Targeting sinonasal undifferentiated carcinoma with a combinatory immunotherapy approach

Austin T K Hoke; Yoko Takahashi; Michelle R Padget; Javier Gomez; Moran Amit; Jared Burks; Diana Bell; Tongxin Xie; Patrick Soon-Shiong; James W Hodge; Ehab Y Hanna; Nyall R London Jr

doi:10.1016/j.tranon.2024.101943

Targeting sinonasal undifferentiated carcinoma with a combinatory immunotherapy approach

Transl Oncol. 2024 Jun:44:101943. doi: 10.1016/j.tranon.2024.101943. Epub 2024 Apr 10.

Authors

Affiliations

¹ Sinonasal and Skull Base Tumor Program, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States; Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, United States.
² Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
³ Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
⁴ Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States.
⁵ Department of Pathology, City of Hope National Medical Center, Duarte, CA, United States.
⁶ ImmunityBio, Culver City, CA, United States.
⁷ Sinonasal and Skull Base Tumor Program, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States; Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address: nyall.london@nih.gov.

Abstract

Purpose: Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy of the sinonasal cavity with poor prognosis and limited treatment options. To investigate the potential for SNUC sensitivity to combinatory immunotherapy, we performed in vitro studies with SNUC cell lines and used multi-spectral immunofluorescence to characterize the in vivo patient SNUC tumor immune microenvironment (TIME).

Experimental design: Human-derived SNUC cell lines were used for in vitro studies of tumor cell susceptibility to natural killer (NK) cell-based immunotherapeutic strategies. Tumor samples from 14 treatment naïve SNUC patients were examined via multi-spectral immunofluorescence and clinical correlations assessed.

Results: Anti-PD-L1 blockade enhanced NK cell lysis of SNUC cell lines ∼5.4 fold (P ≤ 0.0001). This effect was blocked by a CD16 neutralizing antibody demonstrating activity through an antibody-dependent cellular cytotoxicity (ADCC) mediated pathway. ADCC-dependent lysis of SNUC cells was further enhanced by upregulation of PD-L1 on tumor cells by exogenous interferon-gamma (IFN-γ) administration or interleukin-15 (IL-15) stimulated IFN-γ release from NK cells. Combination treatment with anti-PD-L1 blockade and IL-15 superagonism enhanced NK-cell killing of SNUC cells 9.6-fold (P ≤ 0.0001). Untreated SNUC patient tumor samples were found to have an NK cell infiltrate and PD-L1⁺ tumor cells at a median of 5.4 cells per mm². A striking 55.7-fold increase in CK^low tumor cell/NK cell interactions was observed in patients without disease recurrence after treatment (P = 0.022). Patients with higher CD3⁺CD8⁺ in the stroma had a significantly improved 5-year overall survival (P = 0.0029) and a significant increase in CK^low tumor cell/CD8⁺ cytotoxic T cell interactions was noted in long-term survivors (P = 0.0225).

Conclusion: These data provide the pre-clinical rationale for ongoing investigation into combinatory immunotherapy approaches for SNUC.

Keywords: Antibody-dependent cellular cytotoxicity; IL-15; Immune microenvironment; Immunotherapy; Natural killer cells; Sinonasal undifferentiated carcinoma.

Abstract

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