680 Multi-parametric assessment of the immune response to a trio immunotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma

• Published in: Journal for immunotherapy of cancer 2023-11, Vol.11 (Suppl 1), p.A771-A771
• Main Authors: Paustian, Christopher, Moudgil, Tarsem, Rajamanickam, Venkatesh, Simons, Noah, Meng, Ryan, Couey, Marcus, Taylor, Matthew H, Koguchi, Yoshinobu, Stadum, Annie, Christie, Tanisha, Hulett, Tyler, Iwamoto, Noriko, Shimada, Takashi, Minegishi, Yuriko, Vu, Quyen, Redmond, William L, Rushforth, Lessli, Peterson, Abigail, Brady, Bernard, Bell, R Bryan, Bifulco, Carlo, Ueda, Koji, Hilton, Traci, Jensen, Shawn M, Hong-Ming, Hu, Piening, Brian, Urba, Walter J, Fox, Bernard A, Leidner, Rom S
• Format: Article
• Language: English
• Subjects: Antigens; Biopsy; Cancer research; Cloning; Dark matter; Head & neck cancer; Immunotherapy; Lymphocytes; Medical research; Metastasis; Parametric statistics; Proteins; Squamous cell carcinoma; Vaccines
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2023-SITC2023.0680

BackgroundOur group developed a strategy for generating an ‘off-the-shelf’ multivalent proteasome-blocked autophagosome vaccine that contains proteins for many genes commonly overexpressed in adenocarcinoma and squamous cell cancers. This strategy exploits in vitro manipulation of the antigen presentation pathway to concentrate the dominant epitopes presented by MHC, including short-lived proteins (SLiPs), defective ribosomal products (DRiPs), and Dark Matter, the short-lived non-canonical peptides that are not expressed in the thymus and represent potential shared alternative cancer neoantigens.1 In preclinical models this vaccine strategy provides significant protection as a single agent,2 and significantly increased therapeutic efficacy when combined with anti-GITR and anti-PD-1.3 Based on these studies we hypothesize that addition of anti-GITR to the human vaccine, DPV-001, and anti-PD-1, will augment expansion and limit contraction of the anti-cancer immune response. A phase I clinical trial was initiated, and preliminary immunological monitoring data will be presented.MethodsPatients received DPV-001, with sequenced checkpoint inhibition (aPD-1 mAb; retifanlimab), with or without aGITR agonist mAb (INCAGN1876), in recurrent or metastatic HNSCC (NCT04470024). Tumor biopsies were taken pre-treatment, week 2 and 8. Blood samples were taken pre-treatment and at multiple timepoints and analyzed by flow cytometry and seromics. Tumor biopsies and blood were assayed by CITE-seq, scRNA-seq, BCR-seq, and TCR-seq. Multiplex immunofluorescence (mIF) was performed on biopsies.ResultsIn the first 4 patients evaluated, tumor-infiltrating T cells at week 8 increased from pre-treatment levels by an average of 4.3 fold (range 2.9 – 6.7, p=0.032). The density of CD39/CD103 double positive cells, previously shown to identify tumor-reactive T cells,4 also increased in all week 8 biopsies (mean 14.7 fold, range 5–40). All patients showed increased numbers of cells expressing IFN-γ and GZMB and increased numbers of T cells expressing LAG3+ in week 8 biopsies. Preliminary TCR evaluation of the tumor identified proliferation of clones previously undetected in PBL, including αβ T cells, iNKT and MAIT cells. Expansion of clones that predated treatment was also identified.ConclusionsAn increase in intra-tumoral T cells expressing activation and effector molecules is encouraging and studies are underway to expand the number of patients analyzed. Increased expression of LAG3 by T