Background: Although immune checkpoint inhibitors (CPI) are inactive as monotherapy for microsatellite stable (MSS) mCRC, preclinical modeling suggests that addition of other immune-oncology agents can produce antitumor activity. CV301 is a poxviral vaccine against CEA and MUC1. N-803 is an IL-15 superagonist. M9241 is tumor-targeted IL-12. Bintrafusp alfa (BA) is a bifunctional anti-PD-L1/TGF-βRII fusion protein. Methods: Patients with advanced MSS or proficient mismatch repair (pMMR) small bowel or CRC were eligible (NCT04491955). Patients enrolling to Arm 1 received triple therapy with BA 1200 mg IV every 2 weeks, N-803 15 mcg/kg SC every 4 weeks, and CV301 SC on D1, D15, D29, and monthly, thereafter. Patients enrolling to Arm 2 received quadruple therapy, with M9241 (8 mcg/kg or 16.8 mcg/kg SC every 4 weeks) plus BA (300 mg or 1200 mg IV), N-803 (10 mcg/kg SC) and CV301 SC, depending on dose escalation schedule. Results: Thirty patients (2 small intestinal, 17 colon, 11 rectal) were treated. All patients had received prior 5-fluorouracil-based treatment, with 29/30 (96.7%) having received ≥ 2 lines of systemic therapy. Twelve patients received triple therapy; 18 received quadruple therapy. Grade 3 treatment-related AEs (TRAEs) occurred in 8 patients (26.7%); anemia occurred most commonly (n = 5), with grade 3 gastrointestinal hemorrhages occurring in 2 patients (on quadruple therapy). Other grade 3 TRAEs included elevated cardiac troponin, AST, and alkaline phosphatase (n = 1 each; all with triple therapy), and adrenal insufficiency (n = 1; quadruple therapy). No grade 4 or 5 TRAEs occurred. Triple therapy resulted in disease reduction in 2 patients (7.5%, 25.6%); quadruple therapy resulted in disease reduction in 2 patients (26.7%, 70.6%). Median overall survival (OS) for triple and quadruple therapy have not been reached, with 12 month survival being 66.7% (95% CI: 33.7-86.0%) for triple therapy and 77.2% (95% CI: 43.3-92.3%) for quadruple therapy. Conclusions: Combination therapies with CV301, N-803, bintrafusp alfa, and M9241 had manageable safety profiles. Preliminary clinical activity was observed in patients with advanced MSS/pMMR small bowel or CRC. Median OS was promising as compared to historical median survivals of 6-7 months following receipt of multiple lines of therapy. Clinical trial information: NCT04491955.