# Program the Immune System against RAS-driven Cancer

> **NIH NIH R61** · STANFORD UNIVERSITY · 2024 · $207,879

## Abstract

Abstract
 Despite the great progress in recent decades, many types of cancer remain almost fatal. Pancreatic
ductal adenocarcinoma (PDAC) is a remarkable example. One of the challenges is that the vast majority (95%)
of PDACs are driven by mutations within a gene called KRAS, and these KRAS mutations are notoriously difficult
to target with conventional drugs. The first generation of cancer drugs are based on small molecules, the second
generation biologics (large biomolecules such as antibodies that specifically bind to cancer cells), and the latest
generation cells (engineered to recognize and ablate cancer cells). Here our long-term goal is to demonstrate a
new generation of therapeutics, using “circuits” as medicine. Circuits metaphorically refer to collections of
biomolecules engineered to regulate each other and process information inside living cells. While conventional
analyses output metrics to inform physicians, who then make therapeutic decisions, our circuits close the loop,
and will serve as both the analytic and the therapeutic tools. It is a molecular and cellular analysis technology
that queries living cells and actuates therapeutic outputs in real time without human intervention.
 Specifically, we will create circuits to program the immune system and emulate the “abscopal effect”, the
occasional observation that distant tumors shrink when local tumors are treated, most likely due to the immune
system learning the “signature” of the treated tumors and then extrapolating. We will first create the building
blocks for such circuits: sensors that can interrogate whether a cell is in a cancerous state, actuators that can
control the signals sent by cells to engage the immune system, and processors that connect the sensors and
the actuators. These efforts will benefit from our experience of building circuits exclusively using proteins, which
features technical advantages, such as ease of delivery and robustness of functionality in different cellular
contexts, compared to more conventional ways of building circuits based on protein-DNA interactions. We will
then assemble these building blocks into circuits, and quantify and optimize their operation in cultured cells.
Leveraging our expertise in mouse models of PDACs, we will finally test these circuits’ efficacy in vivo. The
premise is to program the outputs specifically from cancer cells to mobilize the immune system and then lyse
these cells to grant the immune system access to all protein sequences that are uniquely present in cancer.
These dead cancer cells will serve essentially as vaccines against other cells that exhibit similar protein
sequence profiles. We will achieve this vaccination effect by either mimicking a specific type of cell death known
to mobilize the immune system, or program the cancer cells to directly and artificially activate T cells – immune
cells responsible for recognizing and ablating cancer cells.
 The expected outcomes of this proposal are not only preclin...

## Key facts

- **NIH application ID:** 10843256
- **Project number:** 5R61CA278398-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Xiaojing J Gao
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $207,879
- **Award type:** 5
- **Project period:** 2023-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843256

## Citation

> US National Institutes of Health, RePORTER application 10843256, Program the Immune System against RAS-driven Cancer (5R61CA278398-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10843256. Licensed CC0.

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