# Project 3:  HHLA2 as a THerapeutic Target in RCC

> **NIH NIH P50** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $284,060

## Abstract

Project 3 Summary
While immune checkpoint inhibitors (ICI) have revolutionized the treatment of many cancers, including
metastatic clear cell renal cell carcinoma (ccRCC), the development of agents that overcome resistance to
anti-PD-1/PD-L1 based therapy represents a critical unmet need for ccRCC patients. We have shown that the
B7 family member HERV-H LTR-associating 2 (HHLA2) is expressed in the majority of ccRCC and recently
have discovered an inhibitory receptor (KIR3DL3) for HHLA2. Monoclonal antibodies that selectively block the
HHLA2/KIRDL3 interaction, which we call the HHLA2 Inhibitory Pathway (HIP), could be an important means
to enhance anti-tumor immune responses. In this proposal, we will study the expression of HHLA2 and it
receptors in kidney cancer on tumor cells and immune cells and the relationship of HHLA2 and PD-L1
expression on tumors cells. Using clinically annotated specimens from clinical trials of patients with ccRCC on
anti-PD-1 therapy, we will determine whether HHLA2 expression is associated with lack of response to PD-1
therapy. We will elucidate the regulatory pathways that are similar and different between HHLA2 and PD-L1 to
better understand the expression of these immune checkpoints in kidney cancer and how their expression may
change over the course of tumor progression and selection pressures. We will identify the optimal reagents for
activating T cells and NK cells through the HHLA2:KIR3DL3 pathway in both in vitro and in vivo models. Our
results will direct the selection of humanized blocking antibodies of HHLA2 Inhibitory Pathway that will move
into primate toxicity and human Phase I clinical trials during year two of this grant.

## Key facts

- **NIH application ID:** 10206027
- **Project number:** 5P50CA101942-17
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** David McDermott
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $284,060
- **Award type:** 5
- **Project period:** 2003-09-18 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206027

## Citation

> US National Institutes of Health, RePORTER application 10206027, Project 3:  HHLA2 as a THerapeutic Target in RCC (5P50CA101942-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10206027. Licensed CC0.

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