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

August 19, 2024 updated by: James Yun-wong Lau, MD, Chinese University of Hong Kong

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Hong Kong
    • N.t.
      • Shatin, N.t., Hong Kong
        • Endoscopy Centre, Prince of Wales Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: MSLN CART
Endoscopic ultrasound guided injection of mesothelin-targeted CAR-T cells
Other: MSLN CART
Endoscopic ultrasound guided injection of mesothelin-targeted CAR-T cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
pathologic response
Time Frame: 3 months
Proportion of major pathologic response on resected specimen of pancreatic tumour
3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of R0 surgical resection
Time Frame: 3 months
Rate of R0 surgical resection after EUS-guided injection of MSLN-targeted CAR-T cells
3 months
Disease free and overall survival
Time Frame: 10 year
Disease free and overall survival
10 year
Radiological response
Time Frame: 4 weeks
Radiological response according to RECIST 1.1 measured on CT 4 weeks after EUS guided MSLN CAR-T injection (i.e. tumor volumetric reduction at trial entry and 4 weeks after MSLN CAR-T injection).
4 weeks
Serious Adverse Event
Time Frame: 1 year
Incidence rate of serious adverse events of grade III and above.
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Chinese University of Hong Kong

Investigators

  • Principal Investigator: James Lau, MD, Prince of Wales Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

February 2, 2024

Primary Completion (Estimated)

February 2, 2026

Study Completion (Estimated)

August 2, 2026

Study Registration Dates

First Submitted

September 19, 2023

First Submitted That Met QC Criteria

September 19, 2023

First Posted (Actual)

September 26, 2023

Study Record Updates

Last Update Posted (Actual)

August 21, 2024

Last Update Submitted That Met QC Criteria

August 19, 2024

Last Verified

August 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • The Chinese University of Hong

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Study Data/Documents

  1. Informed Consent Form

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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