CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Patients must understand and voluntarily sign an informed consent document before any study-related assessments/procedures being conducted.
2. Age ≥ 18 and years at the time of signing the ICF
3. Patients must be able and willing to comply with the study visit schedule and protocol requirements.
4. Patients must have a clinical performance of Eastern Cooperative Oncology Group 0 or 1.
5. Life expectancy ≥12 weeks.
6. Patients must have histologically or cytologically proven unresectable or metastatic tumors. The disease must be refractory to standard therapy or in the first line if they are unable to receive standard therapy or no standard therapy exists for a particular disease.

   a) Select tumor types: breast, gastric, and endometrial tumors. Other selected solid tumors may be included per investigator discretion if the potential benefit is considered based on the literature updates in HER2/p95HER2 expression.
7. Positivity for HER2 expression according to international society guidelines (score in a ISO-certified clinical or equivalent laboratory). To meet study entry eligibility, tumors are required to have at least an intensity score 3+ for HER2 staining following the manufacturer's recommendations
8. Measurable disease by the RECIST v. 1.1 criteria (See Section 7.2 for details). Note: Lesions previously irradiated should not be selected as target lesions unless there has been demonstrated progression in those lesions;
9. Patients are considered medically fit enough to undergo all study procedures and interventions and adequate hematological, renal, and hepatic functions defined by:

   1. Hemoglobin ≥ 9.0 g/dL.
   2. An absolute neutrophil count ≥ 1x10E9/L without the support of filgrastim
   3. Platelets ≥ 100 x10E9/L.
   4. PT and APTT ≤ 1.5x ULN (unless receiving therapeutic anticoagulation). Note: Subjects receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose.
   5. AST or ALT ≤ 3 x ULN. Patients with liver metastases must have AST and ALT ≤ 5.0 x ULN.
   6. Total bilirubin \< 2 mg/dL. Patients with Gilbert's Syndrome must have a total bilirubin ≤ 3.0 mg/dL.
   7. Serum creatinine \< 1.5 mg/dL or measured creatinine clearance ≥ 50 ml/min calculated using the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) × (weight in kg) × (0.85 if female)/72 × (serum creatinine in mg/dL).
10. Patients must be seronegative for HIV antibody.
11. Patients must be seronegative for active hepatitis B (defined as having a negative hepatitis B surface antigen \[HBsAg\] test), and seronegative for hepatitis C antibody. Patients with a history of hepatitis B virus (HBV) infection and having a negative HBsAg test and a positive antibody to hepatitis B surface antigen (HBsAg) are eligible. Patients with the hepatitis C antibody test positive are eligible only if tested for the presence of antigen by RT-PCR and be HCV RNA negative.
12. Patients must have blood tests results negative for active tuberculosis, syphilis, herpes simplex virus, cytomegalovirus, HTLV or Epstein-Barr virus infection.
13. Patients with documented LVEF of ≥ 50%.
14. Patients with documented FEV1, FVC, and DLCO ≥ 50% tested by a pulmonary function test.
15. Patients who are of childbearing potential (postmenarcheal who has not reached a postmenopausal state and has not undergone surgical sterilization) or have partners of childbearing potential must agree to use a highly effective method of contraception during the study and for at least 12 months after the infusion of the p95HER2.CAR-TECH2Me product .
16. Female participants: a female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

    1. Women of non-childbearing potential (WONCBP).
    2. Women of childbearing potential (WOCBP), who:

    i) Agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year from screening until 12 months after the infusion of the p95HER2.CAR-TECH2Me product. Examples of contraceptive methods with a failure rate of \<1% per year include bilateral tubal occlusion, male sterilization, and copper intrauterine devices.

    ii) Have a negative pregnancy test (blood) within one week before the first study treatment administration (applicable to premenopausal women and women 2 years after the start of menopause (menopause is defined as amenorrhea for \< 2 years).
17. Male Participants: during the treatment period and for at least 6 months after the last dose of study treatment, agreement to:

    1. Remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures such as a condom or a contraceptive method that result in a failure rate of \<1% per year, with partners who are WOCBP.
    2. Refrain from donating sperm during the study.
    3. Inform if his partner gets pregnant during this time.
18. Adequate expanding p95HER2.CAR-TECH2Me cells as defined by the T cell production manual before preparative lymphodepleting chemotherapy infusion (available autologous transduced T lymphocytes with 15% or more expression of p95HER2.CAR-TECH2Me as determined by flow-cytometry and killing of p95HER2-positive targets 20 % or greater in cytotoxicity assay.)
19. Any toxicity related to prior systemic therapy must have recovered to grade 1 or less according to NCI-CTCAE v5.0 at least 4 weeks before treatment enrollment, except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy, and Grade 2 peripheral neuropathy.

    Note: Other Grade 2 AEs that are deemed clinically insignificant by treating physician and in consultation with Medical Monitor are permitted.
20. Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.

Exclusion Criteria:

1. Patients with symptomatic and/or untreated brain metastases. Note: Patients with definitively-treated brain metastases will be considered for enrollment after discussion with Medical Monitor if prior to the start of NMA-LD the patient is asymptomatic, clinically stable for ≥3 months, there are no new brain lesions via magnetic resonance imaging (MRI) post-treatment, and the patient does not require corticosteroid treatment.
2. Patients with leptomeningeal carcinomatosis.
3. Patients with an active concurrent or history within the past 3 years of invasive malignancy, except for non-melanoma skin cancer, cervical and bladder carcinoma in situ, good prognosis ductal carcinoma in situ of the breast, or prostate carcinoma that is in remission under androgen deprivation therapy for \> 2 years. Other exceptions may apply and require discussion between the Investigator and the Medical Monitor.
4. Patients with an active systemic infection requiring anti-infective treatment within 14 days before preparative lymphodepleting therapy.
5. Patients with active hepatitis B or hepatitis C.
6. Patients with active autoimmune disease requiring immunosuppressive treatments.
7. Patients with a history of organ or bone marrow transplantation.
8. Patients with any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
9. Patients requiring regular treatment with steroids. Note: use of inhaled, topical steroids and use of systemic physiologic corticosteroid replacement therapy are permitted.
10. Patients with current or history within the last 6 months, as determined by the Investigator, of clinically significant, progressive, and/or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, gastroenterological or neurological disease.
11. Patients with a history of coronary revascularization or ischemic symptoms.
12. History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any origin)
13. Patients with allergies to any of the compounds included in any of the treatment products.
14. Patients with contraindications for cyclophosphamide and fludarabine at per protocol doses (see Investigator Brochure for details).
15. Patients who have received any approved anti-cancer cytotoxic, anti-angiogenic and ICB therapy including radiotherapy within 4 weeks before preparative lymphodepleting therapy.

    Exception: palliative radiotherapy for bone metastasis \> 2 weeks before preparative lymphodepleting therapy, denosumab, bisphosphonates, androgen deprivation therapy for prostate cancer and hormonal therapy for breast cancer.
16. Patients who have received any non-cytotoxic drug and molecular targeted therapy within 4 weeks before preparative lymphodepleting therapy (or within five half-lives of the investigational product, whichever is shorter).
17. Patients who have received any investigational agent within 4 weeks before preparative lymphodepleting therapy (or within five half-lives of the investigational product, whichever is shorter).
18. Patients who have received a live, attenuated vaccination within the 4 weeks before lymphodepleting therapy.
19. Patients who have undergone major surgery in the previous 3 weeks before lymphodepleting therapy.
20. Patients who have previously received any investigational cell or gene therapies.
21. Women of childbearing potential who are pregnant or breastfeeding.
22. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
23. Other severe, acute, or chronic medical condition or laboratory abnormality that may increase the risk associated with study assessed by the Investigator.

主要终点：Number of participants with adverse events and serious adverse events graded according to CTCAE v5.0 · Adverse events and serious adverse events will be collected and summarized by frequency, severity, seriousness, and relationship to study treatment. Events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, when applicable. Cytokine release syndrome and neurotoxicity/ICANS will be graded according to the protocol-specified consensus grading criteria. · Up to 3 months after the infusion；Number of participants with clinically significant abnormalities in clinical safety laboratory tests · Clinical safety laboratory assessments will be performed according to the Schedule of Assessments. Clinically significant new or worsening laboratory abnormalities will be recorded and summarized as adverse events when they meet protocol-defined adverse event criteria. Laboratory values will be assessed using local laboratory reference ranges. The protocol states that abnormal test findings are reported as AEs only if they are symptomatic, require additional testing/intervention or treatment, lead to study drug changes/discontinuation, or are considered AEs by the investigator or sponsor. · Up to 3 months after the infusion；Number of participants with clinically significant abnormalities in 12-lead electrocardiogram findings · Twelve-lead electrocardiograms will be obtained according to the Schedule of Assessments. Clinically significant new or worsening ECG abnormalities will be summarized as adverse events when applicable. · Up to 3 months after the infusion；Number of participants with clinically significant abnormalities in vital sign measurements · Vital signs will be assessed as part of the safety evaluations according to the protocol-specified time points. Clinically significant new or worsening abnormalities will be recorded and summarized as adverse events when applicable. The physical examination section specifies that vital signs, height and body weight are included in complete physical examinations. · Up to 3 months after the infusion；Number of participants with clinically significant abnormalities in physical examination findings · Complete and targeted physical examinations will be performed according to the protocol. New or worsened clinically significant abnormalities identified after baseline will be recorded as adverse events and summarized by frequency. · Up to 3 months after the infusion；Change from baseline in Eastern Cooperative Oncology Group (ECOG)performance status score · Performance status will be measured using the Eastern Cooperative Oncology Group Performance Status Scale. Scores range from 0 to 5, with higher scores indicating worse functional status. · Up to 3 months after the infusion
次要终点：Objective response rate according to RECIST v1.1 as assessed by the investigator；Duration of response according to RECIST v1.1 as assessed by the investigator；Progression-free survival according to RECIST v1.1 as assessed by the investigator；Overall Survival (OS)

• p95HER2.CAR-TECH2Me following lymphodepleting chemotherapy · EXPERIMENTAL · Participants will receive non-myeloablative lymphodepleting chemotherapy consisting of cyclophosphamide 500 mg/m²/day intravenously and fludarabine 30 mg/m²/day intravenously on Days -4 to -2, followed by a single intravenous infusion of autologous p95HER2.CAR-TECH2Me cells on Day 0. Premedication will be administered prior to p95HER2.CAR-TECH2Me infusion according to protocol requirements. The dose of p95HER2.CAR-TECH2Me will vary by dose-escalation cohort.

This is a phase I, open-label, non-randomized, multicenter, dose-escalation trial designed to evaluate the safety, tolerability, and preliminary anti-tumor activity of autologous p95HER2.CAR-TECH2Me T cells in patients with selected advanced HER2-positive (3+) cancers, including locally advanced, recurrent, or metastatic breast, gastric, endometrial, and other selected solid tumors. The study will also assess pharmacokinetics, pharmacodynamics, and immunogenicity of p95HER2.CAR-TECH2Me following intravenous administration. Treatment consists of non-myeloablative lymphodepletion chemotherapy with cyclophosphamide and fludarabine administered on Days -4 to -2, followed by a single infusion of p95HER2.CAR-TECH2Me cells on Day 0. The investigational product is a live cell suspension of autologous CAR-T lymphocytes derived from the patient's peripheral blood. Premedication will be administered before cell infusion according to protocol requirements. The primary objective of the study is to evaluate the safety and tolerability of p95HER2.CAR-TECH2Me and to identify the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Primary endpoints include the nature and frequency of adverse events, serious adverse events, clinically relevant changes in laboratory parameters, electrocardiograms, vital signs, physical examination findings, and ECOG performance status, as well as the incidence and nature of dose-limiting toxicities. Adverse events will be graded according to NCI CTCAE v5.0, with cytokine release syndrome and neurotoxicity graded according to established consensus criteria. Secondary objectives include evaluation of preliminary anti-tumor activity and survival outcomes. Secondary endpoints include objective response rate, duration of response, progression-free survival according to RECIST v1.1 as assessed by the investigator, and overall survival. Approximately 15 patients are planned for enrollment over an estimated 36 to 48 months. The total study duration is expected to be approximately 60 months from the time the first subject signs the pre-screening informed consent form until the last subject completes the final study-related follow-up contact.