Grade 3 adverse events occurred in 10% of patients and included fever, fatigue, dizziness and alterations in clinical laboratory assessments. Furthermore, investigators at the NIH Clinical center have experience with administration of combination M7824 and N-803. As of January 2019, 13 solid tumor cancer patients have been treated with the M7824 1,200 mg IV every 2 weeks + N-803 16 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 (10-15 mcg/kg) SC every 2 weeks combination at the NCI. Four patients received a N-803 dosing of 10 mcg/kg every 2 weeks and 9 patients received N-803 dosing of 15 m cg/kg. No dose limiting, or unexpected toxicities attributed to the combination were observed. One patient with microsatellite stable, metastatic rectal cancer achieved a dramatic drop in CEA and improvement of cough attributed to lung metastasis after 3 treatments of M7824 and N-803. Imaging showed a partial response by RECIST version 1.1 criteria. (Figure 8B). Of note, this patient had received CEA, MUC1, and brachyury targeted adenoviral-based vaccine before enrolling on the M7824 + N-803 study. Figure 8 : A) Carcinoembryonic antigen decrease in a microsatellite stable colorectal cancer patient, who had previously received TriAd vaccine, while on M7824 and N-803.B) Corresponding decrease in lung metastasis in the same patient. A BCEA Vaccine M7824 N-803 17 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 Pharmacodynamic data from Nant suggest optimal T cell and NK cell is achieved with 15 mcg/kg dosing every 3 weeks. Therefore, a one-time dose of 15 mcg/kg N-803 on day 1 of treatment will be used in this study. 1.2.8 Therapeutic brachyury, MUC1 and CEA adenovirus vaccines (TriAd vaccine) The ability of adenoviral vaccination platforms to induce antigen-specific immune responses in human cancers is well studied. While vaccination of individual HNSCC cancer patients against predicted neoantigens has the potential to lead to tumor-specific immunity, the processes involved in developing personalized vaccines is cumbersome and costly. Vaccination against shared antigens commonly expressed in HNSCCs allows for the use of a standardized vaccine platform, and pre-clinical data suggests that “spreading” of T cell responses against neoantigens can be induced following vaccination against tumor-associated antigens (unpublished data, Hamilton laboratory). Query of expression data from the HNSCC cohort of The Cancer Genome Atlas demonstrates that brachyury, MUC1 and CEA are commonly expressed in HNSCCs and represent rational shared antigen targets. (Figure 9). Figure 9: Gene expression of brachyury, MUC1 and CEA from the HNSCC cohort of TCGA. 1.2.9 Clinical Experience with brachyury, MUC1 and CEA adenovirus vaccines at the NCI Administration of adenoviral vaccines encoding for these tumor-associated antigens has shown a manageable toxicity profile and ability to induce antigen specific T cell response in phase I trial conducted by the GMB/LTIB at the NCI. The combination of ETBX-011 (CEA-targeted), ETBX -051 (brachyury-targeted) and ETBX-061 (MUC1-targeted) has been tested in ten subjects. No DLTs were observed.