TIL Gean Therapy Combined With Immunotherapy for Advanced or Metastatic Refractory Breast Cancer

This Phase I/II study evaluates the safety and efficacy of autologous tumor-infiltrating lymphocytes (TIL) therapy combined with Pembrolizumab (Keytruda) immunotherapy in patients with advanced or metastatic refractory breast cancer. TILs will be harvested from patients' tumors, expanded in vitro, and infused back into the patients following a non-myeloablative lymphodepletion regimen. Pembrolizumab, a monoclonal antibody that targets the PD-1 receptor on T cells, will be administered to enhance the immune response. The primary endpoint is to determine the objective response rate (ORR) of this combined therapy. Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and quality of life (QoL). This trial aims to provide a novel, personalized treatment option for patients with limited therapeutic alternatives.

Tumor-infiltrating lymphocytes (TILs) therapy is an advanced form of adoptive cell therapy that harnesses the patient's immune cells to fight cancer. This therapy involves extracting lymphocytes from the tumor, expanding them ex vivo, and reinfusing them into the patient to target and kill cancer cells. This study focuses on combining TIL therapy with Pembrolizumab (Keytruda) and Aldesleukin (IL-2) to enhance the anti-tumor immune response in patients with advanced or metastatic refractory breast cancer, conditions that typically have a poor prognosis and limited treatment options.

This trial involves a multi-step treatment process. First, tumor samples are collected from patients for TIL extraction. Following this, a lymphodepletion regimen using cyclophosphamide and fludarabine is administered to prepare the body for the infusion of expanded autologous TILs. After the TIL infusion, Aldesleukin (IL-2) is given to stimulate the TILs' activity. Pembrolizumab (Keytruda), an immunotherapy that targets the PD-1 receptor on T cells, is also administered to further enhance the immune response against the tumor.

The primary goal of this trial is to determine the objective response rate (ORR) of this combined therapy. Secondary endpoints include the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and changes in the quality of life (QoL) of patients.

Patients will be closely monitored for side effects and reactions during their hospital stay and throughout the follow-up period. Safety will be assessed based on the incidence and severity of adverse events, while efficacy will be evaluated using RECIST v1.1 criteria. By leveraging the patient's own immune cells and combining them with advanced immunotherapies, this trial aims to provide a novel, personalized treatment option for patients with advanced or metastatic refractory breast cancer.

Eligibility Criteria:
Inclusion Criteria:

* Age: 16 years to 90 years
* Histologically diagnosed as primary/relapsed/metastasized Breast Cancer
* Expected life span more than 3 months
* Karnofsky≥60% or ECOG score 0-2
* Test subjects have failed standard treatment regimens, or there are no standard treatment regimens available.
* Test subjects must have tumor regions eligible for biopsy or resection, or malignant body fluid where TILs can be isolated
* At least 1 evaluable tumor lesion
* Hematology and Chemistry（within 7 days prior to enrollment）:
* Absolute count of white blood cells≥2.5×10\^9/L
* Absolute count of neutropils≥1.5×10\^9/L
* Absolute count of lymphocytes ≥0.7×109/L
* Platelet count≥100×10\^9
* hemoglobin≥90 g/L
* Activated partial thromboplastin time (APTT) ≤1.5xULN (Unless received anticoagulant therapy within the previous 3 days)
* International normalized ratio (INR) ≤1.5xULN (Unless received anticoagulant therapy within the previous 3 days)
* Serum creatinine ≤1.5mg/dL(or ≤132.6μmol/L), or clearance rate≥50mL/min
* Serum ALT/AST ≤3×ULN(subjects with liver metastasis ≤3×ULN)
* Totol bilirubin≤1.5×ULN
* No absolute or relative contraindications to operation or biopsy
* Test subjects with child-bearing potential must be willing to practice approved highly effective methods of contraception at the time of informed consent and continue within 1 year after the completion of lymphodepletion
* Any malignant tumor-targeting therapies, including radiotherapy, chemotherapy, and biologics must cease 28 days before obtaining TILs
* Be able to understand and sign the informed consent document;
* Be able to stick to follow-up visit plan and other requirements in the agreement.

Exclusion Criteria:

* Need glucocorticoid treatment, and daily dose of Prednisone greater than 15mg (or equivalent doses of hormones) or outoimmune diseases requiring immunomodulatory treatment
* Forced expiratory volume in one second (FEV1) less than 2L, diffusing capacity of the lung for carbon monoxide (DLCO) (calibrated) less than 40%
* Significant cardiovascular anomalies according to any of the following definitions:
* New York Heart Association (NYHA) Grade III or IV congestive heart failure, clinically significant
* Low blood pressure, uncontrollable symptomatic coronary artery diseases, or ejection fraction less than 35%; Severe cardiac rhythm and conduction anomaly, such as ventricular arrhythmia requiring clinical intervention, second-third degree atrioventricular conductive block, etc.
* Human immunodeficiency virus (HIV) infection or anti-HIV antibody positive, active HBV or HCV infection (HBsAg positive and/or anti-HCV positive), syphilis infection or Treponema pallidum antibody positive.
* Severe physical or mental diseases;
* Have a systemic active infection requiring treatment, or have positive blood cultures(or imaging evidence of infection).
* Having been treated within a month or being treated now with other medicines, or other biologic therapy, chemo-or radiotherapy.
* History of allergy to chemical compounds consisting of chemical and biological substances resembling cell therapy.
* Having received immunotherapy and developed an irAE level greater than Level 3.
* Previous anti-tumor treatment AE did not return to CTCAE5.0 version grade 1 or below (toxicity considered by the investigator as non-safety concerns like alopecia excluded).
* Females in pregnancy or lactation. History of organ transplantation, allogeneic stem cell transplantation, and renal replacement therapy.
* Researchers consider the test subject as having a history of other severe systemic diseases, or other reasons inappropriate for the clinical study.