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

Primary Purpose

Pathogen Infection, EBV Infection, CMV Infection

Status

Unknown status

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

pathogen-specific CTLs

About this trial

This is an interventional treatment trial for Pathogen Infection focused on measuring CTL, Virus CTL, Fungus CTL, TB CTL

Eligibility Criteria

6 Months - 80 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Shenzhen Geno-immune Medical InstituteRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Infusion of pathogen-specific CTLs

Arm Description

Repetitive CTL infusions to treat microbial infections

Outcomes

Primary Outcome Measures

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

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.

Secondary Outcome Measures

The incidence of CTL infusion syndrome mimicking grade Ⅱ~Ⅳ GVHD within 30 days after the last dose of CTL infusion

Reconstitution of anti-microbial immunity monitored by flow cytometry

Number of patients with chronic GVHD-like symptom

Full Information

NCT ID

NCT03159364

First Posted

May 16, 2017

Last Updated

September 18, 2019

Sponsor

Shenzhen Geno-Immune Medical Institute

1. Study Identification

Unique Protocol Identification Number

NCT03159364

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2019

Overall Recruitment Status

Unknown status

Study Start Date

July 15, 2017 (Actual)

Primary Completion Date

July 31, 2020 (Anticipated)

Study Completion Date

December 31, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Shenzhen Geno-Immune Medical Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

CTL, Virus CTL, Fungus CTL, TB CTL

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Infusion of pathogen-specific CTLs

Arm Type

Experimental

Arm Description

Repetitive CTL infusions to treat microbial infections

Intervention Type

Biological

Intervention Name(s)

pathogen-specific CTLs

Intervention Description

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

Primary Outcome Measure Information:

Title

Using CTCAE 4 standard to evaluate the level of adverse events after receiving autologous or allogenic pathogen-specific CTL infusion

Description

to evaluate the level of adverse events with CTCAE 4

Time Frame

24 weeks

Title

Viral load change after Virus-CTL infusion

Description

The viral load response to the Virus-CTL infusion will be assessed by specific PCR of peripheral blood after infusion.

Time Frame

2 months

Secondary Outcome Measure Information:

Title

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

Title

Reconstitution of anti-microbial immunity monitored by flow cytometry

Time Frame

6 months

Title

Number of patients with chronic GVHD-like symptom

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Months

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Lung-Ji Chang, PhD

Phone

+86(755)8672 5195

c@szgimi.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Lung-Ji Chang, PhD

Organizational Affiliation

Shenzhen Geno-Immune Medical Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

Shenzhen Geno-immune Medical Institute

City

Shenzhen

State/Province

Guangdong

ZIP/Postal Code

518000

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Lung-Ji Chang, PhD

Phone

86-755-86725195

c@szgimi.org

12. IPD Sharing Statement

Plan to Share IPD

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

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