# Project 2:  Optimal Targeting of the PD-1/PD-L1 Pathway in MRCC

> **NIH NIH P50** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $389,502

## Abstract

Summary:
Anti-PD-1-based therapies have transformed the management of advanced renal cell carcinoma
(RCC), leading to durable responses in a subset of patients. Despite this progress, the optimal
therapeutic strategy (anti-PD-1 monotherapy versus dual checkpoint inhibition and dual
checkpoint inhibition versus VEGF and PD-1 inhibition) for individual patients remains unclear, and
too many patients still do not receive durable benefit from any of the PD-1 blockade-based therapies.
Moving forward, the critical challenges are (i) how to best match a patient to an immunotherapy
regimen, and (ii) understanding the key drivers and resistors of anti-RCC immunity following
PD-1 blockade. Our unique access to a rich collection of samples from several front-line PD-1-
blockade-based clinical trials and our comprehensive immunopathology and immunogenomics tool-
kit for deeply dissecting the biologic features tumor cells and the immune microenvironment,
uniquely position our group to address these challenges. To achieve the next paradigm shift in the
treatment of patients with RCC, we hypothesize that an improved understanding of the
expression state of RCC cells and their immune microenvironment at baseline provides
critical information that will uncover targets for novel therapies and will rationally guide PD-1
blockade-based combinatorial therapy. We aim to clarify first-line therapy decisions by developing
biomarkers for durable benefit from anti-PD-1 monotherapy, nivolumab/ipilimumab and axitinib/
pembrolizumab combination therapy using existing tissue collections, and then explore/confirm
the value of these markers in the context of prospective phase III trials comparing the
nivolumab/ipilimumab combination to either nivolumab monotherapy or axitinib/pembrolizumab.
Ultimately, our efforts to establish a predictive model of durable benefit will help determine the
appropriate RCC population to receive PD-1/CTLA-4 or PD-1/VEGF blockade, as well as unveil
those patients who receive equal benefit from anti-PD-1 monotherapy or who require a different
therapeutic approach. Moreover, we will use complementary analyses across patient samples
to comprehensively characterize immune cell composition and functional state, determine target
tumor antigens, and specific TCRs that mediate an effective anti-tumor response in RCC with
the goal of ultimately developing novel immunotherapy approaches that enhance or induce specific
and effective anti-tumor immunity. This work has the potential to optimize the application of
currently effective anti-PD-1-based therapies for patients with advanced RCC and to provide new
and effective immunotherapy approaches for those destined to not benefit optimally from current
regimens.

## Key facts

- **NIH application ID:** 10904809
- **Project number:** 5P50CA101942-20
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Catherine Ju-Ying Wu
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $389,502
- **Award type:** 5
- **Project period:** 2003-09-18 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904809

## Citation

> US National Institutes of Health, RePORTER application 10904809, Project 2:  Optimal Targeting of the PD-1/PD-L1 Pathway in MRCC (5P50CA101942-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10904809. Licensed CC0.

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