# Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2024 · $345,281

## Abstract

Metastatic breast cancer (BC) is a major health issue for women across the world. About 40,610 women and 460
men in the US are expected to die this year alone from BC. While there are numerous treatment options for hormone
receptor positive (HR+) and HER2+ BC patients, the standard of care for triple negative BC (TNBC) patients largely
relies on conventional chemotherapy and radiation. Improved options for treating metastatic BC represent a vast
unmet medical need. Recently, several clinical trials investigated combined treatment with either HR pathway
blockers or HER2 antagonists and PI3K inhibitors, since the PI3K pathway is constitutively activated or mutated in
over 50% of BC patients. However, the results have shown only 2-4 months increase in progression free survival and
there is extensive Grade 3 and 4 toxicity with the dosage schedules used. The discovery of immune checkpoint
inhibitors (ICIs) is revolutionizing cancer therapy, but thus far BC patients are not showing strong responses to ICI
therapy, due to low mutational load and minimal infiltration of CD4+ and CD8+ T cells (“cold”).
 Our hypothesis is that response to ICI therapy in immunologically “cold” BCs can be enhanced by combining
therapies that inhibit AKT with paclitaxel (PTX) to induce immunogenic tumor cell death and shift tumor-associated
immune cells to an anti-tumor phenotype. To test this hypothesis, we will utilize immune competent mouse models,
organoid/immune cell co-cultures, and humanized mouse models bearing patient-derived xenograft (PDX) to
determine if PI3K pathway inhibitors, when enhance response to ICIs, and improve survival in mice. There are two
specific aims. Aim 1. To develop the optimal strategy for reducing growth of TNBC through treatment with an AKT
inhibitor, ipatasertib, combined with paclitaxel, and immune checkpoint inhibitors (ICIs) anti-CTLA4 + anti-PD1. Using
immune competent mouse models, we will determine the functional significance of reprograming the tumor immune
environment in mammary tumors in response to AKT inhibition in reference to response to ICIs at early, mid and late
time points during therapy. Mechanisms of therapeutic response will be investigated based upon analysis of the
following parameters: toxicity; tumor growth; metastasis; immune cell content (immunome); cytokine/chemokine
expression profile in tumor, bone marrow, lung and blood samples; angiogenesis; and transcriptome in responding
and non- responding tumors. State of the art technology will include multiplex immunohistochemistry (IHC), flow
cytometry, CyTOF, reverse phase protein analysis (RPPA), RNA sequencing (RNAseq), DNA sequencing (DNAseq)
and pathway analysis. Transcriptomic and immunome signatures predicting response to treatment in mice will be
compared to RNAseq data from ongoing clinical trials available to us and published “response signatures” 26. Aim 2:
To determine the efficacy of treatment with AKT inhibitors combined with PTX and ICIs in two human TNBC...

## Key facts

- **NIH application ID:** 10747362
- **Project number:** 5R01CA243326-05
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Ann Richmond
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $345,281
- **Award type:** 5
- **Project period:** 2019-12-11 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747362

## Citation

> US National Institutes of Health, RePORTER application 10747362, Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway (5R01CA243326-05). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10747362. Licensed CC0.

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