Converting HR+ Breast Cancer Into an Individualized Vaccine

Patients will be on the study for a total of 5 months, this includes 4 months on active study
intervention, with breast surgery at week 16 and one month follow up period, after surgery.
Patients will be randomly assigned to one of these 4 arms - 1. Anti-PD1 antibody
pembrolizumab (Keytruda, Merck) will be infused day 12, at the standard dose of 200 mg IV
over 30 minutes, repeated every 3 weeks until disease progression or unacceptable toxicity.
2. FLT3L (CDX-301, the recombinant human protein by Celldex) will be self-administered
subcutaneously, in 5 consecutive daily injections, week 1, day 1-5. 3. For all arms radiation
therapy to the breast tumor will begin on week 2 (Day 8,10,12), at dose of 8 Gy x 3
fractions, every other day. 4. Letrozole (Femara ®, Novartis) 2.5 mg tabs, once a day, daily
for 4 months, until surgery, and thereafter is decided by the treating physician.

Inclusion Criteria:

- Post-menopausal female ≥ 18 years of age (Post-menopausal status defined as either 1)
at least 2 years without menstrual period or 2) or patients older than 50 with
serological evidence of post-menopausal status or 3) hysterectomized patients of any
age with FSH confirmation of post-menopausal status.

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Biopsy proven diagnosis of ER+HER2- breast cancer.

- Patient needs to be able to understand and demonstrate willingness to sign a written
informed consent document.

Adequate bone marrow reserve and liver function:

WBC ≥ 2000/uL Absolute neutrophil count (ANC) ≥1500/μL Platelets ≥100 000/μL Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La Creatinine OR Measured or calculated creatinine clearance (GFR
can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant
with creatinine levels >1.5 × institutional ULN Total bilirubin ≤1.5 ×ULN OR direct
bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN AST (SGOT) and ALT
(SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) International
normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time
(aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or
aPTT is within therapeutic range of intended use of anticoagulants

Exclusion Criteria:

- Active connective tissue disorders, such as lupus or scleroderma requiring flare
therapy

- Current use of systemic chemotherapy, endoctine therap or HER2-neu targeted therapy

- Pre menopausal patients.

- Male breast cancer patients

- Post surgical excision of breast cancer.

- Previous radiotherapy of the same breast.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
OX-40, CD137).

- Inability to obtain histologic proof of breast cancer

- Has received a live vaccine within 30 days prior to the first dose of study drug.

Examples of live vaccines include, but are not limited to, the following: measles, mumps,
rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin
(BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed
virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are
live attenuated vaccines and are not allowed.

- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment. Note: Participants who have entered the follow-up phase of an
investigational study may participate as long as it has been 4 weeks after the last
dose of the previous investigational agent.

- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.

- Has a known additional malignancy (second primary) that is progressing or has required
active treatment within the past 3 years. Note: Participants with basal cell carcinoma
of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. cervical
cancer in situ) that have undergone potentially curative therapy are not excluded.

- Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.

- Has an active infection requiring systemic therapy.Has a known history of Human
Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by
local health authority.

- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required
unless mandated by local health authority.

- Has a known history of active TB (Bacillus Tuberculosis). Note: optional based on
country.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.