RT Journal Article SR Electronic T1 Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e003476 DO 10.1136/jitc-2021-003476 VO 9 IS 10 A1 Marc Oliva A1 Douglas Chepeha A1 Daniel V Araujo A1 J. Javier Diaz-Mejia A1 Peter Olson A1 Amy Prawira A1 Anna Spreafico A1 Scott V Bratman A1 Tina Shek A1 John de Almeida A1 Aaron R Hansen A1 Andrew Hope A1 David Goldstein A1 Ilan Weinreb A1 Stephen Smith A1 Bayardo Perez-Ordoñez A1 Jonathan Irish A1 Dax Torti A1 Jeffrey P. Bruce A1 Ben X. Wang A1 Anthony Fortuna A1 Trevor J. Pugh A1 Hirak Der-Torossian A1 Ronald Shazer A1 Nickolas Attanasio A1 Qingyan Au A1 Antony Tin A1 Jordan Feeney A1 Himanshu Sethi A1 Alexey Aleshin A1 Isan Chen A1 Lillian Siu YR 2021 UL http://jitc.bmj.com/content/9/10/e003476.abstract AB Background Sitravatinib, a tyrosine kinase inhibitor that targets TYRO3, AXL, MERTK and the VEGF receptor family, is predicted to increase the M1 to M2-polarized tumor-associated macrophages ratio in the tumor microenvironment and have synergistic antitumor activity in combination with anti-programmed death-1/ligand-1 agents. SNOW is a window-of-opportunity study designed to evaluate the immune and molecular effects of preoperative sitravatinib and nivolumab in patients with oral cavity squamous cell carcinoma.Methods Patients with newly-diagnosed untreated T2-4a, N0-2 or T1 >1 cm-N2 oral cavity carcinomas were eligible. All patients received sitravatinib 120 mg daily from day 1 up to 48 hours pre-surgery and one dose of nivolumab 240 mg on day 15. Surgery was planned between day 23 and 30. Standard of care adjuvant radiotherapy was given based on clinical stage. Tumor photographs, fresh tumor biopsies and blood samples were collected at baseline, at day 15 after sitravatinib alone, and at surgery after sitravatinib–nivolumab combination. Tumor flow cytometry, multiplex immunofluorescence staining and single-cell RNA sequencing (scRNAseq) were performed on tumor biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing and circulating tumor DNA and cell-free DNA were evaluated at each time point.Results Ten patients were included. Grade 3 toxicity occurred in one patient (hypertension); one patient required sitravatinib dose reduction, and one patient required discontinuation and surgery delay due to G2 thrombocytopenia. Nine patients had clinical-to-pathological downstaging, with one complete response. Independent pathological treatment response (PTR) assessment confirmed a complete PTR and two major PTRs. With a median follow-up of 21 months, all patients are alive with no recurrence. Circulating tumor DNA and cell-free DNA dynamics correlated with clinical and pathological response and distinguished two patient groups with different tumor biological behavior after sitravatinib alone (1A) versus sitravatinib–nivolumab (1B). Tumor immunophenotyping and scRNAseq analyses revealed differential changes in the expression of immune cell populations and sitravatinib-targeted and hypoxia-related genes in group 1A vs 1B patients.Conclusions The SNOW study shows sitravatinib plus nivolumab is safe and leads to deep clinical and pathological responses in oral cavity carcinomas. Multi-omic biomarker analyses dissect the differential molecular effects of sitravatinib versus the sitravatinib–nivolumab and revealed patients with distinct tumor biology behavior.Trial registration number NCT03575598.Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. Raw and processed gene × cell read count matrices, and interactive analysis visualizations are provided in CReSCENT (CRES-P24, https://crescent.cloud/ Username: reviewer_snow@crescent.cloud, Password: review_2021). *The project will be made Public upon manuscript publication.