The study seeks to establish the safety of neoadjuvant aromatase inhibitor with: DPX-Survivac, DPX-Survivac plus radiation, or DPX-Survivac with cyclophosphamide in stage I to III HR+HER2- breast cancer. There will be sequential enrollment into 3 arms with an anticipated N=6 participants per arm for N=18 participants in total. All participants will receive letrozole 2.5 mg daily during the 6 weeks of neoadjuvant therapy. Neoadjuvant therapy occurs weeks 1-6, with standard of care surgery taking place week 7 to 9.

Women with hormone receptor positive, HER2-negative (HR+/HER2-) breast cancer with large tumors or positive lymph nodes have low response rates with neoadjuvant chemotherapy. Survivin is overexpressed in HR+HER2- breast cancer. Increasing tumor-specific Th1 immunity by administration of DPX-Survivac may alter the immune environment of these tumors. Radiation is a standard component of breast cancer therapy causing a reduction in local recurrences and improved breast cancer specific survival. Low dose cyclophosphamide can deplete regulatory T-cells without altering levels of effector T-cells. The investigators predict that combining a vaccine targeting Survivin, overexpressed in HR+HER2- tumors, with other immune modulating therapies such as radiation or low dose cyclophosphamide can enhance the efficacy of DPX-Survivac.

Primary Objective

1) Safety of neoadjuvant aromatase inhibitor with: DPX-Survivac, DPX-Survivac plus radiation, or DPX-Survivac with cyclophosphamide in stage I to III HR+HER2- breast cancer Secondary Objectives

1. Immunogenicity of each arm, assessed by IFN-γ ELISPOT in PBMC.
2. Immunogenicity of each arm, assessed by GEO-Mx digital spatial profiler evaluation of FFPE tissue and TCRβ evaluation for surviving-specific T cells in the tumor.

Exploratory Objectives

1. Evaluation of the % TIL in the biopsy specimen and at the time of surgery within/between arms
2. Evaluation of the Ki67 changes between the biopsy and at time of surgery within/between arms
3. Comparison of immunogenicity, TIL change, and Ki67 change across arms
4. Epitope spreading within/between arms
5. Evaluation of Triseq (germline, whole exome sequencing, and RNAseq) of the tumor immune environment within/between arms
6. Evaluation of immune environment using multi-parameter immunohistochemistry within/between arms
7. Evaluation by experimental MRI in arm that adds radiation
8. Evaluation of survivin-specific MHC-tetramer staining in PBMC

Inclusion Criteria:

1. Patients must provide informed consent prior to any study-specific procedures and be able to understand and be willing to sign an informed consent document. Results of standard-of-care tests or examinations performed prior to obtaining informed consent and prior to treatment may be used for screening assessments rather than repeating such evaluations if within 30 day of day 1.

2. Women with resectable, non-metastatic breast cancer that is >1 cm, hormone receptor positive, HER2 negative, Ki67>10%.

3. HER2 negative is defined as:

   0-1+ HER2 expression by immunohistochemistry (IHC) OR Fluorescence in situ hybridization (FISH) negative OR HER2 2+ and FISH negative

4. Patients must be at least 28 days post systemic steroids prior to enrollment.

5. Patients must be at least 18 years of age.

6. Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status Score of ≤ 1

7. Adequate laboratory values within 30 days of enrollment defined as follows:

   1. White blood cell (WBC) ≥ 3000/mm3
   2. Hemoglobin (Hgb) ≥ 9 g/dL
   3. Neutrophil count ≥ 1500/mm3
   4. Lymphocyte count ≥ 1000/mm3
   5. Platelet count ≥ 75,000/mm3
   6. Serum creatinine ≤ 2.0 mg/dL or creatinine clearance > 60 ml/min
   7. Total bilirubin ≤ 1.5 mg/dL
   8. Aspartate aminotransferase (AST)/Serum glutamic oxaloacetic transaminase (SGOT) ≤ 2 times the ULN-

8. Patients must have recovered from major infections and, in the opinion of the investigator, do not have any significant active concurrent medical illnesses precluding protocol treatment.

9. The effects of DPX-Survivac on the developing human fetus are unknown. Women on the trial should be post-menopausal based on the NCCN definition of menopause

10. For patients in Arm B only, they must be able to undergo MR imaging as determined by treating physician using the standard Radiation Oncology MR screening process

Exclusion Criteria:

1. Patients may not be receiving any other investigational agents or on concurrent clinical trials while on during the clinical trial period.
2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to DPX-Survivac.
3. Pregnant and pre-menopausal women are excluded from this study because to keep anti-endocrine therapy consistent between patients.
4. Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C.
5. Uncontrolled autoimmune disease. Autoimmune disease allowed if controlled (with or without treatment) for the last 12 months.
6. Patients may not have received or plan to receive neoadjuvant systemic chemotherapy. 7) Patients unable to receive an aromatase inhibitor

8) Prior radiation to the affected breast 9) Previous cancers except for non-melanoma skin cancers or high risk cervical lesions in the past 5 years.

10) Previous breast cancer, tamoxifen, or aromatase inhibitor use. 11) Previous investigational immune therapy use-

Women with resectable, non-metastatic breast cancer