Clinical trial NCT03044743: PD-1 Knockout EBV-CTLs for Advanced Stage Epstein-Barr Virus (EBV) Associated Malignancies
Official title: A Phase I/II Trial of PD-1 Knockout EBV-CTLs for Advanced Stage EBV Associated Malignancies
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
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
Keywords: PD-1
CRISPR Cas9
EBV
advanced stage malignancies
Lead sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Sponsor class: OTHER
First posted: 2017-02-07
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of participants with Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients
timeFrame: 6 months
Secondary outcomes:
measure: Response Rate
timeFrame: 90 days
measure: Progression free survival (PFS)
timeFrame: up to 1 year
measure: Overall Survival (OS)
timeFrame: up to 3 years
measure: The duration of the normalization of tumor marker
timeFrame: up to 3 years
measure: Interferon-γ change of T cells in the peripheral blood stimulated by tumor antigens
timeFrame: Baseline and 1 month, 3 months and 6 months
measure: Th1/Th2 change in the peripheral blood
timeFrame: Baseline and 1 month, 3 months and 6 months
Other outcomes:
Locations:
city: Nanjing
country: China
facility: The Comprehensive Cancer Center of Nanjing Drum Tower Hospital
state: Jiangsu
city: Nanjing
country: China
facility: The Comprehensive Cancer Center of Nanjing Drum Tower Hospital
state: Jiangsu
Study officials:
affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
name: Baorui Liu, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kim SY, Park C, Kim HJ, Park J, Hwang J, Kim JI, Choi MG, Kim S, Kim KM, Kang MS. Deregulation of immune response genes in patients with Epstein-Barr virus-associated gastric cancer and outcomes. Gastroenterology. 2015 Jan;148(1):137-147.e9. doi: 10.1053/j.gastro.2014.09.020. Epub 2014 Sep 22.
citation: Quan L, Chen X, Liu A, Zhang Y, Guo X, Yan S, Liu Y. PD-1 Blockade Can Restore Functions of T-Cells in Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma In Vitro. PLoS One. 2015 Sep 11;10(9):e0136476. doi: 10.1371/journal.pone.0136476. eCollection 2015.
citation: Louis CU, Straathof K, Bollard CM, Ennamuri S, Gerken C, Lopez TT, Huls MH, Sheehan A, Wu MF, Liu H, Gee A, Brenner MK, Rooney CM, Heslop HE, Gottschalk S. Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma. J Immunother. 2010 Nov-Dec;33(9):983-90. doi: 10.1097/CJI.0b013e3181f3cbf4.
citation: Lloyd A, Vickery ON, Laugel B. Beyond the antigen receptor: editing the genome of T-cells for cancer adoptive cellular therapies. Front Immunol. 2013 Aug 5;4:221. doi: 10.3389/fimmu.2013.00221. eCollection 2013.
citation: Su S, Hu B, Shao J, Shen B, Du J, Du Y, Zhou J, Yu L, Zhang L, Chen F, Sha H, Cheng L, Meng F, Zou Z, Huang X, Liu B. CRISPR-Cas9 mediated efficient PD-1 disruption on human primary T cells from cancer patients. Sci Rep. 2016 Jan 28;6:20070. doi: 10.1038/srep20070.
citation: Mali P, Esvelt KM, Church GM. Cas9 as a versatile tool for engineering biology. Nat Methods. 2013 Oct;10(10):957-63. doi: 10.1038/nmeth.2649.