Treg Immunotherapy in Crohn's Disease

Inclusion Criteria:

1. Able and willing to provide written informed consent and able to comply with theprotocol requirements
2. Male or female aged between 18 and 80 (inclusive) years of age at date of consent
3. A diagnosis of Crohn's disease (CD) established ≥12 weeks prior to date of consent bystandard clinical, radiological, endoscopic and histological criteria
4. Documented moderate-to-severe CD with a Crohn's Disease Activity Index (CDAI) >= 220within 3 months of date of consent
5. Active CD (mucosal inflammation) including ulceration, as assessed by colonoscopy atscreening
6. Failure to tolerate or to respond to at least 2 prior lines of standard CD medicationintended to induce or maintain remission, as determined by the referringgastroenterologist. Examples of such medications include, but are not limited to,azathioprine, mercaptopurine, methotrexate, vedolizumab, ustekinumab or anti-tumournecrosis factor antibody therapy. This does not include steroids and 5-ASA medications
7. Stable doses of concomitant medications
8. Normal or non-clinically significant electrocardiogram (ECG), as assessed by theInvestigator at screening
9. Negative stool test for Clostridium difficile and faecal culture for standardpathogens at screening. For non-pathogenic organism, inclusion will be at thediscretion of the Principal Investigator (PI)
10. Negative serology for HIV, Hepatitis B (cAb and sAg), Hepatitis C, HTLV and Syphilisat screening
11. Subject is judged by the principal investigator to be in otherwise good health basedupon the results of all screening investigations in combination with medical historyand physical examination

Exclusion Criteria:

1. A diagnosis of ulcerative colitis or IBD-unclassified
2. CD treatment-naïve patients, defined as patients who have never received or haverefused standard CD treatment
3. History of clinically significant drug or alcohol abuse in the last 12 months prior todate of consent
4. Any history of major immune deficiency disorder, except Crohn's disease
5. Patients with a history of pulmonary embolism or deep vein thrombosis. Current orrecent history (within 1 year prior to screening) of major organ or system failure orcondition, acute or chronic that in the opinion of the investigator should precludeenrollment, except Crohn's disease
6. History of intestinal resection or intra-abdominal surgery within 6 months prior todate of consent
7. Requirement for immediate or imminent surgical, endoscopic or radiologicalintervention for indications including (but not limited to) toxic megacolon,obstruction, massive haemorrhage, perforation, sepsis, or intra-abdominal or perianalabscess
8. Patients with ileostomy or colostomy
9. Patients with short bowel syndrome (less than 1.5m of small bowel)
10. Complication of Crohn's disease such as strictures/stenosis, penetrating disease, orany other manifestation that might require surgery.
11. Patient has received therapeutic enema or suppository, other than required forendoscopy, within 14 days prior to date of consent and/or during the screening period
12. Patients who are currently using anticoagulants including but not limited to warfarin,heparin, enoxaparin, dabigatran, apixaban, rivaroxaban (note that anti-platelet agentssuch as aspirin up to 325mg daily or clopidogrel are permitted)
13. Use of corticosteroids on the day of leukapheresis sampling, prior to the procedure.Dosing should be delayed until after the procedure has been completed. This must bechecked prior to the appointment and rescheduled if use is confirmed.
14. Current medically significant infection i.e. infection(s) requiring treatment withintravenous (IV) anti-infectives within 30 days prior to date of consent or oralanti-infectives for non-Crohn's disease related infections within 14 days prior toscreening visit
15. Subject with an active systemic viral infection or any active viral infection thatbased on the investigator's clinical assessment makes the patient unsuitable for thestudy
16. History of tuberculosis (TB), unless there is documented evidence of completion of afull course of anti-TB treatment prior to screening. For patients with latent TB, asdefined by a physician specialised in TB, they must have received prophylactictreatment for 4 weeks minimum prior to dosing
17. History of moderate to severe congestive heart failure (NYHA class III or IV), recentcerebrovascular accident (within 6 months of screening) and any other condition which,in the opinion of the investigator, would put the subject at risk by participation inthe study
18. Subject with a previous history (within 12 months of consent) of dysplasia of thegastrointestinal tract, or found to have dysplasia in any biopsy performed during thescreening endoscopy unless this is deemed to be a sporadic adenoma and has beencompletely removed
19. Significant laboratory abnormalities: Hb < 100g/L or WBC < 3.5 x 109/L or Plt < 100 x 109/L Creatinine > 1.5x ULN Totalbilirubin > 34 µmol/L or ALT > 2x ULN or GGT > 2xULN. Elevated unconjugated bilirubinrelated to Gilbert's syndrome is allowed
20. Anti-TNF or ustekinumab therapy within 8 weeks of study dosing (day 0). Vedolizumabtherapy within 5 half-lives (15 weeks) of dosing. Exposure to cyclosporine ortacrolimus within 2 weeks of date of consent
21. Patient currently receiving total parenteral nutrition (TPN) or plan to receive TPN atany time during the course of the study
22. Received another investigational drug within 60 days of anticipated study date ofconsent or 5 half lives whichever is greater
23. Patient who previously received stem cell transplantation
24. Current evidence of dysplasia or history of malignancy within the last 5 years of dateof consent (except successfully treated squamous cell or basal cell carcinoma, withoutmetastases or localised carcinoma in situ of the cervix)
25. Pregnant and lactating patients (females of childbearing potential with a positiveserum pregnancy test at screening visit 1 or day -1 at week 0)
26. Female patients of childbearing potential (i.e. not post-menopausal or surgicallysterilised) who are not willing to use effective methods of contraception (includedbut not limited to hormonal contraception, Intrauterine devices, sexual abstinence,vasectomised partner) to prevent pregnancy or abstain from heterosexual activity forthe duration of the trial up to W21 visit
27. Male patients who are not willing to use an effective method of contraception (condoms) for the duration of the study up to W21 visit, when engaging in sexualactivity with a female of childbearing potential
28. Allergy to any component / excipients used for the manufacture of TR004
29. Patient is considered by the investigator, for any reason, to be an unsuitablecandidate for the study