Background Residual disease (RD) after standard neoadjuvant chemotherapy (NAC) is composed of drug resistant cells and associates with increased risk of relapse, especially in triple negative, HER2-positive, and highly proliferative Luminal tumors. Immunotherapy combinations can induce of specific anti-tumor immune responses, such as those mediated by T-cells, and which might represent an additional strategy for the control or elimination of residual tumor cells. Preliminary results in melanoma showed that the combination of T-VEC with an anti PD-L1 or anti CTLA4 has greater efficacy than either therapy alone, without additional safety concerns beyond those expected for each agent. The presence of RD after neoadjuvant chemotherapy (NAC) in early BC patients remains an unmet medical need. We hypothesize that combining T-VEC with Atezolizumab may offer clinical benefit in the preoperative setting for early breast cancer (BC) patients with intermediate to high risk of recurrence who present RD after standard NAC. Methods SOLTI-1503 PROMETEO is an open-label, multicenter trial of T-VEC + Atezolizumab in patients with RD after completing standard NAC. Thirty patients with triple negative BC (TNBC) or Luminal B-like/HER2- will be included. RD must be confirmed by core-biopsy and have a diameter ≥ 15 mm measured by magnetic resonance imaging. Adequate organ function and ECOG PS 0-1 are required. T-VEC is administered intratumorally in week 1 (106 plaque-forming units/mL [pfu/mL]), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) is administered intravenously every 2 weeks for 4 infusions, beginning in week 4. BC surgery will be carried out 1 to 3 weeks after completion of treatment. A protocol amendment was approved, the steering committee of the study decided to change the primary objective of the trial to a more clinical endpoint that is to evaluate the efficacy by the rate of RCB class 0/1 at surgery. Secondary endpoints include rate of pCR, ORR, safety and the increase of mean expression of a gene signature tracking activated CD8 T-cells. The first safety analysis was performed in October 2019. Independent safety date review board considered the trial safe and supported its continuation. To date, 8 patients have been included at 4 sites in Spain. Second safety and efficacy data analysis is planned after 10 patients have completed treatment. If a rate of PD higher than 50% is observed in the first 10 patients, then the trial will be permanently stopped. We expect to achieve 10 patients in July 2020. We thank AMGEN for their provision of Talimogene Laherparepvec and their financial contribution to this clinical study. We thank ROCHE for their provision of Atezolizumab and their financial contribution to this clinical study. Clinical trial identification: NCT03802604 Citation Format: Tomás Pascual, Juan M Cejalvo, Mafalda Oliveira, Maria Vidal, Estela Vega, Sergi Ganau, Ana Julve, Esther Zamora, Ignacio Miranda, Ana Delgado, Begoña Bermejo, Luis de la Cruz-Merino, Manel Juan, Juan M Ferrero-Cafiero, Jordi Canes, Xavier González-Farré, Patricia Villagrasa, Aleix Prat. Solti-1503 PROMETEO: Talimogene laherparepvec (T-VEC) + atezolizumab combination in early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-06.