Overview

This phase Ib trial tests the safety, side effects and best dose of anti-HLA-A2/NY-ESO-1 T-cell receptor (TCR)-transduced autologous T lymphocytes (A2-ESO-1 TCR-T cells) in treating patients with NY-ESO-1 overexpression positive triple negative breast cancer (TNBC) that has come back after a period of improvement (relapsed/recurrent) or that does not respond to treatment (refractory), and that may have spread from where it first started (primary site) to nearby tissue, lymph nodes (advanced) or to other places in the body (metastatic). NY-ESO-1 is an antigen found on the surface of many different types of tumor cells including TNBC. Antigens make it possible for immune cells to recognize and kill germ cells that invade the body, however, it is more difficult for immune cells to recognize antigens on tumor cells. T cells are a special type of immune cell in the blood. These T cells may be trained to recognize the NY-ESO-1 antigen on tumor cells, allowing the T cells to attack and kill those tumor cells. The A2-ESO-1 TCR-T cells are T cells that have been removed from the patient's blood through a process called leukapheresis and then changed in the laboratory to recognize NY-ESO-1 on tumor cells. When given back to the patient, these A2-ESO-1 TCR-T cells find and attack tumor cells that express NY-ESO-1. Chemotherapy drugs, such as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. They are given before the T cells to support optimum activity of the A2-ESO-1 TCR-T cells. IL-2 (aldesleukin) is in a class of drugs known as cytokines. It is a man-made version of a naturally occurring protein that stimulates the body to produce other chemicals which increase the body's ability to fight cancer. A2-ESO-1 TCR-T cells may kill more tumor cells in patients with recurrent or refractory advanced or metastatic TNBC that overexpresses NY-ESO-1.

Eligibility

Inclusion Criteria:

• Female aged >= 18 years
• Histologically confirmed advanced or metastatic TNBC that have relapsed on or are refractory to 2 or more lines of standard-of-care therapy including immune checkpoint inhibitors, chemotherapy, trastuzumab deruxtecan (TDX-d) and poly-ADP ribose polymerase (PARP) inhibitors if indicated, but less than 4 lines of total therapies. TNBC is defined as estrogen receptor (ER) and progesterone receptor negative (< 10% immunohistochemistry [IHC] staining) and HER2 negative (IHC 1+ or 0 AND/OR in situ hybridization negative based on:
  • Single-probe average HER2 copy number < 4.0 signals/cell
  • Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell)
• HLA-A2+ and tumoral overexpression of NY-ESO-1 (2 to 3+ IHC staining in > 50% of

  cells)

• Have measurable disease based on RECIST 1.1
• Life expectancy >= 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Hemoglobin >= 9.0 g/dL (transfusions permitted)
• Absolute neutrophil count (ANC) >= 1500/mm^3
• Platelet count >= 100,000/mm^3
• Creatinine (Cr) < 2 x upper limit of normal (ULN), and Cr clearance (CrCl) >= 50 mL/min by Cockcroft and Gault
• Alanine transaminase (ALT) and aspartate transaminase (AST) < 2 x ULN (Patients with liver metastases whose ALT/AST are < 5 x ULN are eligible for enrollment)
• Bilirubin < 2 x ULN
• White blood cell (WBC) count > 2500/uL and < 15000/uL
• Lymphocyte count >= 500/uL
• Cardiac ejection fraction >= 50%
• Negative serum pregnancy (human chorionic gonadotropin [beta-hCG]) test within 7 days of leukapheresis for women of childbearing potential (WOCBP). WOCBP must be willing to use a highly effective method of contraception for the course of the study through 90 days after A2-ESO-1 TCR-engineered T cell infusion
• Willing and able to provide written informed consent for the study
• Willing to provide biopsy tissues and blood samples as required by the study

Exclusion Criteria:

• Radiation therapy, chemotherapy, or non-cytotoxic investigational agent within 2 weeks of leukapheresis
• Received cyclophosphamide within the past 4 months
• Evidence of New York Heart Association class III or greater cardiac disease
• History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic conduction abnormality within the past 12 months
• History of congenital QT prolongation
• Absolute QT interval of > 470 msec in the presence of > 4.0 mEq/L potassium and > 1.8 mg/dL magnesium
• Brain or leptomeningeal metastases
• Females who are pregnant or breastfeeding
• Hypersensitivity or intolerance to cyclophosphamide, fludarabine, or their components
• Alcoholic liver disease or other hepatic disease with the exception of liver metastases
• History of gastrointestinal bleeding, ulceration, or perforation
• Any severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study, such as severely impaired lung function, any active (acute or chronic) or uncontrolled infection/disorders, and non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the study treatment
• Current use of medications that interact with or compromise the immune system such as steroid doses > 10 mg/day prednisone or equivalent daily within 2 weeks before leukapheresis
• History of immunodeficiency disease or autoimmune disease, with exceptions such as Hashimoto's thyroiditis / hypothyroidism, or controlled Type 1 diabetes
• Have any active and uncontrolled infection.
• Active hepatitis B or hepatitis C infection or seropositive for hepatitis B, and hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then patients must be tested for the presence of antigen by RT-PCR and be HCV RNA negative
• Human immunodeficiency virus (HIV) infection or seropositive for HIV antigens
• Concurrent use of any complementary or alternative medicines
• Unwilling or unable to comply with the study protocol
• Prior major surgery that requires general anesthesia must be completed at least 4 weeks before leukapheresis and surgery that requires local anesthesia (except for study tissue sample collection) must be completed at least 2 weeks before leukapheresis and surgery that requires local anesthesia (except for study tissue sample collection) must be completed at least 2 weeks before leukapheresis