Clinical trials

On 28 October 2016, clinical trials involving CRISPR based gene editing commenced in China, using CRISPR modified PD-1¹ disabled T-cells to treat patients with aggressive lung cancer.

In 2017, the University of Pennsylvania hopes to begin its ambitious CRISPR-related clinical trial (the first and currently only such trial to receive approval in the US) which aims to use CRISPR to perform three different genetic modifications on T-cells. The trial (in patients with myeloma, sarcoma or melanoma) aims not only to use CRISPR to disrupt PD-1 receptor expression, but also to knock out portions of the T-cell’s primary receptor. The reason for the latter is to maximise the effect of a further (non-CRISPR based) modification the researchers will make to the T-cells – introducing an engineered NS ESO-1 receptor to the T-cell. By knocking down/out the primary receptor, preventing PD-1 mediated T-cell deactivation and introducing this engineered new receptor, it is hoped that the T-cells will selectively hone in on NS-ESO-1 antigen displaying cancer cells.

The following clinical trials involving CRISPR are also currently taking place or are proposed to take place (information provided by clinicaltrials.gov):

1. A Safety and Efficacy Study of TALEN and CRISPR-Cas in the Treatment of HPV-related Cervical Intraepithelial Neoplasia (NCT03057912)

This study is not yet open for participant recruitment

• Sponsor: First Affiliated Hospital, Sun Yat-Sen University
• Collaborator: Jingchu University of Technology
• Purpose: This is an open-label and triple cohort study of the safety and efficacy of TALEN and CRISPR-Cas to possibly treat HPV Persistency and human cervical intraepithelial neoplasia without invasion. The primary objective of this study is to evaluate the safety of therapeutic doses and the dosing regimen of TALEN and CRISPR-Cas plasmid.
• Experimental: TALEN (TALEN-HPV16 E6/E7 or TALEN-HPV18 E6/E7) plasmid in gel, administered twice a week for four weeks. CRISPR-Cas (CRISPR-Cas-HPV16 E6/E7T1 or CRISPR-Cas-HPV18 E6/E7T2) plasmid in gel, administered twice a week for four weeks.
• Estimated Enrolment: 60
• Anticipated Study Start Date: 15 July 2017
• Estimated Study Completion Date: 15 July 2018
• Estimated Primary Completion Date: 15 April 2018
  
  

2. Safety of Transplantation of CRISPR CCR5 Modified CD34+ Cells in HIV-infected Subjects with Hematological Malignances (NCT03164135)

This study is currently recruiting participants

• Sponsor: Affiliated Hospital to Academy of Military Medical Sciences
• Collaborators: Peking University, Capital Medical University
• Purpose: The investigators performed this study to evaluate the safety and feasibility of transplantation with CRISPR-Cas CCR5 gene-modified CD34+ hematopoietic stem/progenitor cells for patients that develop AIDS and haematological malignancies. Patients will be treated with antiviral therapy (ART) to achieve undetectable HIV-1 virus in peripheral blood before conditioning. CD34+ cells from donors will be infused into the patients after treatment with CRISPR-Cas to ablate CCR5 gene.
• Experimental: Participants will be transplanted with CD34+ cells which are treated using the CRISPR-Cas system to disrupt CCR5 gene. The persistence of CCR5 gene disruption in engrafted cells will be evaluated by sequencing.
• Estimated Enrolment: 5
• Anticipated Study Start Date: 30 May 2017
• Estimated Study Completion Date: 20 May 2021
• Estimated Primary Completion Date: 20 May 2019
  
  

3. Examining the Knowledge, Attitudes, and Beliefs of Sickle Cell Disease Patients, Parents of Patients with Sickle Cell Disease, and Providers Towards the Integration of CRISPR in Clinical Care (NCT03167450)

This study is not yet open for participant recruitment

• Sponsor: National Human Genome Research Institute (NHGRI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC), National Human Genome Research Institute (NHGRI)
• Purpose: To study the attitudes, beliefs and opinions of those with SCD, parents of those with SCD, and providers on the use of CRISPR-Cas gene-editing. An additional purpose of this study is to assess the utility of an educational tool for improving understanding of CRISPR-Cas.
• Estimated Enrolment: 90
• Anticipated Study Start Date: 1 June 2017
• Estimated Study Completion Date: 30 June 2018
• Estimated Primary Completion Date: 30 June 2018 

4. Identification of Host Factors of Norovirus Infections in Mini-Gut Model

This study is not yet open for participant recruitment

• Sponsor: Chinese University of Hong Kong
• Information provided by (responsible party): CHAN CHI WAI, Chinese University of Hong Kong.
• Purpose: The primary objective in this study is to establish a list of host cellular proteins that mediate norovirus infection.
• Norovirus is one of the most common pathogens attributed to diarrheal diseases from unsafe food. It is also the primary cause of mortality among young children and adults in foodborne infections. Norovirus is not just a foodborne burden. In a recent meta-analysis, norovirus accounts for nearly one-fifth of all causes of (including person-to-person transmission) acute gastroenteritis in both sporadic and outbreak settings and affects all age groups. Undoubtedly, norovirus is of paramount public health concern in both developed and developing countries. Research efforts to better understand norovirus pathobiology will be necessary for targeted intervention.
• From Middle East respiratory syndrome coronavirus to Zika virus, efforts to identify host factors important for mediating virus infection has always been a research priority. Such information will shed light on potential therapeutic targets in antiviral intervention. Norovirus virus-host interaction studies have been hampered by the lack of a robust cell culture model in the past 20 years. In 2016, norovirus has finally been successfully cultivated in a stem cell-derived three-dimensional human gut-like structure called enteroid or mini-gut.
• Experimental: In this study, intestinal stem cells will be isolated from duodenal biopsies collected from participants, followed by differentiation into mini-guts. Genome-wide genetic screening for host essential and restrictive factors will be performed on infected mini-guts by knockout CRISPR and gain-of-functionCRISPR SAM, respectively. Shortlisted candidates will undergo preliminary functional validation in cell lines. These data will provide insights into potential therapeutic targets against norovirus infection.

5. A Study Evaluating UCART019 in Patients with Relapsed or Refractory CD19+ Leukemia and Lymphoma (NCT03166878)

This study is currently recruiting for participants

• Sponsor: Chinese PLA General Hospital
• Information provided by (Responsible Party): Weidong Han, Chinese PLA General Hospital
• Purpose: The main goal of the phase 1 portion of this phase 1/2 trial is to evaluate the safety and tolerability of several doses of UCART019 in patients with relapsed or refractory CD19+ leukemia and lymphoma, so as to establish the recommended dose and/or schedule of UCART019 for the phase 2 portion. The recommended Phase 2 dose will be defined as the highest dose level of UCART019 that induced DLT in fewer than 33% of patients (i.e. one dose level below that which induced DLT in at least two of six patients). The phase 2 portion of the trial will not be initiated until the recommended Phase 2 dose is determined. In the phase 2 portion of this trial, we will mainly determine if UCART019 help the body’s immune system eliminate malignant B-cells. Safety of UCART019 and the impact of this treatment on survival will also be observed.
• Experimental: Gene-disrupted allogeneic CD19-directed BBζ CAR-T cells (termed UCART019) have been generated by combining the lentiviral delivery of CAR and CRISPR RNA electroporation to disrupt endogenous TCR and B2M genes simultaneously. This study will test whether it can evade host-mediated immunity and deliver anti-leukemic effects without graft versus host disease (GvHD).
• Estimated Enrolment: 80
• Anticipated Study Start Date: June 2017
• Estimated Study Completion Date: May 2022
• Estimated Primary Completion Date: May 2022
  
  

6. PD-1 Knockout Engineered T Cells for Advanced Esophageal Cancer (NCT03081715)

This study is currently recruiting participants

• Sponsor: Hangzhou Cancer Hospital
• Collaborator: Anhui Kedgene Biotechnology Co.,Ltd
• Purpose: This study will evaluate the safety of PD-1 knockout engineered T cells in treating advanced esophageal cancer. Blood samples will also be collected for research purposes.
• Experimental: Peripheral blood lymphocytes will be collected and programmed cell death protein 1 (PD-1) gene will be knocked out by CRISPR-Cas in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients.
• Estimated Enrolment: 21
• Anticipated Study Start Date: 20 March 2017
• Estimated Study Completion Date: 30 December 2018
• Estimated Primary Completion Date: 27 February 2018 

7. Stem Cells in NF1 Patients with Tumors of the Central Nervous System

This study is currently recruiting participants

• Sponsor: Children’s Research Institute
• Information provided by (Responsible Party): Roger Packer, Children’s Research Institute
• Purpose: This study seeks to develop stem cells lines in children with NF1-related tumors in the central nervous system (the optic nerve and those from other brain sites). Stem cells from these subjects will provide a critical insight into the mechanisms responsible for tumor progression and symptoms associated with the central nervous system, accelerating the identification of therapeutic targets.
• Experimental
• 3.1 Study Design Cross-sectional collection of NF1 subjects with tumors in the central nervous system as documented by MRI.
• 3.2 Study Visits Subjects will have only one visit to collect the blood sample.
• 3.3 Study Procedures
• 3.31 Blood Draw – Subjects have 20 ml of whole blood drawn during either (1) their sedation for their clinically indicated MRI (IV already being placed for clinical purpose) or (2) through the outpatient laboratory.
• 3.32 Stem Cell Processing – Blood collected will be immediately transferred to the stem cell facility at the National Institutes of Health for processing of the specimens in order to develop stem cell lines.
• 3.33 Demographics – We will collect the subject’s age, gender, race, ethnicity, location of tumours in the central nervous system on MRI, history of vision loss and other neurological deficits.
• 3.34 Statistical Analysis – As a first step to establish a stem cell library from a specific population of NF1 children with nervous system tumours, we will not need statistical analysis at this stage.
• Estimated Enrolment: 20 participants
• Study start date: 27 November 2015
• Estimated Study Completion Date: 1 June 2019
• Estimated Primary Completion Date: 1 June 2019

8. PD-1 Knockout Engineered T Cells for Muscle-invasive Bladder Cancer (NCT02863913)

This study is not yet open for participant recruitment

• Sponsor: Peking University
• Collaborator: Cell Biotech Co., Ltd.
• Purpose: This study will evaluate the safety of PD-1 knockout engineered T cells in treating metastatic advanced bladder cancer. Blood samples will also be collected for research purposes.
• Experimental: Peripheral blood lymphocytes will be collected and the programmed cell death protein 1 (PDCD1) gene will be knocked out by CRISPR-Cas in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients.
• Estimated Enrolment: 20
• Study Start Date: September 2016
• Estimated Study Completion Date: September 2019
• Estimated Primary Completion Date: September 2019

9. PD-1 Knockout Engineered T Cells for Castration‑resistant Prostate Cancer (NCT02867345)

This study is not yet open for participant recruitment

• Sponsor: Peking University
• Collaborator: Cell Biotech Co., Ltd.
• Purpose: This study will evaluate the safety of PD-1 knockout engineered T cells in treating castration‑resistant prostate cancer (CRPC). Blood samples will also be collected for research purposes.
• Experimental: Peripheral blood lymphocytes will be collected and the programmed cell death protein 1 (PDCD1) gene will be knocked out by CRISPR-Cas in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients.
• Estimated Enrolment: 20
• Study Start Date: November 2016
• Estimated Study Completion Date: December 2020
• Estimated Primary Completion Date: November 2020

10. PD-1 Knockout Engineered T Cells for Metastatic Renal Cell Carcinoma (NCT02867332)

This study is not yet open for participant recruitment

• Sponsor: Peking University
• Collaborator: Cell Biotech Co., Ltd.
• Purpose: This study will evaluate the safety of PD-1 knockout engineered T cells in treating metastatic advanced renal cancer. Blood samples will also be collected for research purposes.
• Experimental: Peripheral blood lymphocytes will be collected and programmed cell death protein 1 (PDCD1) gene will be knocked out by CRISPR-Cas in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients.
• Estimated Enrolment: 20
• Study Start Date: November 2016
• Estimated Study Completion Date: November 2020
• Estimated Primary Completion Date: November 2020

11. PD-1 Knockout Engineered T Cells for Metastatic Non-small Cell Lung Cancer (NCT02793856)

This study is currently recruiting participants

• Sponsor: Sichuan University
• Collaborator: Chengdu MedGenCell, Co., Ltd.
• Purpose: This study will evaluate the safety of PD-1 knockout engineered T cells in treating metastatic non‑small cell lung cancer. Blood samples will also be collected for research purposes.
• Experimental: Peripheral blood lymphocytes will be collected and the programmed cell death protein 1 (PDCD1) gene will be knocked out by CRISPR-Cas in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients.
• Estimated Enrolment: 15
• Study Start Date: August 2016
• Estimated Study Completion Date: April 2018
• Estimated Primary Completion Date: April 2018

12. PD-1 Knockout EBV-CTLs for Advanced Stage Epstein-Barr Virus (EBV) Associated Malignancies (NCT03044743)

This study is currently recruiting participants

• Sponsor: Yang Yang
• Information provided by (Responsible Party): Yang Yang, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
• Purpose: 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.
• Experimental: Peripheral blood lymphocytes will be collected and the programmed cell death protein 1 (PDCD1) gene will be knocked out by CRISPR-Cas system and EBV-CTL will be generated in the laboratory (PD-1 Knockout EBV-CTL).
• Estimated Enrolment: 20
• Actual Study Start Date: 7 April 2017
• Estimated Study Completion Date: March 2022
• Estimated Primary Completion Date: March 2020

^{1 PD-1 is a “checkpoint” molecule which is present on the surface of many cancer cells and, when bound to PD-1 receptors on the surface of T-cells, disables the T-cell function.  Monoclonal antibodies such as Merck’s Keytruda, which target the PD-1 receptor, have proven effective against various cancers.}