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Background: We have developed P10s-PADRE, a carbohydrate-mimetic-based peptide, cancer vaccine and demonstrated its safety and immunogenicity in a Phase I clinical trial performed in stage IV breast cancer patients. HR+/HER2- breast cancer is the most common form of breast cancer diagnosed in the United States. These patients face a persistent risk of distant recurrence long after completion of their treatment and new strategies to activate anti-tumor immune responses can improve outcomes of standard therapies. The current study was performed to examine the feasibility, safety and immunogenicity of adding P10s-PADRE to standard-of-care chemotherapy in HR+/HER2− early-stage breast cancer patients. Methods: Five combination schedules were designed based on the timing of immunizations relative to a standard-of-care neoadjuvant chemotherapy regimen. Induction of on-treatment antibody and cellular responses, including T-cells, natural killer (NK) cells, and cytokines was determined. Tumor-infiltrating lymphocytes were quantified in core and surgical biopsies. The data were used to define the treatment effect in general and the vaccine contribution in particular. Results: Combination of P10s-PADRE with chemotherapy was safe and immunogenic. Antibody response was superior in a particular combination schedule, called schedule C, where 3 weekly immunizations preceded the first dose of chemotherapy. We observed that the schedule C, relative to other schedules, displayed an increase in CD16 expression on NK cells, a drop in serum IFN-γ, and an increase in quantity of stromal TILs in residual tumors. Subjects demonstrated a significant reduction in the size of their primary tumor and three subjects achieved pCR. Conclusions: The timing of the immunization relative to the chemotherapy seems to define the type and strength of the immune responses elicited. A particular combination schedule, schedule C, appears promising and the results warrant the conduct of randomized phase II trials. Citation Format: Issam Makhoul, Saddam M Ibrahim, Muhammad Abu-Rmaileh, Fariba Jousheghany, Eric Siegel, Lora J Rogers, John J Lee, Sergio Pina-Oviedo, Ginell R Post, Thaddeus Beck, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi. Timing of the immunization defines immune signature of a peptide cancer vaccine combined with Neoadjuvant chemotherapy in HR+ breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-15.