Background: Elderly patients with head and neck cancer (HNC) represent a growing population that would benefit from novel, less toxic approaches. Recent negative trial results adding ICI to chemo-RT for LAHNSCC (Javelin, Keynote 412) suggest that total nodal irradiation may create an immunosuppressive tumor microenvironment (TME), blunting the efficacy of ICI. This study was undertaken to use pulsed QUAD SHOT as an in-situ vaccine by stimulating the TME prior to delivery of ICI, excluding elective nodal sites, to enhance the immune response. Methods: 33 pts (20 males/13 females), with a median age of 81, seen at two community hospitals, ineligible for curative therapy, were treated with pulsed dose QUAD shot regimen to gross disease (44.4-59.2 Gy) spaced 3 weeks apart with addition of an approved ICI (Pembrolizumab or Cemiplimab). ERT was directed ONLY to GTV p+/-n. ICI was administered in most ptsafter the 1^st QUAD shot to enhance immune response. ICI was continued adjuvantly until a > Grade 3 adverse event (AE) or progression of disease (POD). Pts with either advanced cutaneous or mucosal SCC were included (cSCC, mSCC). 39% presented with N1-2 adenopathy, and 24% presented with recurrent disease. PD-L1 status were not routinely obtained. Results: The median number of ICI cycles delivered was 5 (range 2-24). All pts completed at least 3 QUAD shots. Overall LRC for all 33 pts was 69.7%, with a mean follow-up of 11 months (1-39). LRC for 33 pts at 1 and 2 years after the end of radiation were 61.07% and 55.52%, respectively. The percentage of pts free from elective regional recurrences at 1 and 2 years was 87.13% for both cSCC and mSCC groups. Six pts (18%) experienced distant failure. Freedom from distant failure at 1 yr after QUAD shot completion by pathology was 100.00% for cSCC and 77.08% for mSCC. DFS for all 33 pts at 1 and 2 yrs were 59.39% and 37.12%, respectively. DFS at 1 year for cSCC was 100% and 53% for mSCC. Median DFS for the mSCC was 13.8 months. Overall survival for all 33 pts was 45.45% with a median OS time of 17.7 months. 1 and 2 year OS rates were 65% and 33%. Overall toxicity was low and manageable. Gr 3 mucositis occurred in 1 patient and 5 (15%) developed Gr 2 AE’s. Gr 3/4 IMAR’s were observed in 3 pts and included infusion reaction, colitis, and fatigue/FTT and were discontinued. 4 pts required post QUAD PEG’s unrelated to radiation toxicity and due to POD. Conclusions: In elderly, frail, or comorbidly ill pts with LAHNC, the addition of ICI to involved field pulsed QUAD shot regimen tripled the median OS rate from prior publications with QUAD shot alone from 5.7 months to 17 months in our series. The low percentage of failure in the elective nodal beds was very encouraging based on our hypothesis. This approach represents the next step in an evolution away from conventional RT approaches that engender greater toxicity and warrants further study.