# Inter-metastatic divergency in small cell lung cancer; implications for the design of future immunotherapies

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $367,057

## Abstract

Abstract
Aggressive malignant progression and spreading has limited a clear understanding of the
pathophysiology of SCLC. The overarching goal of this “bedside to bench” project is to elucidate
the role of inter-metastatic divergence in therapeutic resistance in small cell lung cancer (SCLC),
with a focus on how antigenic heterogeneity and dominant immunosuppressive butyrophilins
thwart protective adaptive immune responses in this disease, to develop novel interventions to
overcome these hurdles.
We will leverage a Rapid Tissue Donation (RTD) program established at Moofitt Cancer Center,
which provides timely access to the entire repertoire of metastatic lesions in terminal patients,
who generously donate their tissues for this research. Using this resource, plus CDX models
routinely generated for each SCLC patient, we will define barriers that impair the effectiveness of
immunotherapies. During the 5-year tenure of this grant we will generate a rationale for novel
immunotherapeutic trials to overcome overcome these elusive hurdles, with a focus on antigenic
heterogeneity and the role of immunosuppressive butyrophilins.
Based on our expertise on tumor immunology (Dr. Conejo-Garcia) and clinical immunotherapy
(Drs. Perez), as well as access to a Rapid Tissue Donation program, we postulate that the
effectiveness of immunotherapies against small cell lung cancer is thwarted by heterogeneous
immunogenicity across different tumor masses, along with high expression of
immunosuppressive CD277+ butyrophilins. Based on our preliminary results, our central
hypothesis is that pleural effusions and trogocytic tumor-infiltrating T cells could provide a source
of effector lymphocytes for cell therapies that would target multiple tumor masses, in combination
with targeting immunosuppressive BTN3A butyrophilins and/or tumor-derived antibodies. We
propose the following Specific Aims: Aim 1. Define the role of inter-metastatic heterogeneity in
therapeutic resistance in human SCLC. Aim 2. Design novel T cell immunotherapies that
overcome metastatic heterogeneity in SCLC. Aim 3. Determine the potential of antibodies
produced in SCLC to overcome inter-metastatic heterogeneity. These studies will, first, define the
role and heterogeneity of neoantigens and immune cells in SCLC; a poorly characterized disease,
due in part to its aggressiveness. Most importantly, we will provide a mechanistic rationale for
more effective immunotherapies that target the diversity and dominant immunosuppressive
drivers of this human disease, which will target in novel clinical trials at Moffitt.

## Key facts

- **NIH application ID:** 10896914
- **Project number:** 5R01CA278907-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jose R Conejo-Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $367,057
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896914

## Citation

> US National Institutes of Health, RePORTER application 10896914, Inter-metastatic divergency in small cell lung cancer; implications for the design of future immunotherapies (5R01CA278907-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10896914. Licensed CC0.

---

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