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.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of anti-HLA-A2/NY-ESO-1 TCR-transduced autologous T lymphocytes (A2-ESO-1 TCR-engineered T cells) in patients with relapsed/refractory locally advanced or metastatic TNBC that overexpresses NY-ESO-1 by using the Bayesian optimal interval (BOIN) design. II. To determine the dose-limiting toxicities (DLTs) of A2-ESO-1 TCR-engineered T cells in patients with relapsed/refractory locally advanced or metastatic TNBC that overexpresses NY-ESO-1, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v)5.0. SECONDARY OBJECTIVES: I. To evaluate the antitumor activity of A2-ESO-1 TCR-engineered T cells, as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. II. To evaluate the immunological activity (i.e., persistence, function) of A2-ESO-1 TCR-engineered T cells. EXPLORATORY OBJECTIVE: I. To evaluate the correlative markers of A2-ESO-1 TCR-engineered T cells, including but not limited to PD-L1 expression and immune cell populations such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). OUTLINE: This is a dose-escalation study of A2-ESO-1 TCR-T cells. Patients undergo leukapheresis on day -28 then receive cyclophosphamide intravenously (IV) over 1 hour on days -7 and -6 followed by fludarabine IV over 30 minutes on days -5 to -1. Patients then receive A2-ESO-1 TCR-T cells IV over 30 minutes on day 0 followed by aldesleukin IV over 15 minutes on days 0 to 2. Patients also undergo blood sample collection and computed tomography (CT) scans throughout the study. Additionally, patients may undergo a breast biopsy, a mammogram, breast magnetic resonance imaging (MRI), and breast ultrasound (US) at screening and follow up, and echocardiography (ECHO) or multi-gated acquisition scan (MUGA) at screening. After completion of study treatment, patients are followed up at 3, 6, and 12 months and then yearly for up to 15 years or until disease progression, voluntary study withdrawal or study discontinuation, whichever occurs first.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Given IV
Given IV
Undergo biopsy of breast tumor
Undergo blood sample collection
Undergo CT scan
Given IV
Undergo ECHO
Given IV
Undergo leukapheresis
Undergo breast MRI
Undergo mammogram
Undergo MUGA scan
Undergo ultrasound of breast
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
RECRUITINGMaximum tolerated dose (MTD) of anti-HLA-A2/NY-ESO-1 T-cell receptor (TCR)-transduced autologous T lymphocytes (A2-ESO-1 TCR-engineered T cells)
Will employ the Bayesian optimal interval to find the MTD.
Time frame: Up to 6 weeks after A2-ESO-1 TCR-engineered T cell infusion
Incidence of dose-limiting toxicities
Defined as any treatment-related death or any greater than or equal to grade 3 adverse event (AE) as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Time frame: Up to 6 weeks after A2 ESO-1 TCR-engineered T cell infusion
Antitumor activity
Antitumor activity will be assessed by RECIST 1.1. Complete Response (CR) = disappearance of all target lesions, Partial Response (PR) = at least a 30% decrease in the sum of the longest diameter of target lesions, using the baseline sum longest diameter as a reference, Stable Disease (SD) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD) using the smallest sum longest diameter since treatment start as reference, PD = At least a ≥20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: At pre-treatment and 6 months post-treatment
Change in PD-1 expression on T cells
Levels of PD-1 expression on T cells will be monitored. Post-treatment biomarker measurements will be compared to the pre-treatment values using a one-sided paired t-test and nonparametric Wilcoxon signed-rank test.
Time frame: At pre-treatment and 6 months post-treatment
Change in NY-ESO-1-specific TCR-engineered T cells
Levels of NY-ESO-1-specific TCR-engineered T cells will be monitored to determine whether these T cells are persistent. Post-treatment biomarker measurements will be compared to the pre-treatment values using a one-sided paired t-test and nonparametric Wilcoxon signed-rank test.
Time frame: At pre-treatment and 6 months post-treatment
Change in regulatory T cells (Treg)
Because NY-ESO-1-specific TCR-engineered CD4+ T cells may differentiate into Treg cells, levels of Treg cells will be monitored. Post-treatment biomarker measurements will be compared to the pre-treatment values using a one-sided paired t-test and nonparametric Wilcoxon signed-rank test.
Time frame: At pre-treatment and 6 months post-treatment
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