TY - JOUR
T1 - Outcome and Immune Correlates of a Phase II Trial of High-Dose Interleukin-2 and Stereotactic Ablative Radiotherapy for Metastatic Renal Cell Carcinoma
AU - Hannan, Raquibul
AU - Mohamad, Osama
AU - Diaz De Leon III, Alberto
AU - Manna, Subrata
AU - Pop, Laurentiu M.
AU - Zhang, Ze
AU - Mannala, Samantha
AU - Christie, Alana
AU - Christley, Scott
AU - Monson, Nancy
AU - Ishihara, Dan
AU - Hsu, Eric J.
AU - Ahn, Chul
AU - Kapur, Payal
AU - Chen, Mingyi
AU - Arriaga, Yull E
AU - Courtney, Kevin
AU - Cantarel, Brandi
AU - Wakeland, Edward K.
AU - Fu, Yang Xin
AU - Pedrosa, Ivan
AU - Cowell, Lindsay
AU - Wang, Tao
AU - Margulis, Vitaly
AU - Choy, Hak
AU - Timmerman, Robert D.
AU - Brugarolas, James
N1 - Funding Information:
We thank the patients who participated in the study and their families. The authors thank Dr. Jonathan Feinberg for scientific editing of the manuscript. The authors also thank the Genomics (Dr. Edward Wakeland and Dr. Prithvi Raj), Microarray (Dr. Quan-Zhen Li and Ms. Indu Raman), Proteomics (Dr. Andrew Lemoff), and Tissue Management Shared Resource (Dr. Cheryl Lewis) Core Facilities at UT Southwestern, Dallas, TX. This work was financially supported by a Clinigen Inc. (formerly Prometheus Laboratories) grant; NIH grant 5R01CA258584-02 (T. Wang); Cancer Prevention and Research Institute of Texas grant CPRIT RP190208 (T. Wang); Simmons Cancer Center DSSR, UT Southwestern Medical Center 5P30CA142543 (T. Wang); NCI SPORE grant P50CA196516 (A. Christie, C. Ahn, P. Kapur, K. Courtney, I. Pedrosa, T. Wang, V. Margulis, and J. Brugarolas); NIH grant 5RO1CA154475 (P. Kapur and I. Pedrosa); NIH grant U01CA207091 (I. Pedrosa); American Cancer Society grant RSG-16-004-01-CCE (R. Hannan); and CPRIT MIRA RP180725 (R. Hannan).
Funding Information:
R. Hannan reports grants from Prometheus Laboratories during the conduct of the study. A. Christie reports grants from NIH during the conduct of the study, as well as grants from NIH and CPRIT outside the submitted work. Y. Arriaga reports other support from Bristol Myers Squibb and IBM Watson Health outside the submitted work. K. Courtney reports grants from Astellas, as well as personal fees from Janssen and Exelixis outside the submitted work. I. Pedrosa reports grants from NIH during the conduct of the study, as well as personal fees from Health Tech International, Merck, and Bayer Healthcare outside the submitted work. R.D. Timmerman reports grants from Varian Medical Systems, Elekta Oncology, and Accuray Inc. outside the submitted work. J. Brugarolas reports personal fees from Arrowhead, Exelixis, Calithera, Eisai, and Johnson & Johnson outside the submitted work, as well as grants from NIH and CPRIT. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/12/15
Y1 - 2021/12/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-2083
DO - 10.1158/1078-0432.CCR-21-2083
M3 - Article
C2 - 34551906
AN - SCOPUS:85122365200
VL - 27
SP - 6716
EP - 6725
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 24
ER -