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

NCT06054308 | Withdrawn

• 1 other identifier: The Chinese University of Hong
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pancreatic Cancer

Outcome Measures

Primary Outcomes (1)

• pathologic response

  Proportion of major pathologic response on resected specimen of pancreatic tumour

  3 months

Secondary Outcomes (4)

• Radiological response

  4 weeks

• Rate of R0 surgical resection

  3 months

• Serious Adverse Event

  1 year

• Disease free and overall survival

  10 year

Study Arms (1)

MSLN CART

EXPERIMENTAL

Endoscopic ultrasound guided injection of mesothelin-targeted CAR-T cells

Other: MSLN CART

Interventions

MSLN CART OTHER

Endoscopic ultrasound guided injection of mesothelin-targeted CAR-T cells

MSLN CART

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Chinese University of Hong Kong: lead

Study Sites (1)

Endoscopy Centre, Prince of Wales Hospital

Shatin, N.T., Hong Kong

Location

Related Publications (8)

• Park W, Chawla A, O'Reilly EM. Pancreatic Cancer: A Review. JAMA. 2021 Sep 7;326(9):851-862. doi: 10.1001/jama.2021.13027.

  PMID: 34547082 BACKGROUND

• Springfeld C, Ferrone CR, Katz MHG, Philip PA, Hong TS, Hackert T, Buchler MW, Neoptolemos J. Neoadjuvant therapy for pancreatic cancer. Nat Rev Clin Oncol. 2023 May;20(5):318-337. doi: 10.1038/s41571-023-00746-1. Epub 2023 Mar 17.

  PMID: 36932224 BACKGROUND

• Ghaneh P, Palmer D, Cicconi S, Jackson R, Halloran CM, Rawcliffe C, Sripadam R, Mukherjee S, Soonawalla Z, Wadsley J, Al-Mukhtar A, Dickson E, Graham J, Jiao L, Wasan HS, Tait IS, Prachalias A, Ross P, Valle JW, O'Reilly DA, Al-Sarireh B, Gwynne S, Ahmed I, Connolly K, Yim KL, Cunningham D, Armstrong T, Archer C, Roberts K, Ma YT, Springfeld C, Tjaden C, Hackert T, Buchler MW, Neoptolemos JP; European Study Group for Pancreatic Cancer. Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2023 Feb;8(2):157-168. doi: 10.1016/S2468-1253(22)00348-X. Epub 2022 Dec 12.

  PMID: 36521500 BACKGROUND

• Fietkau R, Ghadimi M, Grützmann R, Wittel UA, Jacobasch L, Uhl W, Croner RS, Bechstein WO, Neumann UP, Waldschmidt D, Boeck SH, Moosmann N, Reinacher-Schick AC, Golcher H, Adler W, Semrau S, Kallies A, Hecht M, Tannapfel A, Oettle H. Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: First results of the CONKO-007 trial. J Clin Oncol. 2022;40: issue 16 suppl.4008

  BACKGROUND

• Chen SH, Hung WC, Wang P, Paul C, Konstantopoulos K. Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation. Sci Rep. 2013;3:1870. doi: 10.1038/srep01870.

  PMID: 23694968 BACKGROUND

• Kachala SS, Bograd AJ, Villena-Vargas J, Suzuki K, Servais EL, Kadota K, Chou J, Sima CS, Vertes E, Rusch VW, Travis WD, Sadelain M, Adusumilli PS. Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma. Clin Cancer Res. 2014 Feb 15;20(4):1020-8. doi: 10.1158/1078-0432.CCR-13-1862. Epub 2013 Dec 13.

  PMID: 24334761 BACKGROUND

• Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, Pastan I. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res. 2007 Sep 1;13(17):5144-9. doi: 10.1158/1078-0432.CCR-07-0869.

  PMID: 17785569 BACKGROUND

• Wang H, Chetty R, Hosseini M, Allende DS, Esposito I, Matsuda Y, Deshpande V, Shi J, Dhall D, Jang KT, Kim GE, Luchini C, Graham RP, Reid MD, Basturk O, Hruban RH, Krasinskas A, Klimstra DS, Adsay V; Pancreatobiliary Pathology Society. Pathologic Examination of Pancreatic Specimens Resected for Treated Pancreatic Ductal Adenocarcinoma: Recommendations From the Pancreatobiliary Pathology Society. Am J Surg Pathol. 2022 Jun 1;46(6):754-764. doi: 10.1097/PAS.0000000000001853. Epub 2021 Dec 15.

  PMID: 34889852 BACKGROUND

MeSH Terms

Conditions

Pancreatic Neoplasms

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Study Officials

• James Lau, MD

  Prince of Wales Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 19, 2023
• First Posted: September 26, 2023
• Study Start: February 2, 2024
• Primary Completion: February 2, 2026
• Study Completion: August 2, 2026
• Last Updated: August 21, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

HK (1)