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

Phase I/II Multicenter Trial of Antigen-specific Cytotoxic T Cells in the Treatment of Opportunistic Infections

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.

Study Overview

• Status: Unknown
• Conditions: Tuberculosis; CMV Infection; EBV Infection; Adenovirus Infection; Fungus Infection; Pathogen Infection; BKV Infection
• Intervention / Treatment: Biological: pathogen-specific CTLs

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
• Enrollment (Anticipated): 100
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China, 518000
      • Recruiting
      • Shenzhen Geno-Immune Medical Institute
      • Contact: Lung-Ji Chang, PhD; Phone Number: 86-755-86725195; Email: c@szgimi.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 80 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Infusion of pathogen-specific CTLs; Repetitive CTL infusions to treat microbial infections	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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Shenzhen Geno-Immune Medical Institute

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 15, 2017
• Primary Completion (ANTICIPATED): July 31, 2020
• Study Completion (ANTICIPATED): December 31, 2021

Study Registration Dates

• First Submitted: May 16, 2017
• First Submitted That Met QC Criteria: May 16, 2017
• First Posted (ACTUAL): May 18, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 19, 2019
• Last Update Submitted That Met QC Criteria: September 18, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: CTL; Virus CTL; Fungus CTL; TB CTL
• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Disease Attributes; DNA Virus Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Parasitic Diseases; Tumor Virus Infections; Mycobacterium Infections; Herpesviridae Infections; Infections; Communicable Diseases; Mycoses; Tuberculosis; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Adenoviridae Infections; Opportunistic Infections
• Other Study ID Numbers: GIMI-IRB-17009

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No