PD-1 Knockout EBV-CTLs for Advanced Stage Epstein-Barr Virus (EBV) Associated Malignancies

Phase 1

• Conditions: Stage IV Gastric Carcinoma; Stage IV Nasopharyngeal Carcinoma; T-Cell Lymphoma Stage IV; Stage IV Adult Hodgkin Lymphoma; Stage IV Diffuse Large B-Cell Lymphoma
• Interventions: Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Interleukin-2

• Registration Number: NCT03044743
• Lead Sponsor: Yang Yang

Brief Summary

This study will evaluate the safety of PD-1 knockout EBV-CTL cells in treating EBV (Epstein-Barr virus) positive advanced stage malignancies. Blood samples will also be collected for research purposes.

Detailed Description

This is a study of CRISPR-Cas9 mediated PD-1 knockout-T cells from autologous origin. Patients are assigned to receive 4 circles of cell therapy. The safety and clinical response are evaluated. Biomarkers and immunological markers are also monitored.

Study Timeline

• Study First Submitted: 2017-01-22
• Study First Submitted QC: 2017-02-06
• Study First Posted: 2017-02-07
• Status Verified: 2017-04
• Study Start: 2017-04-07
• Last Update Submitted: 2017-04-28
• Last Update Posted: 2017-05-02
• Primary Completion: 2020-03
• Study Completion: 2022-03

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Pathologically verified stage IV gastric carcinoma, nasopharyngeal carcinoma and lymphoma with measurable lesions (At least one measurable lesion or the immunotherapy)
• Pathologically verified as EBV positive malignancies
• Human leukocyte antigen (HLA) genotypes: HLA-A02, HLA-A24 or HLA-A11 genotypes
• Progressed after standard treatment or the patients refused to accept the standard treatment
• Performance score: 0-1
• Expected life span: >= 3 months
• Toxicities from prior treatment has resolved. Washout period is 1 months
• Major organs function normally
• Women at pregnant ages should be under contraception
• Willing and able to provide informed consent

Exclusion Criteria

• Patients with possible drug allergy of immunotherapy
• Patients with active bacterial or fungal infections
• Coagulopathy, or ongoing thrombolytics and/or anticoagulation
• Blood-borne infectious disease, e.g. hepatitis B, hepatitis C and HIV
• History of coronary artery disease, asthma, or vascular disease or other disease inappropriate for treatment deemed by treating physician
• With other tumors except for in situ cervical cancer, treated squamous cell carcinoma and bladder cancer (Ta and TIS) or other malignancies that have been treated with radical therapy (at least for 5 years before the enrollment)
• With other immune diseases, or chronic use of immunosuppressants or steroids
• Pregnant and lactating women
• Compliance cannot be expected
• Other conditions requiring exclusion deemed by physician

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PD-1 knockout EBV-CTL	Interleukin-2	Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will be knocked out by CRISP-Cas9 system and EBV-CTL will be generated in the laboratory (PD-1 Knockout EBV-CTL). Fludarabine at 30mg/m2 and Cyclophosphamide at 300mg/m2 single dose will be administered 3 days i.v. before cell infusion. A total of 2 x 10\^7/kg PD-1 Knockout CTL will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Interleukin-2 (IL-2) will be given daily( iv) since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit（IU）/day . Patients will receive a total of four cycles of treatment.
PD-1 knockout EBV-CTL	Fludarabine	Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will be knocked out by CRISP-Cas9 system and EBV-CTL will be generated in the laboratory (PD-1 Knockout EBV-CTL). Fludarabine at 30mg/m2 and Cyclophosphamide at 300mg/m2 single dose will be administered 3 days i.v. before cell infusion. A total of 2 x 10\^7/kg PD-1 Knockout CTL will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Interleukin-2 (IL-2) will be given daily( iv) since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit（IU）/day . Patients will receive a total of four cycles of treatment.
PD-1 knockout EBV-CTL	Cyclophosphamide	Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will be knocked out by CRISP-Cas9 system and EBV-CTL will be generated in the laboratory (PD-1 Knockout EBV-CTL). Fludarabine at 30mg/m2 and Cyclophosphamide at 300mg/m2 single dose will be administered 3 days i.v. before cell infusion. A total of 2 x 10\^7/kg PD-1 Knockout CTL will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Interleukin-2 (IL-2) will be given daily( iv) since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit（IU）/day . Patients will receive a total of four cycles of treatment.

Primary Outcome Measures

Name	Time	Method
Number of participants with Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients	6 months

Secondary Outcome Measures

Name	Time	Method
Progression free survival (PFS)	up to 1 year
Overall Survival (OS)	up to 3 years
Response Rate	90 days
The duration of the normalization of tumor marker	up to 3 years
Interferon-γ change of T cells in the peripheral blood stimulated by tumor antigens	Baseline and 1 month, 3 months and 6 months
Th1/Th2 change in the peripheral blood	Baseline and 1 month, 3 months and 6 months

Trial Locations

Locations (1)

The Comprehensive Cancer Center of Nanjing Drum Tower Hospital; 🇨🇳 Nanjing, Jiangsu, China