Antigen-specific Cytotoxic T Cells in the Treatment of Opportunistic Infections

• ClinicalTrials.gov Identifier: NCT03159364
• Recruitment Status: Unknown
• First Posted: May 18, 2017
• Last Update Posted: September 19, 2019
• Sponsor: Shenzhen Geno-Immune Medical Institute
• Information provided by (Responsible Party): Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute

Tracking Information

• First Submitted Date: May 16, 2017
• First Posted Date: May 18, 2017
• Last Update Posted Date: September 19, 2019
• Actual Study Start Date: July 15, 2017
• Estimated Primary Completion Date: July 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 6, 2018)

• Using CTCAE 4 standard to evaluate the level of adverse events after receiving autologous or allogenic pathogen-specific CTL infusion [ Time Frame: 24 weeks ]
  to evaluate the level of adverse events with CTCAE 4
• Viral load change after Virus-CTL infusion [ Time Frame: 2 months ]
  The viral load response to the Virus-CTL infusion will be assessed by specific PCR of peripheral blood after infusion.

Original Primary Outcome Measures (submitted: May 16, 2017)

• Using CTCAE 4 standard to evaluate the level of adverse events after receiving autologous or allogenic virus-CTL infusion [ Time Frame: 24 weeks ]
  to evaluate the level of adverse events with CTCAE 4
• viral load change after CTL infusion [ Time Frame: 3 months ]
  The viral load response to the CTL infusion will be assessed by CMV/EBV specific PCR of peripheral blood everyday after infusion.

Current Secondary Outcome Measures (submitted: July 6, 2018)

• The incidence of CTL infusion syndrome mimicking grade Ⅱ~Ⅳ GVHD within 30 days after the last dose of CTL infusion [ Time Frame: 1 months ]
• Reconstitution of anti-microbial immunity monitored by flow cytometry [ Time Frame: 6 months ]
• Number of patients with chronic GVHD-like symptom [ Time Frame: 6 months ]

Original Secondary Outcome Measures (submitted: May 16, 2017)

• The incidence of Ⅱ~Ⅳ°aGVHD within 30 days after the last dose of CTL infusion [ Time Frame: 1 months ]
• Reconstitution of antiviral immunity monitored by flow cytometry [ Time Frame: 6 months ]
• Number of patients with chronic GVHD [ Time Frame: 6 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Antigen-specific Cytotoxic T Cells in the Treatment of Opportunistic Infections
• Official Title: Phase I/II Multicenter Trial of Antigen-specific Cytotoxic T Cells in the Treatment of Opportunistic Infections
• Brief Summary: Epstein Barr Virus (EBV) or Cytomegalovirus (CMV) infection results in significant morbidity and mortality in hematopoietic stem cell transplantation (HSCT) patients. HSCT patients often face opportunistic infections due to the immunosuppressive state during transplantation. Antimicrobial drugs are usually used for prophylactic purposes and for treatment after early detectable infections. Unfortunately, some patients develop resistance to such drug treatment. In addition to HSCT patient, immune compromised patient may also be victim to opportunistic infections. Many infections can be effectively managed by functional immune recovery. In this study, the safety and efficacy of microbial-specific cytotoxic T lymphocytes (CTLs) will be investigated.

Detailed Description

Background:

Opportunistic infections are major causes of transplant-related morbidity and mortality in immunosuppressed patients, especially in the early post-transplant period. CMV, EBV, adenovirus (AdV), BK virus (BKV) and other viruses or non-viral pathogens may lead to life-threatening infections after transplantation.

Adoptive immunotherapy with cytotoxic T lymphocytes (CTLs) reactive with specific microbial antigens has proven to be effective without stimulating acute graft-versus-host disease (GVHD) owing to the significantly reduced nonspecific alloreactivity. This study aims to evaluate the safety and efficacy of treating opportunistic infections with microbial-specific CTLs in immune compromised patients.

Objective:

Primary study objectives: Infusion of autologous or allogenic pathogen-specific CTL to patients by I.V., to evaluate the safety.

Secondary study objectives: To evaluate the anti-microbial efficacy of IV-infused autologous or allogenic pathogen-specific CTLs.

Design:

Peripheral blood mononuclear cells (PBMC) will be obtained through apheresis. T cells from PBMC will be activated and enriched by dendritic cells with pathogen specific antigens. Cell preparation time is approximately 12-17 days. Subject will receive infusions of 1x105~1x106 cells/kg body weight of CTLs via IV infusion. Patients are followed weekly for one month after the infusion, monthly for 3 months, and then every 3 months until the trial ends.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Pathogen Infection
• EBV Infection
• CMV Infection
• Adenovirus Infection
• BKV Infection
• Fungus Infection
• Tuberculosis

Intervention

Biological: pathogen-specific CTLs

Patients will receive approximately 1x10^5~1x10^6 CTLs/kg as a single infusion via IV injection and may receive additional infusions.

Study Arms

Experimental: Infusion of pathogen-specific CTLs

Repetitive CTL infusions to treat microbial infections

Intervention: Biological: pathogen-specific CTLs

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: May 16, 2017): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2021
• Estimated Primary Completion Date: July 31, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Subjects with or without hematopoietic stem cell transplantation / organ transplant recipients need to meet the following conditions:

• Evidence of CMV, EBV, ADV, BKV or known pathogen infection (viral DNA, immunohistochemical cytology positive); contraindications or invalid to anti-microbial drugs.
• Subjects with virus DNA increased in the 2 consecutive peripheral blood samples (≥ 1000 genomic copies/ml blood) at least 24 hours apart.
• Initial hematopoietic reconstitution: neutrophils (ANC) ≥ 0.5x109 / L, platelet (PLT) ≥ 20x109 / L.
• Patients with pahogen disease (organ/ tissue infiltration) symptoms, fever, diarrhea, or lymphadenopathy, regardless of the level of peripheral blood virus DNA, and confirmed by the presence of viral DNA or microbial antigens within body fluid or biopsy.
• The subject / guardian has signed a written consent form before any trial begins.

Proper renal and hepatic functions (ULN denotes "upper limit of normal range"):

• Creatinine ≤ 2*ULN.
• Bilirubin ≤ 2*ULN.
• SGOT ≤ 3*ULN.
• SGPT≤ 3*ULN.

If CTL is not from the patient's own, then the provider of CTLs needs to meet the following criteria:

• Did not receive chemotherapy or radiotherapy within 4 weeks prior to blood collection, and did not take any steroids for the previous week, did not use Penicillin or β-lactam antibiotics, or the lowest dose of other antibiotics.
• White blood cells ≥ 3,500 / μl, lymphocytes ≥ 750 / μl.
• Obtain a signed informed consent from the patient and / or the guardian or the donor of the BMT recipient.
• Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or tuberculosis (TB) test is negative.
• Physical examination in line with the standard of healthy blood donors.

Exclusion Criteria:

• Subject infected with HCV (HCV antibody positive), HBV (HBsAg positive), HIV (HIV antibody positive), or HTLV (HTLV antibody positive).
• GVHD (graft-versus-host disease) performance score at II-IV.
• Subject is albumin-intolerant.
• Subject with life expectancy less than 4 weeks.
• Subject participated in other investigational somatic cell therapies within past 30 days.
• Subject with positive pregnancy test result.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 80 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT03159364
• Other Study ID Numbers: GIMI-IRB-17009
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Shenzhen Geno-Immune Medical Institute
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Lung-Ji Chang, PhD; Shenzhen Geno-Immune Medical Institute

• PRS Account: Shenzhen Geno-Immune Medical Institute
• Verification Date: September 2019