An Open-Label Phase I/II Study of Autologous Tumor-Draining Lymph Node-Derived Lymphocytes for Advanced HER2-Negative Breast Cancer
RATIONALE: Patients with HER2-negative advanced breast cancer have limited choice on targeted therapies, and often show only modest responses to available immunotherapies. Adoptive cell therapy with tumor-infiltrating lymphocytes has difficulties in preparing enough cells from solid tumors and overcoming the exhaustion and dysfunction of T cells, which limit its clinical use. Tumor-draining lymph node-derived lymphocytes (LNLs) that have abundant tumor-specific T cells, rather than exhausted T cells, are easier to produce. It is not yet known whether LNL treatment is safe and effective in patients with advanced HER2-negative breast cancer. PURPOSE: This open-label phase I/II trial is to study the safety and efficacy of autologous LNL in patients with advanced HER2-negative breast cancer.
∙ In order to be eligible for participation in this trial, the participant must:
• Have signed the informed consent to study participation.
• Be a female subject and aged between 18 and 70 years.
• Have locally advanced or recurrent inoperable HER2-negative breast cancer (Stage IIIB\
∙ IIIC) which cannot be treated with curative intent OR have metastatic breast cancer (Stage IV). HER2-negative breast cancer is defined by the most recent ASCO/CAP guidelines. Participants should appear clinically stable in the opinion of the investigator.
• Participants with estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive breast cancer have failed at least one line of hormonal therapy or CDK4/6 inhibitor, or are appropriate candidates for chemotherapy. Participants with ER-positive and/or PR-positive breast cancer may have received unlimited prior chemotherapy. Participants with triple-negative breast cancer (TNBC) may have received unlimited prior treatments for breast cancer.
• Have not received the chemotherapeutic drugs and immune checkpoint inhibitor intended to be used in this study in the prior treatments for the Stage IIIB, IIIC or IV breast cancer. Participants who received the same chemotherapeutic drugs and/or immune checkpoint inhibitor in the (neo)adjuvant setting as in this study are eligible, only if ≥12 months have elapsed between the completion of treatment with curative intent (e.g., date of primary breast tumor surgery or date of last adjuvant chemotherapy administration, whichever occurred last) and the enrollment of this study.
• Have not received any prior adoptive cell therapy.
• Be suitable for treatment with nab-paclitaxel or gemcitabine/carboplatin and camrelizumab as judged by the investigator.
• Have accessible tumor-draining lymph nodes by surgery to grow LNL.
• Have measurable disease based on RECIST 1.1. Target lesions situated in a previously irradiated area are considered measurable, only if they have shown unequivocal progression based on RECIST 1.1 after radiation therapy.
⁃ Have provided recently or newly obtained biopsy from a locally advanced or recurrent inoperable or metastatic tumor lesion for pathological examination of molecular subtype and PD-L1 expression, unless contraindicated due to site inaccessibility and/or participant safety concerns.
⁃ Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
⁃ Have life expectancy ≥4 months.
⁃ Demonstrate adequate normal organ function:
⁃ NOTE: Blood component or cytokine therapy is not allowed within 14 days before surgery.
∙ Routine blood test:
‣ Absolute neutrophil count (ANC) ≥1.5×10\^9/L
⁃ Lymphocyte count (LC) \>0.5×10\^9/L
⁃ Platelets (PLT) ≥100×10\^9/L
⁃ Hemoglobin (Hb) ≥90 g/L
∙ Liver function test:
‣ AST and ALT ≤2.5 ×ULN (≤5×ULN for participants with liver metastases)
⁃ ALP ≤2.5 ×ULN (≤5×ULN for participants with liver or bone metastases)
⁃ Total bilirubin ≤1.5×ULN (≤3.0 mg/dL for participants with Gilbert's syndrome)
∙ Renal function test:
• • Calculated creatinine clearance (CrCL) ≥45 mL/min OR creatinine ≤1.5 × ULN
∙ Coagulation function test:
‣ APTT ≤1.5 ×ULN
⁃ INR or PT ≤1.5×ULN
∙ Doppler echocardiography:
• • Left ventricular ejection fraction (LVEF) ≥50%
∙ Pulmonary function test:
‣ FEV1≥60%
⁃ Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through one year (or longer as specified by local institutional guidelines) after the last dose of study treatment. Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days prior to LNL infusion.
⁃ Have a specified washout period from prior anticancer therapies to the enrollment:
∙ Angiogenesis inhibitors: 4 weeks
‣ Chemotherapy or targeted therapy: 3 weeks
‣ Radiotherapy: 2 weeks
‣ Hormonal therapy: one week
⁃ Have recovered from prior therapy-related adverse events to Grade≤1 per CTCAE version 5.0 criteria or met the criteria of normal organ function specified above, except for second-degree peripheral nerve injury, alopecia, leukoderma, hypothyroidism controlled by thyroid hormone replacement therapy, type 1 diabetes controlled by insulin therapy, and other irreversible toxic events that would not be exacerbated by LNL infusion as judged by the investigator (e.g., hearing loss).