MSTP in PhD Training
Current advisor: Todd A. Fehniger, MD, PhD
Undergraduate university: University of California-Berkeley, 2015
Enrollment year: 2017
Mechanism of CD8 regulation of human natural killer cell biology
Hematologic malignancies such as acute myeloid leukemia (AML) remain clinically challenging and refractory to traditional chemotherapy approaches. For many patients, hematopoietic cell transplant (HCT) is the only curative treatment, whereby part of the efficacy is driven by donor natural killer (NK) cells that target the recipient’s leukemic cells. Natural killer cell adoptive therapy for AML patients represent a promising approach for improving patient outcomes. Work done in the Fehniger lab has defined a strategy to induce a memory-like (ML) phenotype of isolated NK cells using a stimulation with IL-12, IL-15, and IL-18 that demonstrates enhanced proliferation, cytotoxicity, and persistence both in vitro and in vivo. A phase 1 study using ML NK cells in relapsed/refractory AML patients showed approximately 50% of patients achieving a complete remission, although the mechanisms driving treatment failure are not clearly understood. Multidimensional immune correlative analysis of donor NK cells identified a negative association between CD8 expression on NK cells and treatment response. However, the role of CD8 on human conventional and ML NK cells remains unknown.
Aim 1 of my project focuses on determining the mechanisms by which CD8+ conventional and ML NK cells have compromised proliferation, and the subsequent impact on tumor control in vivo. Specifically, the contributions of telomere length, chromatin accessibility, and metabolic differences will be investigated. Aim 2 focuses on defining the function of the CD8 molecule itself through highly efficient CRISPR-Cas9 based knockdown, and the subsequent impact on conventional and ML NK cell cytotoxicity, signaling, and survival. Together, these results will further inform future NK cell therapy designs and enhance our understanding of CD8 and its contributions to fundamental aspects of NK cell biology.s I for NK cells.
Berrien-Elliott MM, Foltz JA, Russler-Germain DA, Neal CC, Tran J, Gang M, Wong P, Fisk B, Cubitt CC, Marin ND, Zhou AY, Jacobs MT, Foster M, Schappe T, McClain E, Kersting-Schadek S, Desai S, Pence P, Becker-Hapak M, Eisele J, Mosior M, Marsala L, Griffith OL, Griffith M, Khan SM, Spencer DH, DiPersio JF, Romee R, Uy GL, Abboud CN, Ghobadi A, Westervelt P, Stockerl-Goldstein K, Schroeder MA, Wan F, Lie WR, Soon-Shiong P, Petti AA, Cashen AF, Fehniger TA. 2022 Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia. Sci Transl Med, 14(633):eabm1375.
Cubitt CC, McClain E, Becker-Hapak M, Foltz JA, Wong P, Wagner JA, Neal CC, Marin ND, Marsala L, Foster M, Schappe T, Soon-Shiong P, Lee J, Berrien-Elliott MM, Fehniger TA. 2022 A novel fusion protein scaffold 18/12/TxM activates the IL-12, IL-15, and IL-18 receptors to induce human memory-like natural killer cells. Mol Ther Oncolytics, 24():585-96.
Marin ND, Krasnick BA, Becker-Hapak M, Conant L, Goedegebuure SP, Berrien-Elliott MM, Robbins KJ, Foltz JA, Foster M, Wong P, Cubitt CC, Tran J, Wetzel CB, Jacobs M, Zhou A, Russler-Germain D, Marsala L, Schappe T, Fields RC, Fehniger TA. 2021 Memory-like differentiation enhances NK cell responses to melanoma. Clin Cancer Res, 27(17):4859-69.
Wagner JA, Wong P, Schappe T, Berrien-Elliott MM, Cubitt C, Jaeger N, Lee M, Keppel CR, Marin ND, Foltz JA, Marsala L, Neal CC, Sullivan RP, Schneider SE, Keppel MP, Saucier N, Cooper MA, Fehniger TA. 2020 Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity. Cell Rep, 31(9):107720.
Berrien-Elliott MM, Cashen AF, Cubitt CC, Neal CC, Wong P, Wagner JA, Foster M, Schappe T, Desai S, McClain E, Becker-Hapak M, Foltz JA, Cooper ML, Jaeger N, Nonavinkere Srivatsan S, Gao F, Romee R, Abboud CN, Uy GL, Westervelt P, Jacoby MA, Pusic I, Stockerl-Goldstein KE, Schroeder MA, DiPersio J, Fehniger TA. 2020 Multidimensional analyses of donor memory-like NK cells reveal new associations with response after adoptive immunotherapy for leukemia. Cancer Discov, 10(12):1854-1871.