CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Signed informed consent form
2. Documentation of tumor FRa expression by IHC at the Hospital of the University of Pennsylvania (≥ 10% of tumor cells). Subjects must have archived tumor tissue available.
3. Disease-specific criteria:

   a. NSCLC Patients: i. Metastatic or recurrent lung adenocarcinoma with cytologically or pathologically confirmed malignant pleural effusion.

   ii. Failure of at least one prior line of standard of care therapy for advanced stage disease.
4. Patients must have evidence of active disease as defined by RECIST 1.1 criteria
5. Patients with asymptomatic CNS metastases that have been treated (and are off steroids for the treatment of CNS disease) are allowed. They must meet the following criteria

   1. No concurrent treatment for the CNS disease
   2. No progression of CNS metastasis on MRI at screening
   3. No evidence of leptomeningeal disease or cord compression
6. Adequate organ function defined as:

   1. Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 30 cc/min; Patient must not be on dialysis
   2. ALT/AST ≤ 3x upper limit of normal range
   3. Serum total bilirubin ≤ 1.5 mg/dl, unless the subject has Gilbert's syndrome (if so, serum total bilirubin must be ≤ 3.0 mg/dl)
   4. Must have a minimum level of pulmonary reserve defined as \< Grade 1 dyspnea and pulse oxygen \> 92% on room air
   5. Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO or MUGA
7. Male or female age ≥ 18 years
8. Eastern Cooperative Oncology Group (ECOG) Performance Status that is either 0 or 1
9. Subjects must be a possible clinical candidate for standard of care treatment with a commercial checkpoint inhibitor, as per physician-investigator assessment.

Exclusion Criteria:

1. Any clinically significant pleural effusion that cannot be drained with standard approaches.
2. Patients with significant lung disease as follows:

   1. Patients with radiographic evidence of greater than lobar lymphangitic pulmonary involvement, greater than lobar bronchial wall thickening suggestive of peribronchial lymphatic disease extension, and/or evidence of extensive bilateral parenchymal metastatic burden.Note: "Greater than lobar" = "in more than 1 lobe".
   2. Patients with radiographic and/or clinical evidence of active radiation pneumonitis.
   3. Patients with radiographic evidence of underlying interstitial lung disease, including evidence of unresolved drug toxicity from any agent (e.g. chemotherapy, targeted agents, amiodarone, nitrofurantoin, etc.).
   4. Patients with radiographic evidence of significant pleural effusion that is not readily amenable to minimally invasive drainage.
3. Active hepatitis B or hepatitis C infection
4. Any other active, uncontrolled infection
5. Class III/IV cardiovascular disability according to the New York Heart Association Classification
6. Active invasive cancer, other than the proposed cancer included in this protocol, within 2 years prior to eligibility confirmation by a physician-investigator. \[Note: non-invasive cancers treated with curative intent (e.g., non-melanoma skin cancer) may still be eligible\].
7. Dependence on systemic steroids or immunosuppressant medications.
8. Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods
9. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone daily. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
10. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)

主要终点：Incidence of adverse events as assessed by CTCAE V5.0 · Type, frequency, severity, and attribution of adverse events. · Up to 15 years post-MOv19-BBz CAR T cell administration；Occurrence of treatment-limiting toxicities (TLTs) · Unacceptable toxicity as defined by the protocol. · 28 days post-MOv19-BBz CAR T cell administration
次要终点：Evaluate study feasibility；Objective Response Rate (ORR)；Duration of Response (DOR)；Progression Free Survival (PFS)；Overall Survival (OS)

• Dose Level 1 (DL1) · EXPERIMENTAL · single dose of 5x10(7) MOv19-BBz CAR T cells administered via intrapleural infusion following lymphodepleting chemotherapy
• Dose Level -1 (DL-1) · EXPERIMENTAL · 2.5x10(7) MOv19-BBz CAR T cells adminstered via intrapleural infusion, following lymphodepleting chemotherapy. This dose level will only be explored if ≥ 2 TLTs occur at any time in DL1.

This is a Phase I open-label clinical trial to assess the safety, feasibility, and preliminary efficacy of intrapleural administration of MOv19-BBz CAR T cells in patients with FRa+ cancers. This study will be initiated in patients with metastatic or recurrent non-small cell lung cancer (NSCLC) only. Subjects will receive a single dose of MOv19-BBz CAR T cells via intrapleural infusion following lymphodepleting chemotherapy. Subjects without an existing intra-pleural catheter will have a temporary pleural catheter placed for the study. Subjects may initiate treatment with commercial checkpoint inhibitors per routine care beginning at least 28 days after receiving MOv19-BBz CAR T cells.