A Phase I/II Trial of PD-1 Knockout EBV-CTLs for Advanced Stage EBV Associated Malignancies
Overview
- Phase
- Phase 1
- Sponsor
- Yang Yang
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- Number of participants with Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients
Overview
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 Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
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.
Intervention: Fludarabine (Drug)
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.
Intervention: Cyclophosphamide (Drug)
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.
Intervention: Interleukin-2 (Drug)
Outcomes
Primary Outcomes
Number of participants with Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients
Time Frame: 6 months
Secondary Outcomes
- 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)
Investigators
Yang Yang
MD, PhD, MSCR
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School