CF33-hNIS-antiPDL1 for the Treatment of Metastatic Triple Negative Breast Cancer

This phase I trial tests the safety, side effects, and best dose of CF33-hNIS-antiPDL1 in treating patients with triple negative breast cancer that has spread to other places in the body (metastatic). CF33-hNIS-antiPDL1 is an oncolytic virus. This is a virus that is designed to infect tumor cells and break them down.

PRIMARY OBJECTIVE:

I. To determine the safety and tolerability of a novel chimeric oncolytic orthopoxvirus, oncolytic virus CF33-expressing hNIS/Anti-PD-L1 antibody (CF33-hNIS-antiPDL1), by the evaluation of toxicities including: type, frequency, severity, attribution, time course, reversibility and duration according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0 criteria.

SECONDARY OBJECTIVES:

I. To determine the optimal biologic dose (OBD) (defined as a safe dose that induces an immune response in tumors \[increase checkpoint target PD-L1 by at least 5% and/or increase T cell infiltration by at least 10%\]) and the recommended phase II dose (RP2D) for future expansion trial.

II. To determine tumor response rates by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (primary) and immune-modified (i)RECIST (secondary).

III. To document possible therapeutic efficacy and evaluate progression-free survival, overall survival and response.

EXPLORATORY OBJECTIVE:

I. To determine the immune and genomic profiles of tumors before and after CF33-hNIS-antiPDL1 therapy.

OUTLINE: This is a dose-escalation study.

Patients receive CF33-hNIS-antiPDL1 intratumorally (IT) on days 1 and 15. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 3 months for 1 year.

Eligibility Criteria:
Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative

  * Assent, when appropriate, will be obtained per institutional guidelines
* Agreement to research biopsies on study, once during study and end of study, exceptions may be granted with study principal investigator (PI) approval
* \>= 18 years
* Eastern Cooperative Oncology Group (ECOG) =\< 2
* Histologically confirmed metastatic triple negative breast cancer. Triple negative status will be defined as estrogen receptor (ER) and progesterone receptor (PR) =\< 10% by immunohistochemistry (IHC) and HER2 negative, per American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines
* Measurable disease by RECIST 1.1
* Patients must have progressed on or been intolerant of at least 2 prior lines of therapy for advanced/metastatic disease. Patients that qualify for immunotherapy and/or PARP inhibitors must have progressed on or been intolerant of these agents
* Fully recovered from the acute toxic effects (except alopecia) to =\< grade 2 to prior anti-cancer therapy
* Must have a superficial tumor (cutaneous, subcutaneous), breast lesion or nodal metastases amenable to safe repeated intratumoral injections per treating physician and interventional radiologist review
* Absolute neutrophil count (ANC) \>= 1,500/mm\^3

  * NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement
* Platelets \>= 100,000/mm\^3

  * NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
* Total bilirubin =\< 1.5 X upper limit of normal (ULN)
* Aspartate aminotransferase (AST) =\< 2.5 x ULN

  * If liver metastases are present: AST =\< 5 x ULN
* Alanine aminotransferase (ALT) =\< 2.5 x ULN

  * If liver metastases are present: ALT =\< 5 x ULN
* Serum creatinine =\< 1.5 mg/dL or creatinine clearance of \>= 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula
* Prothrombin (PT) =\< 1.5 x ULN
* Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN
* Women of childbearing potential (WOCBP): negative serum pregnancy test
* Agreement by females and males of childbearing potential\* and their partners to use an effective method of birth control (defined as a hormonal or barrier method) or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

Exclusion Criteria:

* Chemotherapy, biological therapy, immunotherapy or investigational therapy within 14 days prior to day 1 of protocol therapy
* Major surgery or radiation therapy within 28 days of study therapy
* Has received a vaccination within 30 days of first study injection
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
* Clinically significant uncontrolled illness
* Active infection requiring antibiotics
* Known history of immunodeficiency virus (HIV)
* Patients with a known history of hepatitis B or hepatitis C infection who have active disease as evidenced by hepatitis (Hep) B surface antigen status or Hep C polymerase chain reaction (PCR) status obtained within 14 days of cycle 1, day 1
* Another malignancy within 3 years, except non-melanomatous skin cancer
* Females only: Pregnant or breastfeeding
* Patients may not have clinically unstable brain metastases. Patients may be enrolled with a history of treated brain metastases that are clinically stable for \>= 4 weeks prior to start of study treatment
* Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)