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Background ASP-1929 photoimmunotherapy (PIT) is an investigational treatment that combines cell surface binding of an anti-EGFR antibody conjugated to IRDye®700DX with red-light illumination for selective cell killing. While PIT elicits anti-tumor immunity in preclinical models, 1 2 this is the first clinical study to evaluate the effect of PIT in the tumor microenvironment of operable primary or recurrent tumors prior to standard of care (SOC) surgical resection.Methods Nine patients (7 HNSCC, 2 cuSCC) received ASP-1929 PIT, followed by SOC surgical resection approximately 21 days later. The primary endpoint of efficacy was evaluated by pathological tumor response (pTR), specifically pTR-2 as defined by Uppaluri, et al. 3 Biomarker samples for all patients were collected prior to ASP-1929 infusion, at 1 and 14 ± 2 days post-PIT, and at surgical resection. Single-cell RNA sequencing (scRNAseq) was used to identify changes in immune cell populations and gene expression using fresh tumor biopsies. Cytokine changes in the blood were evaluated by Meso Scale Discovery electrochemiluminescence. Flow cytometry was conducted for immunophenotyping peripheral blood mononuclear cells (PBMCs).Results pTR ranged from 26-99%, with 7 of 9 patients (78%) achieving pTR-2. scRNAseq analysis of paired tumor biopsies pre- vs 24 hr post-PIT revealed consistent changes in immune cell populations across all patients analyzed, with a trend towards increased monocytes/macrophages and dendritic cells and a significant increase in neutrophils (p<0.01, figure 1). Gene expression analysis showed an increase in IL-1B, TNF, IL-1R1, and IL-6. There was a significant increase in IL-6 (p<0.05) and a trend toward increase in TNFα (p=0.084) in patient plasma 24 hr post-PIT compared to baseline. Flow cytometry analysis of PBMCs 24 hr post-PIT revealed a significant increase in proliferating NK cells (Ki67+, p<0.05) and a significant decrease in immature (CD56hiCD16-, p<0.05) and cytotoxic NK cells (CD56lowCD16hi, p<0.05), indicating a possible shift of these NK cells from the blood to the tumor microenvironment of the PIT-treated tumors. On day 16 post-PIT, there was a significant increase in both PD1+CD4+ and Ki67+CD4+ T cell populations (p<0.05). Additional analyses of the periphery and tumor microenvironment are ongoing.Conclusions In this study, all patients showed tumor targeting by ASP-1929 PIT with measurable pTR and consistent activation of immunity by multiple analysis methods. The data reveals an early induction of inflammation as a pharmacodynamic marker of photoimmunotherapy in the clinical setting and warrants further evaluation of ASP-1929 PIT as a treatment modality for HNSCC and cuSCC.Ethics Approval This study was approved by National Institutes of Health (NIH) Institutional Review Board; IRB number 000462.Participants gave informed consent before taking part.References Ogawa M, Tomito Y, Nakamura Y, et al. Immunogenic cancer cell death selectively induced by near infrared photoimmunotherapy initiates host tumor immunity. Oncotarget. 2017;8:10425-10436.Hsu MA, Okamura SM, De Magalhaes Filho CD, et al. Cancer-targeted photoimmunotherapy induces antitumor immunity and can be augmented by anti-PD-1 therapy for durable anticancer responses in an immunologically active murine tumor model. Cancer Immunol Immunother. 2023;72(1):151-168.Uppaluri R, Campbell KM, Egloff AM, Zolkind P, Skidmore ZL, Nussenbaum B, et al. Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial. Clin Cancer Res. 2020;26(19):5140-5152.Abstract 193 Figure 1UMAP Cell Types Across Patients Show Consistent Immune Cell Changes Following ASP-1929 PIT. Uniform Manifold Approximation and Projection (UMAP) plot showing the major clusters of all cells across patients pre-PIT (Day 2) and 24h post PIT (Day 3). Cells are color coded by their associated cell clusters. PIT=Photoimmunotherapy