Abstract
BackgroundClinically localized renal cell carcinoma is treated primarily with surgery followed by observation or adjuvant sunitinib in selected high-risk patients. The checkpoint inhibitor immunotherapeutic agents nivolumab and ipilimumab have recently shown a survival benefit in the first-line metastatic setting. To date, there have been no reports on the response of localized renal cancer to modern immunotherapy. We report a remarkable response of an advanced tumor thrombus to combined immunotherapy which facilitated curative-intent resection of the non-responding primary renal tumor. We characterized the tumor microenvironment within the responding and non-responding tumors.Case presentationA 54-year-old female was diagnosed with a locally advanced clear cell renal cell carcinoma with a level IV tumor thrombus of the vena cava. She was initially deemed unfit for surgical resection due to poor performance status. She underwent neoadjuvant immunotherapy with nivolumab and ipilimumab with a complete response of the vena cava and renal vein tumor thrombus, but had stable disease within her renal mass. She underwent complete surgical resection with negative margins and remains disease-free longer than 1 year after her diagnosis with no further systemic therapy. Notably, pathologic analysis showed a complete response within the vena cava and renal vein, but substantial viable cancer remained in the kidney. Multichannel immunofluorescence was performed and showed marked infiltration of immune cells including CD8+ T cells and Batf3+ dendritic cells in the thrombus, while the residual renal tumor showed a non-T cell-inflamed phenotype.ConclusionsPreoperative immunotherapy with nivolumab and ipilimumab for locally advanced clear cell renal cancer resulted in a complete response of an extensive vena cava tumor thrombus, which enabled curative-intent resection of a non-responding primary tumor. If validated in larger cohorts, preoperative immunotherapy for locally advanced renal cell carcinoma may ultimately impact surgical planning and long-term prognosis.
Highlights
Localized renal cell carcinoma is treated primarily with surgery followed by observation or adjuvant sunitinib in selected high-risk patients
This trial led to the Food and Drug Administration (FDA) approval of nivolumab in combination with ipilimumab for first-line International Metastatic renal cell carcinoma (RCC) Database Consortium (IMDC) intermediate or poor-risk metastatic RCC
We report a case of a profound response of an RCC tumor thrombus to combined immunotherapy with ipilimumab and nivolumab, with radiographic and immunopathologic signs of tumor resistance in the primary kidney tumor
Summary
We present a case of locally advanced RCC with a complete response within the tumor thrombus of the IVC and renal vein to preoperative nivolumab plus ipilimumab, which facilitated curative-intent resection of the non-responding primary renal tumor. In this case, the tumor thrombus showed evidence of a T cell-inflamed tumor microenvironment with co-localization of Batf3+ dendritic cells and CD8+ T cells and patchy expression of PD-L1, whereas the immunotherapy-resistant primary renal tumor showed T cell exclusion without PD-L1 expression. Surgical resection of advanced tumor thrombus in renal cell carcinoma is technically challenging and associated with added surgical morbidity This case supports further investigation into preoperative combined immunotherapy, with the intent to facilitate curative surgical resection in patients with locally advanced RCC with tumor thrombus. Abbreviations CTLA4: cytotoxic T-lymphocyte-associated protein 4; IMDC: International Metastatic RCC Database Consortium; ORR: overall response rate; OS: overall survival; PD1: programmed cell death protein 1; PD-L1: programmed cell death ligand 1; RCC: renal cell carcinoma; TKI: tyrosine kinase inhibitor
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