Outcome and Immune Correlates of a Phase II Trial of High-Dose Interleukin-2 and Stereotactic Ablative Radiotherapy for Metastatic Renal Cell Carcinoma

Raquibul Hannan, Osama Mohamad, Alberto Diaz De Leon III, Subrata Manna, Laurentiu M. Pop, Ze Zhang, Samantha Mannala, Alana Christie, Scott Christley, Nancy Monson, Dan Ishihara, Eric J. Hsu, Chul Ahn, Payal Kapur, Mingyi Chen, Yull E Arriaga, Kevin Courtney, Brandi Cantarel, Edward K. Wakeland, Yang Xin FuIvan Pedrosa, Lindsay Cowell, Tao Wang, Vitaly Margulis, Hak Choy, Robert D. Timmerman, James Brugarolas

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Purpose: This phase II clinical trial evaluated whether the addition of stereotactic ablative radiotherapy (SAbR), which may promote tumor antigen presentation, improves the overall response rate (ORR) to high-dose IL2 (HD IL2) in metastatic renal cell carcinoma (mRCC). Patients and Methods: Patients with pathologic evidence of clear cell renal cell carcinoma (RCC) and radiographic evidence of metastasis were enrolled in this single-arm trial and were treated with SAbR, followed by HD IL2. ORR was assessed based on nonirradiated metastases. Secondary endpoints included overall survival (OS), progression-free survival (PFS), toxicity, and treatment-related tumor-specific immune response. Correlative studies involved whole-exome and transcriptome sequencing, T-cell receptor sequencing, cytokine analysis, and mass cytometry on patient samples. Results: Thirty ethnically diversemRCC patients were enrolled. A median of two metastaseswere treatedwith SAbR.Among 25 patients evaluable byRECISTv1.1,ORRwas 16%with 8%complete responses. Median OS was 37 months. Treatment-related adverse events (AE) included 22 grade ≥3 events that were not dissimilar from HD IL2 alone.Therewere no grade 5AEs.Acorrelationwas observed between SAbR to lung metastases and improved PFS (P 0.0165). Clinical benefit correlated with frameshift mutational load, mast cell tumor infiltration, decreased circulating tumor-associated T-cell clones, and T-cell clonal expansion. Higher regulatory/CD8 T-cell ratios at baseline in the tumor and periphery correlatedwith no clinical benefit. Conclusions: Adding SAbR did not improve the response rate to HDIL2 in patients withmRCCin this study. Tissue analyses suggest a possible correlation between frameshift mutation load as well as tumor immune infiltrates and clinical outcomes.

Original languageEnglish (US)
Pages (from-to)6716-6725
Number of pages10
JournalClinical Cancer Research
Volume27
Issue number24
DOIs
StatePublished - Dec 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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