Neoadjuvant cabozantinib restores CD8+ T cells in patients with locally advanced non-metastatic clear cell renal cell carcinoma: a phase 2 trial.

Autor:	Bilen MA; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA., Vo BT; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Liu Y; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA., Greenwald R; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Davarpanah AH; Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, USA., McGuire D; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.; Emory Vaccine Center, Emory University, Atlanta, GA, USA., Shiradkar R; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA., Li L; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA., Nazha B; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA., Brown JT; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA., Williams S; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Session W; Winship Cancer Institute, Emory University, Atlanta, GA, USA., Russler G; Winship Cancer Institute, Emory University, Atlanta, GA, USA., Caulfield S; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Pharmaceutical Services, Emory University School of Medicine, Atlanta, GA, USA., Joshi SS; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Narayan VM; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Filson CP; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Ogan K; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Kucuk O; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA., Carthon BC; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA., Del Balzo L; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Cohen A; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Boyanton A; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Prokhnevska N; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Cardenas MA; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Sobierajska E; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Jansen CS; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Patil DH; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Nicaise E; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Osunkoya AO; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA., Kissick H; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.; Emory Vaccine Center, Emory University, Atlanta, GA, USA., Master VA; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Aug 08. Date of Electronic Publication: 2024 Aug 08.
DOI:	10.21203/rs.3.rs-4849400/v1
Abstrakt:	Cabozantinib is an oral multikinase inhibitor approved for treatment in metastatic renal cell carcinoma (RCC). We hypothesized that neoadjuvant cabozantinib could downstage localized tumors, facilitating partial nephrectomy, and facilitating surgery in patients with locally advanced tumors that would require significant adjacent organ resection. We, therefore, conducted a phase 2, single-arm trial of cabozantinib treatment for 12 weeks in 17 patients with locally advanced biopsy-proven non-metastatic clear cell RCC before surgical resection. Six patients (35%) experienced a partial response, and 11 patients (65%) had stable disease. We identified that plasma cell-free DNA (cfDNA), VEGF, c-MET, Gas6, and AXL were significantly increased while VEGFR2 decreased during cabozantinib treatments. There was a trend towards CD8+ T cells becoming activated in the blood, expressing the proliferation marker Ki67 and activation markers HLA-DR and CD38. Cabozantinib treatment depleted myeloid populations acutely. Importantly, immune niches made up of the stem-like CD8+ T cells and antigen presenting cells were increased in every patient. These data suggest that cabozantinib treatment was clinically active and safe in the neoadjuvant setting in patients with locally advanced non-metastatic clear cell RCC and activated the anti-tumor CD8+ T cell response. The trial is registered at ClinicalTrials.gov under registration no. NCT04022343. Competing Interests: Completing interests M.A.B. has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi and has received grants to his institution from Merck, Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Exelixis, Nikang, Loxo Oncology, Ambrx, Regeneron, Acrivon Therapeutics, Amgen, Genome & Company, AAA, Peloton Therapeutics, and Pfizer for work performed as outside of the current study. The other authors declare no competing interests.
Databáze:	MEDLINE
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