Mesothelin-targeted CAR-T Cells as a Neo-adjuvant Treatment in Patients With Resectable Pancreatic Cancers: a Feasibility Study
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.
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 R0 resection (2). In the ESPAC-5 study, neoadjuvant combination chemotherapy did not increase rate of resection who had borderline-resectable disease but appears to improve overall survival (OS) (3). The Charité Onkologie (CONKO-007) trial showed that the addition of radiation to chemotherapy improved R0 resection rate and complete pathological response (pCR) but did not impact on OS (4).
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 minimally 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 in about 80% of PDAC.
Mesothelin is the receptor of tumor antigen CA-125 (also known as MUC16). Tumor expressing CA-125 can combine with mesothelin on the surface of mesothelial cells in pleural or peritoneal cavity, resulting in increased cell adhesion and promoting metastatic diffusion (5). In pancreatic cancers, mesothelin plays a role in tumorigenesis by increasing cell proliferation, migration and S phase cell population. Its limited expression in normal human tissues and high expression in many cancers make it an attractive tumor-related antigen for cancer treatment (6).
There are several immunotherapies targeting MSLN for PDAC treatment, including antibody-based drugs (monoclonal antibodies, antibody-drug conjugates, immunotoxins), vaccines, and CART cell therapy. For example, the recombinant protein preparation SS1(dsFv)PE38 (SS1P), which is composed of high affinity Fv (variable fragment) targeting MSLN and Pseudomonas exotoxin A (PE) fusion, has entered clinical trials as a drug (7). There is also an antibody-drug conjugate, Anetumab ravtansine (BAY 94-9343), which is made by conjugating human anti-MSLN antibody with maytansinol tubulin inhibitor (DM4) through a connector containing disulfide bond. In vivo, anetumab ravtansine is specifically localized in tumors that express MSLN and inhibits the growth of pancreatic cancer, ovarian cancer, mesothelioma and other tumors. 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 following 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 hypothesize that 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.
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:
( • 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 )