# Project 2: Determinants of Response and Resistance to DNA-Damaging Radiation Plus Immunotherapy Combinations in Triple Negative Breast Cancer

> **NIH NIH P50** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $338,306

## Abstract

Project 2: Determinants of Response and Resistance to DNA-Damaging Radiation Plus Immunotherapy
Combinations in Triple Negative Breast Cancer – PROJECT SUMMARY/ABSTRACT
Anti-PD1 (aPD1) immune checkpoint inhibition combined with four chemotherapeutic agents is the current
standard-of-care for most patients with early-stage triple negative breast cancer (TNBC). However, treatment
resistance and treatment-related toxicities persist as dual challenges that must be overcome with new
strategies to guide personalized chemo-immunotherapy combinations. Data from our group and others have
established the association between DNA damage-induced necroptosis (DDIN) and promotion of anti-tumor
immune responses. Project 2 will investigate the role of DDIN as a determinant of response to RT plus anti-
PD1 combination therapy using preclinical TNBC genetically engineered mouse models (GEMM) and
correlative biomarker analyses of pre/post-treatment primary tumor, metastatic lymph node, and blood
specimens from an ongoing clinical trial of preoperative anti-PD1 therapy, with or without RT, in early-stage
TNBC with lymph node metastasis. In Aim 1, we will develop a gene signature of necroptosis proficiency and
evaluate it as a predictive biomarker of RT/aPD1-induced spatial reprogramming of the tumor
microenvironment. In Aim 2, we will determine whether RT/aPD1 can elicit systemic neoantigen-directed T
and B cell responses, and whether neoantigen vaccination can overcome RT/aPD1 resistance induced by
necroptosis deficiency. Project 2 will be supported in bioinformatics and statistical analyses by Core B and in
spatial transcriptomics and clinical trial biospecimen analyses by Core C. The proposed studies will identify
predictive biomarkers to guide future clinical trials of RT plus anti-PD1 combination therapy in early-stage
TNBC—including testing strategies to reduce treatment toxicity by minimizing chemotherapy in patients
expected to respond to RT/aPD1—and establish contexts where neoantigen vaccination may help to overcome
radio-immunotherapy resistance.

## Key facts

- **NIH application ID:** 10935475
- **Project number:** 2P50CA058223-29A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Gaorav P. Gupta
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $338,306
- **Award type:** 2
- **Project period:** 1997-08-05 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935475

## Citation

> US National Institutes of Health, RePORTER application 10935475, Project 2: Determinants of Response and Resistance to DNA-Damaging Radiation Plus Immunotherapy Combinations in Triple Negative Breast Cancer (2P50CA058223-29A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10935475. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*