CELL INTELLIGENCE · 肿瘤细胞治疗研究

ELIGIBILITY CRITERIA 1.1 Inclusion Criteria

* Participant must have the ability to understand and the willingness to sign a written informed consent.
* Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable exceptions may be granted with Study PI approval.
* Age \> 18 years.
* ECOG Performance status 0 - 2 or KPS ≥70%.
* Documented platinum resistant EOC (defined as disease that has progressed within six months of completing platinum therapy, or lack of response or disease progression while receiving the most recent platinum-based therapy, respectively). Progression may be determined radiographically (not RECIST) or by new onset of malignant pleural effusion. Participant may have at least 1 measurable lesion or disease measured by PCI at the time of surgery.
* Documented TAG72+ (\> 1% cells ≥ +1 intensity) tumor expression by IHC (MAb CC49) as evaluated by COH Pathology Core.
* In addition to platinum agents, participant must have received and failed, or have been intolerant to taxanes, liposomal doxorubicin or other agents known to confer clinical benefit. Participants are not required to fail all of these chemotherapy agents if, in the investigator's opinion, they would benefit from treatment on the current protocol.
* No known contraindications to leukapheresis, steroids or tocilizumab.
* Participant of reproductive potential must agree to use acceptable birth control methods throughout study therapy and for 3 months after final dose of study treatment.
* \_ANC ≥ 1,000/mm3
* Total serum bilirubin ≤ 1.5 x ULN Patients with Gilbert syndrome may be included if their total bilirubin is \< 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN.
* AST \< 3 x ULN if liver metastasis: AST \< 5 x ULN)
* ALT \< 3 x ULN if liver metastasis: ALT \< 5 x ULN)
* Participants not receiving therapeutic anticoagulation: INR or aPTT ≤1.5 x ULN
* Creatinine clearance of ≥ 50 mL/min per the Cockcroft-Gault formula
* Cardiac function (12 lead-ECG) without acute abnormalities requiring investigation or intervention
* Left ventricular ejection fraction \>40%
* QuantiFERON-TB Gold or equivalent\*

1.2 Exclusion Criteria

* Participant has not yet recovered from toxicities of prior therapy.
* Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition or other agents used in this study.
* History of (non-infectious or COVID-related) pneumonitis that required steroids or current pneumonitis
* Current signs and/or symptoms of bowel obstruction
* History of inflammatory bowel disease
* History of gastrointestinal perforation or symptomatic diverticular disease
* History of intra-abdominal abscess within the past 3 months.
* Patients with known peritoneal adhesions that preclude the placement of an intraperitoneal catheter in the opinion of the surgeon placing the intraperitoneal catheter.
* Participant with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of signing the 'Screening/Leukapheresis/Treatment' consent.
* Participant with known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, including seizure disorder.
* Known bleeding disorders (e.g., von Willebrand's disease or hemophilia).
* History of stroke or intracranial hemorrhage within 6 months prior to signing the 'Screening/Leukapheresis/Treatment' consent.
* History of other malignancies, except for malignancy surgically resected (or treated with other modalities) with curative intent with no known active disease present for ≥ 3 years, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin.
* Uncontrolled active infection.
* Active hepatitis B or hepatitis C infection.
* HIV infection.
* Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures.

  o Massive ascites requiring therapeutic paracentesis will not be cause for ineligibility, per se, but will be evaluated on an individual basis. Investigators who have questions regarding assessing ascites are asked to speak with the Principal Investigator.
* Subject has received or plans to receive the following therapy/treatment prior to leukapheresis or lymphodepleting chemotherapy, unless stopped according to the washout requirements:
* Prospective participants who, in the opinion of the Investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).

主要终点：Incidence of dose limiting toxicities (DLTs) · Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated. · Up to 28 days；Incidence of adverse events · Adverse Events are graded using NCI CTCAE v.5. · Up to 1 year post treatment
次要终点：Persistence of CAR T cells；Expansion of CAR T cells；Response (iRECIST)；Overall survival (OS)；Progression-free survival (PFS)；Serum cytokine profile

• Treatment (TAG72-CAR T cells) · EXPERIMENTAL · Patients receive fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients receive TAG72-CAR T cells IP on day 0.

This phase I trial tests the safety, side effects, and best dose of TAG72-chimeric antigen receptor (CAR) T cells in treating patients with epithelial ovarian cancer that remains despite treatment with platinum therapy (platinum resistant). T cells are infection fighting blood cells that can kill tumor cells. The T cells given in this study will come from the patient and will have a new gene put in them that makes them able to recognize TAG72, a protein on the surface of tumor cells. These TAG72-specific T cells may help the body's immune system identify and kill TAG72+ cancer cells.