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

Stage IV Adult Hodgkin Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03044743
• Other study ID #: PD-1-KO-EBV-CTL
• Status: Recruiting
• Phase: Phase 1/Phase 2
• First received: January 22, 2017
• Last updated: April 28, 2017
• Start date: April 7, 2017
• Est. completion date: March 2022

Study information

• Verified date: April 2017
• Source: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
• Contact: Baorui Liu, MD
• Phone: 0086-25-83106666-61331
• Email: baoruiliu07[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: March 2022
• Est. primary completion date: March 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Hodgkin Disease
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, T-Cell
• Nasopharyngeal Neoplasms
• Stage IV Adult Hodgkin Lymphoma
• Stage IV Diffuse Large B-Cell Lymphoma
• Stage IV Gastric Carcinoma
• Stage IV Nasopharyngeal Carcinoma
• Stomach Neoplasms
• T-Cell Lymphoma Stage IV

Intervention

Drug:
• Fludarabine
To modify immune micro-environment
• Cyclophosphamide
To modify immune micro-environment
• Interleukin-2
To sustain the survival of infused T cells

Locations

Country	Name	City	State
China	The Comprehensive Cancer Center of Nanjing Drum Tower Hospital	Nanjing	Jiangsu
China	The Comprehensive Cancer Center of Nanjing Drum Tower Hospital	Nanjing	Jiangsu

Sponsors (1)

Lead Sponsor	Collaborator
Yang Yang

Country where clinical trial is conducted

China, 

References & Publications (6)

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. — View 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. — View 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. — View 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. Review. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients		6 months
Secondary	Response Rate		90 days
Secondary	Progression free survival (PFS)		up to 1 year
Secondary	Overall Survival (OS)		up to 3 years
Secondary	The duration of the normalization of tumor marker		up to 3 years
Secondary	Interferon-? change of T cells in the peripheral blood stimulated by tumor antigens		Baseline and 1 month, 3 months and 6 months
Secondary	Th1/Th2 change in the peripheral blood		Baseline and 1 month, 3 months and 6 months