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

Sponsor

Yang Yang (Other)

Overall Status

Unknown status

CT.gov ID

NCT03044743

Collaborator

(none)

Enrollment

Locations

Arm

58.8

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Fludarabine Drug: Cyclophosphamide Drug: Interleukin-2	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Trial of PD-1 Knockout EBV-CTLs for Advanced Stage EBV Associated Malignancies

Actual Study Start Date :

Apr 7, 2017

Anticipated Primary Completion Date :

Mar 1, 2020

Anticipated Study Completion Date :

Mar 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PD-1 knockout EBV-CTL 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.	Drug: Fludarabine To modify immune micro-environment Other Names: Fludara Drug: Cyclophosphamide To modify immune micro-environment Other Names: Cytoxan Drug: Interleukin-2 To sustain the survival of infused T cells Other Names: IL-2

Arm

Intervention/Treatment

Experimental: PD-1 knockout EBV-CTL

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.

Drug: Fludarabine

To modify immune micro-environment

Other Names:

Fludara

Drug: Cyclophosphamide

To modify immune micro-environment

Other Names:

Cytoxan

Drug: Interleukin-2

To sustain the survival of infused T cells

Other Names:

IL-2

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Response Rate [90 days]
Progression free survival (PFS) [up to 1 year]
Overall Survival (OS) [up to 3 years]
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Comprehensive Cancer Center of Nanjing Drum Tower Hospital	Nanjing	Jiangsu	China	210008
2	The Comprehensive Cancer Center of Nanjing Drum Tower Hospital	Nanjing	Jiangsu	China	210008

Sponsors and Collaborators

Yang Yang

Investigators

Principal Investigator: Baorui Liu, MD, The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University