An Open-Label Phase I/II Study of Autologous Tumor-Draining Lymph Node-Derived Lymphocytes as Neoadjuvant Therapy for HER2-Negative Breast Cancer
RATIONALE: Patients with HER2-negative breast cancer not responding to initial neoadjuvant chemotherapy might have lower chances for a pathologic complete response (pCR) at definitive surgery, indicating worse prognosis. Adoptive cell therapy has demonstrated efficacy in advanced breast cancer, but whether the addition of adoptive cell therapy to neoadjuvant chemotherapy could increase the pCR rate remains unclear. Tumor-draining lymph node-derived lymphocytes (LNLs) that have abundant tumor-reactive T cells, but not exhausted T cells, are easy to produce. It is not yet known whether LNL treatment is safe and effective in patients with HER2-negative breast cancer not responding to neoadjuvant chemotherapy. PURPOSE: This open-label phase I/II trial is to investigate the safety and efficacy of autologous LNL in patients with HER2-negative breast cancer not responding to neoadjuvant chemotherapy.
‣ 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.
• Provide a core needle biopsy which is histologically confirmed as invasive breast cancer. Excisional biopsy or surgical biopsy is not allowed.
• Have received two cycles of doxorubicin or epirubicin, plus cyclophosphamide, and had stable disease (SD) confirmed by breast MRI.
• Have breast cancer defined as the following combined primary tumor (T), regional lymph node (N), and distant metastasis (M) staging per AJCC for breast cancer staging criteria version 8 based on breast MRI assessment:
• The minimum size of the primary tumor was 1 cm in largest diameter by breast MRI, N0-3, M0.
• Have HER2-negative breast cancer, defined as 0-1+ by immunohistochemistry or 2+ by immunohistochemistry without HER2 amplification by FISH.
• Have known hormone receptor status (estrogen receptor \[ER\], progesterone receptor \[PgR\]), Ki67 value and, if institutional standard permits, known tumor grade.
• Have not received prior therapies for breast cancer, including but not limited to, chemotherapy (except two cycles of doxorubicin or epirubicin, plus cyclophosphamide), radiotherapy, hormonal therapy, targeted therapy, biological therapy and surgery.
• Have accessible tumor-draining lymph nodes by surgery to grow LNL. Participants have not received sentinel lymph node biopsy (SLNB) and ipsilateral axillary lymph node dissection (ALND) for the breast cancer lesion.
⁃ Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
⁃ 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 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 prior to the surgery for obtaining the lymph nodes, 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).