1481 Off-the-shelf dark matter immunotherapy in head & neck cancer: mechanistic insights and clinical efficacy

<h3>Background</h3> DPV-001 is an off-the-shelf biologic containing proteins that are overexpressed by adenocarcinoma and squamous cell cancers. It is enriched for short-lived proteins (SLiPs) and defective ribosomal products (DRiPs), containing canonical and non-canonical alternative cancer neoantigens (dark matter, at least 30 microproteins) in spectrin-coated microvesicles targeted to CLEC9A⁺ conventional dendritic cells (cDC).^{1 2} Preclinical models demonstrated enhanced antitumor activity when the murine version of DPV-001 was combined with co-stimulatory agonist(s) and delayed PD-1 blockade(d.PD-1), which formed the basis of the current trial. <h3>Methods</h3> Patients were randomized to receive heterologous prime-boost DPV-001 + sequenced d.PD-1 (retifanlimab Q4W) +/- GITR agonist (INCAGN-1949 Q2W). Tumor biopsies were obtained at baseline, week 2 and week 8, with longitudinal blood and serum sampling. Phenotypic and molecular studies were performed. <h3>Results</h3> 18 pts have been treated (9 PD-1 refractory &amp; 9 PD-1 naïve). Objective response was observed in 3/9 PD-1 refractory, and in 5/9 PD-1 naïve patients, including two complete responses, one of which continues past 24 months. Responses were observed in HPV+ and HPV- patients and 5 responders had PD-L1 CPS scores of &lt;5. We observed irAE’s (G1-3, no G4), at a breadth &amp; frequency greater than would be expected for PD-1 alone, attesting to bioactivity. Tumor biopsy analysis by scRNA-seq identified expanded T cell clones displaying tumor-reactive effector phenotypes which were not detectable at baseline (n=6 pts x 3 biopsy timepoints). In the first patient, TCR reconstruction and functional evaluation of three expanded T cell clones confirmed reactivity against HLA-matched tumors, with one TCR recognizing HNSCC, LUAD, RCC, and melanoma cell lines. <h3>Conclusions</h3> DPV-001 + sequenced d.PD-1 +/- GITR showed promising response rates of 56% (PD-1 naïve) and 33% (PD-1 refractory) in recurrent/metastatic HNSCC pts. Initial functional studies suggests this treatment expanded T cell clones against shared antigens. Ongoing studies are directed at unraveling the nature of the antigens recognized (canonical or dark matter), and whether they persist. <h3>Acknowledgements</h3> Incyte, Murdock Charitable Trust, Providence Portland Medical Foundation, Nancy Lematta, Lynn Loacker, Cindy and Steve Harder, The Chiles Foundation, Robert W. Franz and Elsie Franz Finley <h3>Trial Registration</h3> NCT04470024. <h3>References</h3> Nicoletta Cieri, Catherine J Wu. Splice it up: atypical transcripts to boost leukemia immunotherapy. <i>Immunity</i> 2021;<b>54</b>:608–610 Bernard A Fox, Walter J Urba, Shawn M Jensen, David B Page, Brendan D Curti, Rachel E Sanborn, Rom S Leidner. Cancer’s Dark Matter: Lighting the Abyss Unveils Universe of New Therapies. <i>Clin. Can. Res. Clin Cancer Res</i> 2023;<b>29</b>(12):2173–2175. <h3>Ethics Approval</h3> This study was approved by Providence Health System’s Ethics Board; approval number 2020000480.