Mesothelin-targeted CAR-T Cells as a Neo-adjuvant Treatment in Patients With Resectable Pancreatic Cancers: a Feasibility Study

Pancreatic ductal adenocarcinoma (PDAC) is a cancer of grave prognosis, with only about 10% of patients alive at 5 years after diagnosis. Primary surgical resection is feasible in about 10-15% of patients with an early-stage disease. Another 30-35% of patients have locally advanced disease with invasion into major vasculature but without detectable metastases. Surgery offers a chance of cure. The introduction of adjuvant multi-agent chemotherapy has improved prognosis after surgery. In the management of patients with PDAC, the role of neoadjuvant therapy is less certain. Neoadjuvant therapy for pancreatic cancer can in theory control early systemic spread and improve rate of having no macroscopic or microscopic residual tumor (R0 resection). In the The European Study Group for Pancreatic Cancer (ESPAC-5) study, neoadjuvant combination chemotherapy did not increase rate of resection who had borderline-resectable disease but appears to improve overall survival (OS). Chimeric antigen receptor (CAR) T-cell therapy may represent a new paradigm in the treatment of pancreatic cancer. Mesothelin (MSLN) is a 40 kDa membrane protein not expressed in normal cells, but highly expressed in a variety of cancer cells, such as mesothelioma, lung, breast, ovarian, gastric and pancreatic cancer. MSLN is expressed about 80% of PDAC. There are several immunotherapies targeting MSLN for PDAC treatment, including antibody-based drugs (monoclonal antibodies, antibody-drug conjugates, immunotoxins), vaccines, and CAR-T cell therapy. The safety of CAR-T cells targeting MSLN in the treatment of cancers has also been verified in several clinical trials on lung cancers (NCT01583686, NCT02414269, NCT01355965). Professor Li Peng's group at the Chinese Academy of Science designed third generation CAR-T cells targeting MSLN and validated their use in both human PDAC cell lines, animal models, and in 4 patients with advanced malignancies. In a 42-year-old man with metastatic PDAC, the MSLN targeted CAR-T treatment led to complete response follow several hepatic artery infusion and intravenous infusion. These early cases confirmed the safety of these MSLN targeted CAR-T cells. In the current proposed feasibility study, the researcher hypothesise that Endoscopic ultrasound (EUS)-guided injection of MSLN targeted CAR-T cells into PDAC can induce a tumor response, improve rate of R0 resection and translate into better patient survival.

Sex

All

Minimum age

18 Years

Maximum age

100 Years

Inclusion Criteria:

* Patients with histologically confirmed pancreatic cancer planned for curative resection.
* Age 18 to 70 years old
* Measurable tumors according to RECIST 1.1s
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
* A sufficient number of T cells taken through lymphopheresis (CD3+ T cells\>1x109).
* Patients with preserved organ function as evidenced by
* Haematological: Hemoglobin ≥ 8g/dL; Platelet ≥ 75×109/L; INR≤1.5; Absolute neutrophil count (ANC) ≥ 1.5

  ×109 /L; Absolute lymphocyte count ≥ 0.4×109 /L
* Renal: Creatinine \< 1.5 upper limit normal (ULN) mg/dL or Creatinine clearance ≥40 ml/min
* Bilirubin \<1.5 ULN μmol/L; Alanine Aminotransferase (ALT) \<3 IU/L; Albumin ≥30 g/L
* Willing and able to provide written, signed informed consent
* Sexually active subjects must be willing to use an acceptable method of contraception such as double barrier contraception during treatment and for 12 months after the last dose
* Females of childbearing potential must have a negative serum pregnancy test at screening and willing to have additional pregnancy tests during the study.
* Females considered non-childbearing potential include those who have been in menopause for at least 1 year or had tubal ligation at least 1 year prior to screening, or who have had total hysterectomy

Exclusion Criteria:

* Patients with AIDS
* Patients with serum HBsAg positive
* The patient has an active or uncontrolled infection.
* Subjects with severe heart, brain, liver, kidney or hematopoietic diseases, or psychosis who are not suitable for surgical resection
* In the first evaluation experiment, expansion ability of T cells activated by Cluster of Differentiation (CD) CD3/CD28 magnetic beads is less than 5 times.
* Pregnant or lactating women
* Those who participate in other clinical trials.
* History of chronic pancreatitis or Immunoglobulin G4 (IgG4) disease
* Patients who require splenectomy during surgery for pancreatic cancer. History of second malignancy except for any of the following:

( • Carcinoma in situ of the cervix or non-melanoma skin cancer ) ( • A cancer diagnosed and curatively treated ≥5 years prior to leukapheresis with no subsequent evidence of cancer recurrence )

* History of or waiting for organ transplantation, including liver transplantation
* Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation

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