Mechanism of Resistance to GNC-038 in Relapsed and Refractory Diffuse Large B-cell Lymphoma

Mechanism of Resistance to GNC-038, a Tetra-specific T Cell Engager, in Relapsed and Refractory Diffuse Large B-cell Lymphoma

This is an exploratory study embedded in the Phase Ib/II clinical trial of CD3 x 4-1BB x CD19 x PD-L1 tetra-specific T cell engager GNC-038 in relapsed and refractory diffuse large B-cell lymphoma initiated by the corresponding pharmaceutical company. By measuring immune cell components and their functional phenotypes in peripheral blood and tumor tissues before and after the subject's medication, this study aims to identify key immune cell populations and immune molecules which play an important role in resistance to GNC-038 treatment, so as to optimize drug design and develop combination therapies to improve treatment efficacy.

Study Overview

• Status: Recruiting
• Conditions: Diffuse Large B Cell Lymphoma

• Study Type: Observational
• Enrollment (Anticipated): 15

Contacts and Locations

• Study Contact: Name: Weili Zhao, M.D. and Ph.D; Phone Number: 13512112076; Email: zhao.weili@yahoo.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200025
      • Recruiting
      • Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
      • Contact: Weili Zhao, M.D. and Ph.D; Phone Number: 13512112076; Email: zhao.weili@yahoo.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

This study plans to include 10 subjects enrolled in the GNC-038 Phase Ib/II clinical trial in Ruijin Hospital. It also plans to include five patients who have tonsillectomy in Ruijin Hosptial due to obstructive sleep apnea and hyponea syndrome as the control group.

Description

Inclusion Criteria:

For Group 1, the selection criteria are firstly concordant with those of the corresponding clinical trial. On this basis, additional selection criteria for this study are:

• Lymph node lesions with long diameter ≥ 2cm.
• Subjects have the ability and willingness to follow the visit, biosample collection and other research-related processes prescribed by the research program and to sign informed consent forms.

For Group 2, the selection criteria are:

• The subject is able to understand the informed consent form, and voluntarily participates and signs the informed consent form;
• Age between 18 and 80;
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 points.

Exclusion Criteria:

For Group 1, the exclusion criteria are totally concordant with those of the corresponding clinical trial. There is no additional exclusion criteria for this study.

For Group 2, the exclusion criteria are:

• History of past or present malignant diseases;
• Patients with active autoimmune diseases, or patients with a history of autoimmune diseases, including but not limited to Crohn's disease, ulcerative colitis, systemic lupus erythematosus, sarcoidosis, Wegener's granulomatosis, polyvascular inflammation granuloma, Grave's disease, rheumatoid arthritis, pituitary inflammation, ophthalmic pigmentitis, autoimmune hepatitis, systemic sclerosis, Hashimoto thyroiditis, autoimmune vasculitis, autoimmune neuropathy (Guillain- Barre syndrome), etc.;
• Human immunodeficiency virus antibody positive, active tuberculosis, active hepatitis B virus infection (HBsAg-positive or HBcAb-positive, HBV-DNA test positive), hepatitis C virus infection (HCV antibody-positive and HCV-RNA test positive), EB virus infection (EBV-DNA test positive), cytomegalovirus infection (CMV-DNA test positive) or herpes simplex virus infection (HSV-DNA test positive);
• Pregnant or nursing women;
• Previous organ transplants or allogeneic hematopoietic stem cell transplants;
• Under treatment of immunosuppressants, including but not limited to cyclosporine, tacrolimus, corticosteroids, etc., within 1 month prior to sampling;
• Fever (temperature >37.5 ℃) within 1 month prior to sampling, or using antibiotics due to respiratory, gastrointestinal, urinary tract infections, etc.;
• Other situations in which the researchers consider it inappropriate for the patient to participate in this study.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Subjects of the GNC-038 clinical trial (1); Patients enrolled in the GNC-038 Phase Ib/II clinical trial in Shanghai Ruijin Hospital.
Non-malignant controls (2); Patients who have tonsillectomy due to obstructive sleep apnea and hyponea syndrome.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The abundance and phenotypes of immune cell subtypes within tumor or normal tonsil tissues measured by single-cell RNA sequencing.	Core needle biopsies of lymph node lesions (in Group 1) or resected normal tonsil tissues (in Group 2) will be collected. 5' end single-cell RNA sequencing plus single-cell T cell receptor sequencing will be performed. The abundance and phenotypes of immune cell subtypes will be investigated using the above data.	In Group 1: change from screening to six weeks after treatment initiation, and to disease relapse or progression assessed up to 6 months after last treatment. In Group 2: immediately following tonsil resection.
The abundance and phenotypes of peripheral blood T cell subtypes measured by mass cytometry by the time-of-flight.	Peripheral blood mononuclear cells will be collected and mass cytometry by the time-of-flight will be performed to analyze a panel of T cell subtyping and functional surface molecules.	In Group 1: change from screening to day 22 and day 43 after treatment initiation, to 30 days after treatment ending, and to disease relapse or progression assessed up to 6 months after last treatment. In Group 2: within a week before tonsil resection.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor cytogenetic and molecular genetic abnormalities.	In Group 1, core needle biopsies of lymph node lesions will be collected, and whole exome sequencing will be performed to detect tumor cytogenetic and molecular genetic abnormalities. Peripheral blood mononuclear cells will also be collected and sequenced as healthy tissue reference.	During screening, six weeks after treatment initiation, and at disease relapse or progression assessed up to 6 months after last treatment.
Tumor gene expression profiles.	In Group 1, core needle biopsies of lymph node lesions will be collected, and bulk RNA sequencing will be performed to analyze gene expression profiles of tumors.	In Group 1: during screening, six weeks after treatment initiation, and at disease relapse or progression assessed up to 6 months after last treatment. In Group 2: immediately following tonsil resection.

Collaborators and Investigators

• Sponsor: Ruijin Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2022
• Primary Completion (Anticipated): September 1, 2023
• Study Completion (Anticipated): September 1, 2024

Study Registration Dates

• First Submitted: September 3, 2021
• First Submitted That Met QC Criteria: December 27, 2021
• First Posted (Actual): January 13, 2022

Study Record Updates

• Last Update Posted (Actual): August 31, 2022
• Last Update Submitted That Met QC Criteria: August 26, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
• Other Study ID Numbers: TRANS001-TeTE

Drug and device information, study documents

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