Background: Talimogene laherparepvec (TVEC) is a modified oncolytic herpes simplex 1 (HSV1) virus that may enhance tumor immune infiltration and is currently FDA-approved for the treatment of unresectable cutaneous, subcutaneous, and nodal melanoma. Anti-tumor responses have been seen both locally and systemically, and an abscopal systemic effect has been described in distant organ metastases. Methods: In this single arm, open label Phase 1b study, patients received intra-tumoral TVEC (first dose 10⁶ PFU/mL followed by 10⁸ PFU/mL q2-3 weeks; volume based on tumor size up to max 4mL) in combination with CT (gemcitabine/carboplatin [GC], nab-paclitaxel [Nab-P], or paclitaxel [P]) or ET at the discretion of the treating physician. All patients had at least one 1 cm lesion that was injectable at the bedside. The primary endpoint was safety and tolerability. The secondary endpoint was response by RECIST 1.1. Blood and tissue-based immune correlates including injected and neighboring non-injected lesions were evaluated. Results: 19 pts were enrolled on this study (2/5/20 – 1/25/23) and evaluable for toxicity with 1 pt non-evaluable for efficacy due to early discontinuation. Median age was 52.1 years. Nine pts (47%) had HR+/HER2- BC and 10 pts (53%) had TNBC. Injected lesions included intact subcutaneous skin nodules (7), non-fungating breast or chest wall lesions (12), and fungating breast or chest wall lesions (9). Pts had a median of 3 prior lines of systemic therapy in the metastatic setting (range 0-9). 13 pts (74%) had visceral metastases. Pts received TVEC with the following treatment partners: GC (n=8, 42%), Nab-P (n=7, 37%), P (n=2, 11%), ET (n=2, 10%). Median treatment duration was 11.6 weeks (range 1.0-45.0 weeks). Grade 3-4 treatment-related adverse events included neutropenia (n=5, 26%), anemia (n=1, 5%), thrombocytopenia (n=1, 5%), and injection site skin ulceration (n=1, 5%). Three pts (16%) had Grade 1-2 injection site skin ulceration. Response per RECIST 1.1 was evaluated in 16 pts (2 pts had rapid progression prior to first response evaluation): PR (n=2, 13%), SD (n=5, 31%), and PD (n=9, 56%). Disease response at the site of TVEC injection was clinically evaluated in 18 pts, with response rates (RR) as follows: partial response (PR) (n=11, 61%), stable disease (SD) (n=4, 22%), and progressive disease (PD) (n=3, 17%). Mass cytometry (CyTOF) analysis demonstrated a decrease in HLA-DR expression circulating lymphocytes and in TIM3 expression across multiple cell types in responders vs. non-responders; updated correlative analyses will be presented. Conclusions: The addition of intra-tumoral TVEC to CT or ET is safe and tolerable in pts with advanced BC. This treatment induces changes in circulating immune responses. Clinical trial information: NCT03554044.