# Project 1: Siglec15 as a new target for lung cancer immunotherapy

> **NIH NIH P50** · YALE UNIVERSITY · 2023 · $392,133

## Abstract

PROJECT SUMMARY
The inability of tumor infiltrating lymphocytes (TILs) to target and kill tumor cells is a major hurdle in treating
many malignancies. New treatment strategies that block immune inhibitory mechanisms, such as antibodies
that block the interaction of programmed death-1 (PD-1) with its ligand, B7 homolog 1 (B7-H1, also known as
PD-L1), have shown promising efficacy in the clinic. Termed checkpoint inhibitor therapy, these drugs have
been approved for many indications, including melanoma, Hodgkin lymphoma and lung cancer, and are
increasingly being used in combination or in conjunction with other cancer therapies, such as chemotherapy
and radiation. Although checkpoint inhibitor treatments have resulted in durable clinical responses in a large
proportion of cases, many patients present with tumor types that do not respond to treatment. For instance,
~26% of NSCLC cases, which are negative for B7-H1/PD-L1 and positive for TILs, have been shown to be
resistant to anti-PD-1/B7-H1(PD-L1) (anti-PD) therapy. This type of NSCLC, denoted as Type III, is suspected
to harbor a mechanism of immune inhibition distinct from other NSCLC types, which has been found to be
driven, at least in part, by sialic acid binding immunoglobulin-like lectin 15 (siglec-15). Siglec-15 expression is
mutually exclusive from B7-H1/PD-L1 expression in NSCLC cohorts and has been shown to inhibit T cell
proliferation and effector function. Blocking of siglec-15 using anti-siglec-15 (S15) monoclonal antibody (mAb)
is therapeutic in mouse models and human cell culture systems and results in amplified T cell responses.
Based on these findings, a phase I/II, dose escalation, safety and tolerability clinical trial for S15 mAb
treatment in patients with advanced or metastatic solid tumors is on-going. Although preliminary studies have
generated promising results with regard to the potential efficacy of S15 mAb in the clinic, the mechanism of
S15-mediated immune suppression remains unknown. Furthermore, to enhance and improve treatment
response rates, more work must be done to identify pertinent biomarkers for S15 mAb therapy and modes that
modulate S15 expression. Finally, developing combination strategies that alter the tumor microenvironment
(TME), such that conversion of the tumor Type is achieved, is imperative for successful targeting and killing of
tumor by immune cells and in attaining increased patient response rates to available checkpoint inhibitor
therapies. A newly generated immune PDX (iPDX) mouse model, which uses patient-derived tumor tissue to
recapitulate and manipulate immune cell responses in the TME, will be utilized to investigate these topics
specifically in the NSCLC setting. A proposed investigator-initiated phase II clinical trial in patients with S15+
advanced NSCLC who have progressed on PD-1 axis inhibitor therapy will evaluate S15 mAb efficacy and
support biomarker validation studies. Strategies to combine S15 mAb with other agents, such as anti...

## Key facts

- **NIH application ID:** 10690060
- **Project number:** 5P50CA196530-09
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** DAVID L RIMM
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $392,133
- **Award type:** 5
- **Project period:** 2015-08-26 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690060

## Citation

> US National Institutes of Health, RePORTER application 10690060, Project 1: Siglec15 as a new target for lung cancer immunotherapy (5P50CA196530-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10690060. Licensed CC0.

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