Neoantigen Derived DCs as Cancer Treatment

Personalized Neoantigen Derived Dendritic Cell-Based Immunotherapy as Cancer Treatment

Tumor lysate or carcinoembryonic antigen (CEA) derived DCs-based therapy is safe and can elicites remarkable T-cell responses but mostly did not really transfer into significant clinical benefit. One possible reason is the lack of effective antigen and the immunosuppressive microenvironment. Now we are exploring another new strategy, prediction of neoantigen for priming DCs as cell-based therapy with or without booster of anti-VEGF/anti-PD-1.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor; Refractory Tumor
• Intervention / Treatment: Biological: Dendritic Cell Vaccine; Drug: Lenvatinib; Drug: Nivolumab

Detailed Description

The human immune system can recognize and destroy cancer cells but cancer cells are capable of escaping from immune system by different ways, including the PD-1/PDL-1 axis and the VEGF signaling pathway. The PD-1/PD-L1 axis represents an adaptive immune resistance mechanism exerted by tumor cells. Previous study also revealed VEGF-A could induce tumor-associated macrophages, Treg cells, and myeloid-derived suppressor cells, creating an immunosuppressive microenvironment that prevent the maturation of dendritic cells (DCs) and inhibit the activation of NK cells and T cells. Our research group already completed some early phase clinical trials of DCs-based therapy, which illustrated tumor lysate or carcinoembryonic antigen (CEA) derived DCs-based therapy is feasible and safe in patients with advanced colorectal cancer and lung cancer, respectively. However, although DCs-based therapy elicited remarkable T-cell responses but mostly did not really transfer into significant clinical benefit in previous study. One possible reason is the lack of effective antigen and the immunosuppressive microenvironment. Now we are exploring another new strategy, prediction of neoantigen for priming DCs as cell-based therapy with or without booster of anti-VEGF/anti-PD-1.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kuan-Chung Hsiao, PhD; Phone Number: 65108 +886-6-7000123; Email: randolph.hsiao@gmail.com
• Study Contact Backup: Name: Yung-Yeh Su, MD; Phone Number: 65181 +886-6-7000123; Email: yysu@nhri.edu.tw

Study Locations

• Taiwan
  • Kaohsiung, Taiwan
    • Not yet recruiting
    • Kaohsiung Medical University Hospital
    • Contact: Li-Tzong Chen, MD, PhD; Email: leochen@nhri.edu.tw
  • Tainan, Taiwan
    • Recruiting
    • National Cheng-Kung University Hospital
    • Contact: Yung-Yeh Su, MD; Phone Number: 65181 +886-6-7000123; Email: yysu@nhri.edu.tw
  • Tainan, Taiwan
    • Recruiting
    • National Institute of Cancer Research
    • Contact: Yung-Yeh Su, MD; Phone Number: 65181 +8867-7000123; Email: yysu@nhri.edu.tw
    • Principal Investigator: Li-Tzong Chen, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ≥20 years of age
• Provide written informed consent
• Histologically confirmed stage IV pancreatic cancer, liver cancer, biliary tract cancer and colorectal cancer (excluding sarcoma and neuroendocrine tumor) that refractory or intolerance to standard therapies for their condition (there is no effective treatment by investigator judgement)
• Completed tumor and germline DNA and RNA sequencing and the neoantigen prediction
• Patients with chronic hepatitis B is eligible if receiving anti-hepatitis B agents and the HBV DNA level < 2000 IU/ml prior to the preparation phase. Patients with chronic hepatitis C are eligible if HCV RNA is undetectable (<15 IU/ml) prior to the preparation phase

• Adequate organ function

  • Absolute neutrophil count >1000/mcL
  • Hemoglobin > 8.0 g/dl
  • Platelet > 50000/mcL
  • PT/aPTT < 1.5 x upper limit of normal (ULN)
  • AST/ALT < 3 x ULN
  • Bil(T) < 1.5 x ULN
  • BUN/Cr < 1.5 x ULN

• Adequate immune system as defined by

  • IgG > 614 mg/dl
  • IgM > 53mg/dl
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• Life expectancy at least>12weeks
• At least one measurable target lesion as defined by RECIST 1.1

Exclusion Criteria:

• Sarcoma、neuroendocrine tumor
• Last anticancer therapy administered within 2 weeks and any AEs should be ≤ grade 2 prior to leukapheresis
• Patients who cannot tolerate leukapheresis and follow-up blood sampling of 50ml at day 43, day 85 and end-of- treatment.
• Any known active infection as judged by the investigator
• Any known chronic active infection of HIV, HTLV-1 or HTLV-2
• Requirement of systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to the screen phase. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Other immunocompromising condition that in the opinion of the treating physician renders the patient a poor candidate for this trial
• Pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device (IUD), abstinence, etc.)
• Patients with history of penicillin allergy
• Other medical problems or conditions that, in the opinion of the investigator, would make participation in the study hazardous for the patient

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: DCs monotherapy; DCs injection on day 1, 8, 15, 29, 85, 141, 197, 253 and 309.	Biological: Dendritic Cell Vaccine; Approximately 1.5 x 10^6±20% cells will be subcutaneously injected to the patient's inguinal area (either left side or right side can be injected, only one area will be injected each time) on day 1, 8, 15, 29, 85, 141, 197, 253 and 309.; Other Names: DCs
Experimental: Arm 2: DCs with booster of anti-VEGF/anti-PD-1.; DCs injection on day 1, 8, 15, 29, 85, 141, 197, 253 and 309 plus lenvatinib 10mg QD on day 43-77 and nivolumab 3mg/kg on day 43, 57 and 71.	Biological: Dendritic Cell Vaccine; Approximately 1.5 x 10^6±20% cells will be subcutaneously injected to the patient's inguinal area (either left side or right side can be injected, only one area will be injected each time) on day 1, 8, 15, 29, 85, 141, 197, 253 and 309.; Other Names: DCs; Drug: Lenvatinib; Lenvatinib 10mg/day on day 43-77; Other Names: Lenvima; Drug: Nivolumab; Nivolumab 3mg/kg on day 43, 57 and 71.; Other Names: OPDIVO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects experienced limiting toxicities in the first 6 weeks.	The following toxicities that happened during first 6 weeks are considered LTs. Toxicities are graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0: >=Grade 3 non-hematological toxicity; >=Grade 4 hematological toxicity; Any death not clearly due to the underlying disease or extraneous causes.; Any case meeting Hy's law; Recurrent grade 2 pneumonitis	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients who had a clinical response	Response was assessed by the iRECIST.	1 year
Number of participants who did not progressed or survived at 1 year	1 year progression-free survival and overall survival rate	1 year
Number of subjects experienced any ≥ grade 3 toxicities.	any ≥ grade 3 toxicities rate	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects experienced immune response	The production of IFN-γ that occurs subsequent to the dendritic cells-based therapy as determined by ELISPOT Assay or Flow Cytometry Analysis. Other immune response biomarker study including but not limited to whole exome sequencing, bulk RNA sequencing and single cell RNA sequencing.	1 year

Collaborators and Investigators

• Sponsor: National Health Research Institutes, Taiwan
• Collaborators: National Cheng-Kung University Hospital
• Investigators: Principal Investigator: Li-Tzong Chen, MD, PhD, Kaohsiung Medical University Hospital, and Center for Cancer Research, Kaohsiung Medical University

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2023
• Primary Completion (Estimated): March 30, 2025
• Study Completion (Estimated): March 30, 2026

Study Registration Dates

• First Submitted: March 2, 2023
• First Submitted That Met QC Criteria: March 2, 2023
• First Posted (Actual): March 14, 2023

Study Record Updates

• Last Update Posted (Actual): August 25, 2023
• Last Update Submitted That Met QC Criteria: August 23, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: immunotherapy; cancer vaccine; neoantigen
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Nivolumab; Lenvatinib
• Other Study ID Numbers: A-BR-108-087

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No