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NIH grant 1K99CA312828-01: Investigation and engineering of natural killer cells for cancer immunotherapy
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Lei Peng. Award: $143251.
Start: 2026-09-11T00:00:00.
SUMMARY
SPECIFIC AIMS | Natural killers (NK) hold great promise for cellular immunotherapy. But their clinical efficacy
especially against solid tumors remains limited. To overcome this barrier, it is critical to identify novel molecular
targets that can enhance NK cell function and persistence. Functional genetic screens offer a powerful platform
to uncover such therapeutic regulators. Toward this goal, I established a CAR-NK gain-of-function (GOF)
CRISPR screening system and performed an in vivo GOF screen in CAR-NK cells. Our screen identified a
number of novel functional boosters of NK cells including components of G protein signaling pathways. Among
them, OR7A10 emerged as the top hit. Our preliminary data demonstrated overexpression (OE) of OR7A10 in
CAR NK cells improved metabolic fitness and significantly enhanced the anti-tumor activity of CAR-NK cells in
several preclinical tumor models. However, the downstream signaling mechanism, gene regulatory networks,
and translational potential of OR7A10 remain to be elucidated. In this K99/R00 project, I will dissect the
mechanism of OR7A10-mediated regulation in NK cells and evaluate OR7A10-engineered CAR-NK cells as a
next-generation therapeutic for solid tumor. The Specific Aims are: Aim 1 (K99 Phase): Define the signaling
pathway by which OR7A10 enhances NK cell anti-tumor function. Aim 2 (K99-R00 Phase): Determine whether
OR7A10-mediated reprogramming enhances CAR-NK efficacy and persistence in orthotopic GBM. Vertebrate
animal models are necessary to evaluate the in vivo anti-tumor efficacy and persistence of engineered CAR-NK
cells within the complex tumor microenvironment, which cannot be adequately modeled using in vitro systems
alone. Aim 3 (R00 Phase): Engineer tunable and generalizable G-protein-based CAR-NK engineering platforms.
In summary, this K99/R00 project introduces a new in vivo screening platform for NK cells and identifies OR7A10
as a potent, novel NK cell booster. Successful completion of this work will yield critical mechanistic insights into
NK cell regulation and support the development of more effective NK cell-based therapies. It will also provide
the foundation for my transition to an independent academic research career.document fetched 2026-09-20 02:42