infected Cells. Immunity 47:159-170.e10