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Updated: Jul 5, 2025
Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma
Nirmish Singla1,2, Thomas R Nirschl3,4,5, Aleksandar Z Obradovic6
1Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Park 213, Baltimore, MD, 21287, USA. nsingla2@jhmi.edu.
Abstract:
Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.
Insights
Neoadjuvant nivolumab (anti-PD-1) therapy before nephrectomy induces a pro-inflammatory tumor state in high-risk clear cell renal cell carcinoma (ccRCC). Tumor immune infiltration predicts response, supporting perioperative immune checkpoint inhibition (ICI) strategies.
Area of Science:
- Uro-oncology
- Immunotherapy
- Renal Cell Carcinoma Research
Background:
- High-risk, non-metastatic clear cell renal cell carcinoma (ccRCC) has significant recurrence rates post-nephrectomy.
- Novel perioperative strategies are crucial to improve outcomes for these patients.
- Immune checkpoint inhibitors (ICIs) targeting PD-1 are a promising therapeutic avenue.
Purpose of the Study:
- To evaluate the safety and immune effects of neoadjuvant nivolumab prior to nephrectomy in non-metastatic ccRCC.
- To elucidate the impact of PD-1 inhibition on tumor immune cell populations.
- To correlate the tumor immune microenvironment with anti-PD-1 response.
Main Methods:
- Prospective, phase I clinical trial involving 15 evaluable patients with non-metastatic ccRCC.
- Administration of neoadjuvant nivolumab before nephrectomy.
- Analysis of tumor tissue to assess immune cell populations and correlate with treatment response.
Main Results:
- Nivolumab durably induced a pro-inflammatory state within the primary ccRCC tumor.
- Baseline immune cell infiltration in the primary tumor correlated with nivolumab responsiveness.
- Nivolumab increased CTLA-4 expression; nephrectomy increased circulating sPD-L1, sPD-L3 (sB7-H3), and s4-1BB.
Conclusions:
- Neoadjuvant nivolumab shows potential for high-risk ccRCC, inducing favorable immune changes while the tumor is in situ.
- Tumor immune infiltration is a key biomarker for predicting response to PD-1 inhibition.
- Findings support the development of perioperative ICI strategies, potentially in combination therapies.
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