Matthias Brand (Ulm; Pittsburgh, PA, US), Aditi Kulkarni (Pittsburgh, PA, US), Housaiyin Li (Pittsburgh, PA, US), Pragati Upadhyay (Pittsburgh, PA, US), Simon I. Chiosea (Pittsburgh, PA, US), Patricia M. Santos (Pittsburgh, PA, US), Brian R. Isett (New York, NY, US; Pittsburgh, PA, US), Marion Joy (Pittsburgh, PA, US), Gabriel L. Sica (Pittsburgh, PA, US), Umamaheswar Duvvuri (New York, NY, US; Pittsburgh, PA, US), Seungwon Kim (Pittsburgh, PA, US), Mark Kubik (Pittsburgh, PA, US), Fei Tu (Pittsburgh, PA, US), Tullia C. Bruno (Pittsburgh, PA, US), Dario A.A. Vignali (Pittsburgh, PA, US), Anthony R. Cillo (Pittsburgh, PA, US), Riyue Bao (Pittsburgh, PA, US), Dan P. Zandberg (Pittsburgh, PA, US), Jing Hong Wang (Pittsburgh, PA, US), Lazar Vujanovic (Pittsburgh, PA, US), Robert L. Ferris (Chapel Hill, NC, US; Pittsburgh, PA, US)
Introduction: Nivolumab (Nivo) monotherapy demonstrate modest efficacy in the treatment of metastatic HNSCC. Neoadjuvant trials incorporating Nivo may facilitate the development of more effective combination therapies in patients with surgically resectable HNSCC. This study evaluates the efficacy of combining Nivo with additional immune checkpoint inhibitors, specifically CTLA4 (ipilimumab, Ipi) and LAG3 (relatlimab, Rela).
Material/Methods: This is a phase II randomized trial of neoadjuvant Nivo alone, or in combination with Ipi or Rela for 4 weeks prior to surgery. Response was evaluated using RECIST and standard pathologic response criteria. Pre- and post-treatment tumor samples were subjected to multispectral imaging and single cell RNA sequencing (scRNAseq) for T cell receptors and gene pathways analysis to identify biomarkers of response or progression.
Results: Forty-two patients were enrolled with 37 available for analysis. No serious study drug-related AEs or unexpected surgical delays/complications were observed. RECIST response was not associated with pathologic response. Pathologic response rates were more frequent with Nivo/Rela (11/15, 73%) versus Nivo/Ipi (7/11, 64%) or Nivo (5/12, 42%) and correlated with favorable clinical outcomes. Spatial imaging revealed a Nivo/Ipi-specific influx of CD4+ helper T cells in the tumor and stroma, while scRNAseq of CD4+ T cells revealed ICR expression that correlates with pathologic response to Nivo/Rela.
Discussion: Neoadjuvant combinations of Nivo/Ipi or Nivo/Rela were safe and linked to encouraging pathologic responses when compared to Nivo monotherapy. While the trial continues to enroll, a more comprehensive assessment of this strategy is necessary. Clinical trial information: NCT04080804.
Acknowledgements
This research was funded by BMS CA223049 (RLF), P50 CA097190 (RLF), R01 CA206517 (RLF), R01 DE031947 (RLF, LV, JHW), R01CA282074 (RLF and JHW) and DFG research fellowship #522169450 (MB). This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided by using the HTC cluster, supported by NIH award number S10OD028483. This research utilized the UPMC Hillman Cancer Center Flow Cytometry Core Facility, supported in part by award P30 CA047904 (RLF).
Ethics Approval
This study was approved by University of Pittsburgh"s Institutional Review Board; approval number HCC 18-139/CA224-056
Declaration of Interests
D.P.Z. declares competing interests with BICARA (steering committee), Seagen (steering committee), Inhibrx(consulting), Macrogenics (consulting), Prelude Therapeutics (advisory board), and Merck (advisory board) and research support (institutional) from Merck, BMS, AstraZeneca, GlaxoSmithKline, Aduro, Macrogenics, Bicara, and Novasenta. R.L.F. is cofounder and stockholder of Novasenta, and declares competing interests with Aduro Biotech, Inc. (consulting), AstraZeneca/MedImmune (clinical trial, research funding), Bristol-Myers Squibb (advisory board, clinical trial, research funding), EMD Serono (advisory board), MacroGenics Inc. (advisory board), Merck (advisory board, clinical trial), Novasenta (consulting, stock, research funding), Numab Therapeutics AG (advisory board), Pfizer (advisory board), Sanofi (consultant), Tesaro (research funding) and Zymeworks Inc. (consultant). T.C.B serves on the scientific advisory board of Walking Fish Therapeutics, BeSpoke Therapeutics, Mestag Therapeutics, Kalivir Therapeutics, and Galvanize Therapeutics. TCB is a consultant for Attivare Therapeutics and Tabby Therapeutics. L.V. is a co-inventor of a methodology licensed to INmune Bio, Inc. where DN-TNF can be used to prevent or treat malignancies. R.B. declares PCT/US15/612657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof), PCT/US63/055227 (Methods and Compositions for Treating Autoimmune and Allergic Disorders); D.A.A.V. has patents covering LAG3, with others pending, and is entitled to a share in net income generated from licensing of these patent rights for commercial development. D.A.A.V: cofounder and stock holder – Novasenta, Potenza, Tizona, Trishula; stock holder – Oncorus, Werewolf; patents licensed and royalties - BMS, Novasenta; scientific advisory board member - Tizona, Werewolf, F-Star, Bicara, Apeximmune, T7/Imreg Bio; consultant - BMS, Incyte, Regeneron, Ono Pharma, Peptone, Avidity Partners; funding - BMS, Novasenta. A.R.C. is a consultant for AboundBio. The other authors declare no competing interests
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