CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Histological confirmation of primary cancers
* Histologic confirmation of CD70 on primary tumor, lymph node, or BM biopsy
* At least one recurrent or progressive metastatic lesion or new metastatic lesion(s).
* KPS ≥ 70.
* 18 years or older.
* Adequate bone marrow and organ function as defined below:

  * CBC with differential with adequate bone marrow function as defined below:
  * Absolute neutrophil count (ANC) ≥ 10000 cells/mm3.
  * Platelet count ≥ 75,000 cells/mm3.
  * Hemoglobin ≥ 9 g/dl. (use of transfusion or other intervention to achieve Hgb ≥ 9 g/dl is acceptable.)
* Adequate renal function as defined below:

  * BUN ≤ 25 mg/dl
  * Creatinine ≤ 1.7 mg/dl
* Adequate hepatic function as defined below:

  * Bilirubin ≤ 2.0 mg/dl
  * ALT ≤ 5 times institutional upper limits of normal for age
  * AST ≤ 5 times institutional upper limits of normal for age
* A diagnostic contrast-enhanced brain MRI must be performed within 28 days prior to study enrollment.
* For females of childbearing potential, a negative serum pregnancy test at enrollment.
* Women of childbearing potential (WOCBP) must be willing to use an acceptable contraceptive method to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug.
* Males with female partners of childbearing potential must agree to practice adequate contraceptive methods throughout the study and should avoid conceiving children for 24 weeks following the last dose of the study drug.
* Ability of the patient to understand and willingness to sign an IRB approved written informed consent document.
* Steroid dose equivalent to dexamethasone dose of ≤ 6mg daily at the time of enrollment.
* Patients treated on any other investigational therapy must discontinue that treatment prior to study entry.

Exclusion Criteria:

• Known immunosuppressive disease or human immunodeficiency virus (HIV) infection.

Rationale: The need to exclude patients with an immunosuppressive disease or human immunodeficiency virus infection is necessary because the management of potential toxicities from the study drug may involve treatment that is significantly immunosuppressive.

* Participant has ongoing toxicity ≥ grade 2 per the CTCAE version 5.0 considered clinically significant and in the opinion of the investigator, attributable to prior antineoplastic therapies.
* Participant has received any chemotherapy or other immunotherapy within 14 days prior to the first dose of study intervention.
* Severe, active co-morbidity, defined as follows:

  * Unstable angina and/or congestive heart failure requiring hospitalization.
  * Transmural myocardial infarction within the last 6 months.
  * Acute bacterial or fungal infection requiring intravenous antibiotics.
  * Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization.
  * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.
  * Patients with an autoimmune disease requiring medical management with immunosuppressants.
  * Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy.
* Pregnant or lactating women, due to possible adverse effects on the developing fetus or infant.

主要终点：Number and percentage of participants with dose-limiting toxicities after receiving 8R-70CAR T-cell therapy · Safety is defined as ≤ 1 DLT out of 6 patients is observed at the 1x10\^8 cells/Kg dose. Dose-Limiting toxicity (DLT) will be defined as any adverse event attributable (possible, probable, or definite) to the administration of 8R-70CAR T cells and occurring from the time of infusion through 28 days post-infusion. Safety variables and variables that define the DLTs will be summarized using descriptive statistics by dose level. Number and percentage of patients with DLTs and its 95% confidence interval (CI) will be estimated based on the exact binomial distribution by dose level. · 28 days post-infusion；Proportion of participants who receive an infusion of 8R-70CAR T-cell therapy · Feasibility will be defined as the ability to infuse 8R-70CAR T-cell safely in 66.7 % of enrolled patients (patients who signed consent and were deemed eligible for the study). · enrollment up to 10 weeks

• IL-8 receptor-modified patient-derived activated CD70 CAR T cells · EXPERIMENTAL · Two dose levels Cohort 1 will receive 1 x 10\^7 cells/kg; Cohort 2 will receive 1 x 10\^8 cells/kg

This is a Phase I Study evaluating the safety and feasibility of IL-8 receptor-modified patient-derived activated CD70 CAR T cells in adult patients with brain metastases from primary cancer, with either newly diagnosed lesions or recurrent or progressive disease after prior therapy.