# Synthetic IL9R signaling to rewire T cells for adoptive cell therapy of cancer

> **NIH NIH R37** · STANFORD UNIVERSITY · 2022 · $369,646

## Abstract

PROJECT SUMMARY
Adoptive cell therapy (ACT) using engineered T cells – such as chimeric antigen receptor (CAR) or T cell receptor
(TCR) modified T cells – is an effective immunotherapy for hematologic malignancies. Success with ACT has
been elusive for solid tumors, which present unique challenges to T cells. ACT also requires conditioning
chemotherapy to deplete a patient’s endogenous T cells, which results in significant toxicity. Our goal is to
engineer T cells with synthetic functions to overcome hurdles of ACT for solid tumors including the need for
conditioning chemotherapy, which would dramatically improve the feasibility and safety of this therapy.
In this proposal we use the orthogonal IL2 cytokine-receptor pair developed by our collaborator Dr. Garcia at
Stanford. Orthogonal IL2Rβ (o2R) is only activated by the orthogonal IL2 (oIL2) cytokine, and not by wildtype
IL2. When activated, o2R signals through the intracellular domain (ICD) of IL2Rβ, which involves cooperation
with the native common gamma chain (γc). Leveraging this cooperation, we studied chimeric orthogonal
receptors in which the IL2Rβ ICD of o2R is replaced with ICDs of receptors for other γc cytokines, such that oIL2
elicits the corresponding γc signal. Of these chimeras, signaling through the IL9R ICD (o9R) generated a unique
STAT phosphorylation profile and differentiation trajectory, prompting further exploration in vivo. Despite a
weaker proliferative signal than o2R signaling, o9R signaling resulted in T cells with superior anti-tumor efficacy,
an effect pronounced in the absence of lymphodepletion.
To translate this finding into a viable treatment for patients with advanced solid tumors will require an
understanding of the functional features of o9R signaling T cells that permit their anti-tumor efficacy, especially
in the absence of conditioning chemotherapy. Our preliminary data led us to focus on two of these features,
which we tackle in Aims 1 and 2. In Aim 1, we focus on the peripheral in vivo effects of o9R signaling that rely
on interaction with the host, especially lymph node homing and priming. We hypothesize that the o9R signaling
reprograms T cells in the periphery for efficient lymph node homing and spatial positioning that promotes priming
that is critical for their anti-tumor effects in vivo. Aim 1 will use both TCR- and CAR- based syngeneic mouse
solid tumor models of ACT. In Aim 2, we turn to the cell-intrinsic effects of o9R signaling on effector capacity in
the face of chronic antigen stimulation. We hypothesize that o9R signaling interferes with the epigenetic changes
that drive T cell dysfunction in the context of chronic antigen stimulation, resulting in superior effector capacity.
Aim 2 will primarily use human T cells engineered with a TCR specific for the NY-ESO-1 antigen along with the
pmel model.
Our complementary aims outline an approach to define the effects of IL9R signaling in T cells that underlie their
anti-tumor functions in solid tumo...

## Key facts

- **NIH application ID:** 10504059
- **Project number:** 1R37CA273074-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Anusha Kalbasi
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $369,646
- **Award type:** 1
- **Project period:** 2022-09-30 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10504059

## Citation

> US National Institutes of Health, RePORTER application 10504059, Synthetic IL9R signaling to rewire T cells for adoptive cell therapy of cancer (1R37CA273074-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10504059. Licensed CC0.

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