The Clinical Implications of Immune Checkpoint Pathways in PCNSL

The Clinical Implications and Functional Roles of Immune Checkpoint Pathways in Primary Central Nervous System Lymphomas

Central nervous system lymphoma (CNSL) is a rare brain tumor constituting 3% of all newly diagnosed brain tumors, and 2% to 3% of all cases of non-Hodgkin lymphoma. There are two subtypes of CNSL. Owing to its low incidence, there is limited prospective and/or randomized data to guide the therapy of CNSL. Current knowledge about optimal diagnostic, prognostic and therapeutic strategies of CNSL is urged.

The immune system plays a fundamental role in controlling and eradicating cancer but is held in check by inhibitory receptors and ligands. These immune checkpoint pathways, which normally maintain self-tolerance and limit collateral tissue damage during anti-microbial immune responses, can be co-opted by cancer to evade immune destruction. A plethora of regulatory molecules have been identified. Among them, three have been studied most intensively: cytotoxic T lymphocyte antigen 4 (CTLA4) binding to CD80 or CD86, programmed cell death protein 1 (PD-1) binding to PD-1 ligand 1 (PD-L1) or PD-L2, and SIRPαbinding to CD47. Agents inhibiting CTLA-4, PD1, PD-L1 and CD47 are showing compelling antitumor activity in several solid and hematological cancers. Exploring the role of immune checkpoint pathways in CNSL may help us to establish the rational targeted therapies.

In this study, the investigators will investigate the protein expression of several specific molecules in immune checkpoint pathways such as PD-L1, PD-L2 and CD47 in the large neurological resection specimens by immunohistochemical staining of patients with CNSL. Besides, the concentrations of above molecules and other prognostic relevant factors such as chemokine CXCL13, Interleukin-10 and soluble CD19 in the cerebrospinal fluid (CSF) at initial diagnosis and after treatment will be evaluated using enzyme-linked immunosorbent assays. About 100 patients with CNSL will be recruited. The protein expression of the above molecules will be correlated with the clinical outcome of patients with CNSL. The feasibility of adopting these CSF molecules as useful diagnostic or prognostic biomarkers in CNSL will also be investigated.

Study Overview

• Status: Completed
• Conditions: Lymphoma, B-Cell
• Intervention / Treatment: Other: non-intervention

Detailed Description

Goal The goal and purpose of this study is to investigate the clinical implications and functional roles of immune checkpoint pathways in CNSL.

There are two specific aims:

1. The adoption of protein expression of immune checkpoint pathways (CTLA-4, PD-L1, PD-L2, CD47) as a prognostic factor in patients with PCNSL. To fulfill this aim, the protein expression of CTLA-4, PD-L1, PD-L2, and CD47 in the neurosurgical resection specimens of patients with PCNSL will be evaluated by immunohistochemistry (IHC) techniques. The results will be correlated with clinical features and outcome of the patients with CNSL. Once parameters for these tissues are established it will be possible to speculate about the tumor grade, survival and response to treatment of these patients.
2. The feasibility of adopting CSF CTLA-4, PD-L1, PD-L2, and sCD47 as useful diagnostic and prognostic biomarkers in patients with CNSL. To fulfill this aim, the concentrations of CSF CTLA-4, PD-L1, PD-L2 and sCD47 will be evaluated at the timings of initial diagnosis and after each cycle of systemic chemotherapy by enzyme-linked immunosorbent assays (ELISAs). The concentrations of these CSF molecules at initial diagnosis will be correlated with the prognosis of patients with CNSL. Besides, the investigators will compare the serial follow-up concentrations of these markers after each cycle of systemic chemotherapy to find out whether the presence of decreased concentrations will response to therapy.

This may help to discovery new diagnostic, prognostic and potential therapeutic strategies for patients with CNSL.

• Study Type: Observational
• Enrollment (Actual): 46

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Patients with newly diagnosed PCNSL at National Taiwan University Hospital from January 1996 to December 2020

Description

Inclusion Criteria:

• 1. Patients with newly diagnosed PCNSL at National Taiwan University Hospital from January 1996 to December 2020
• 2. Patients aged 20 years and older

Exclusion Criteria:

• 1. Subjects who are involved in any interventional treatment that might change experimental biomarkers, such as PD-L1 inhibitor, PD-1 inhibitor, anti CTLA-4 agents…etc before tumor and CSF sampling.
• 2. Pregnancy or breast-feeding

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS was measured from the date of the first diagnosis to the end of the follow-up period, death from any cause, or the date of the last known follow-up examination.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS was measured from the date of the first diagnosis until the end of the follow-up period, the date of relapse or progressive disease, death from any cause, or the last known follow-up examination, whichever came first.	5 years
Treatment response	Tumor responses were assessed through brain MRI or CT in all patients after two or three cycles of chemotherapy as well as at treatment completion.	1 year

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Principal Investigator: Chieh-Lung Cheng, Dr, NTUH

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2016
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: February 15, 2019
• First Submitted That Met QC Criteria: November 6, 2019
• First Posted (Actual): November 8, 2019

Study Record Updates

• Last Update Posted (Actual): January 18, 2023
• Last Update Submitted That Met QC Criteria: January 16, 2023
• Last Verified: December 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
• Other Study ID Numbers: 201608069RINB

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