CMV Specific T Cell Therapy After Allogeneic Stem Cell Transplantation.

NCT ID: NCT03067155

Last Updated: 2022-12-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 1 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-10-31
• Study Completion Date: 2021-12-31

Brief Summary

Viral infections remain an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT), especially after myelo-ablative conditioning and if the donor is antigen-mismatched or haplo-identical.. In the described setting the patient's own immune system has been destroyed by the necessary highly immuno- and myelo-ablative conditioning and all memory against infections has been deleted. Therefore, there is a high risk for several viral infections and other infectious organisms.Both primary viral infections and reactivations can occur, and patients can become refractory to antiviral treatments, or in some cases an adequate antiviral treatment is unavailable or too toxic. In this study, the investigators will target CMV, as refractory CMV infection and disease is accompanied by an extremely high mortality rate and therefore the development of new treatment approaches is required. Despite the available antiviral drugs, a considerable number of patients are facing an insufficient control of CMV reactivation after SCT. Because reconstitution of CMV-specific T cells confer protection against the development of CMV disease after SCT, attempts have been made to restore antiviral immunity by direct infusion of CMV-specific T cells. Most clinical cellular immunotherapy protocols for CMV treatment have used CMV-specific cytotoxic CD8+ T-cell lines generated by repetitive in vitro stimulation with CMV antigens with success. Despite the proven efficacy, use of cellular therapy in the clinic has been limited, because the approach is time and labor consuming and requires specialized facility allowing handling of the therapeutic cells according to good manufacturing practice. In addition, no sustained response was seen after adoptive transfer that involved only cytotoxic CD8+ T cells. This phenomenon is supported by the fact that recall responses to latent infections depend on the presence of CD4+ T cells to help cytotoxic CD8+ T cells. An alternative approach for the transfer of T-cell immunity is the isolation of Ag-specific T cells ex vivo from the blood of CMV seropositive donors, based on interferon γ (IFN-γ) secretion of T cells after in vitro stimulation with viral Ag, resulting in a combination of CD4+ T helper and cytotoxic CD8+ CMV specific T cells. Using this strategy, a short-term ex vivo protocol was developed for the isolation of pp65 (CMV immunodominant protein)-specific T cells. Since then, several centers have used this protocol in the clinic, infusing low numbers of pp65-specific T cells, that were able to restore protective T-cell immunity against CMV in a post SCT setting in patients with refractory CMV disease or viremia. For this protocol the investigators have set up and validated this method of CMV-specific T-cell generation in the Ghent University Hospital and the investigators will make it available for other Belgian transplant centers.

Conditions

Hematological Malignancies; CMV Infection

Keywords

allogeneic stem cell transplantation; CMV reactivation

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment group

The patients for which a suitable donor product can be obtained will be included in the treatment arm of the protocol. Treatment consists of the administration of CMV-specific T-cells, administered through intravenous transfusion. Depending on response in viral load and GVHD status, a second and/or third administration is possible.

Group Type: EXPERIMENTAL

CMV-specific T cells

Intervention Type: GENETIC

Control group

Patients for which the investigator can't obtain a suitable donor product, will be included in the control group consisting of standard anti-viral treatment.

Group Type: ACTIVE_COMPARATOR

Standard anti-viral therapy

Intervention Type: DRUG

Continue with the anti-viral treatment as per standard of care.

Interventions

CMV-specific T cells

Intervention Type: GENETIC

Standard anti-viral therapy

Continue with the anti-viral treatment as per standard of care.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients:

1. All underlying diseases that form an indication for allogeneic stem cell transplantation

2. Underwent allogeneic stem cell transplantation with a donor that fulfills the following criteria:

• CMV-seropositive at the time of transplant and
• Age 18-70 years 3) Having a CMV reactivation or primary infection or disease with the following characteristics: CMV PCR at least twice positive AND CMV infection relapsing after 3 successful treatment episodes with gancyclovir OR Refractory to treatment with available antiviral drugs which is defined as follows: Persistent positive CMV PCR > detection limit 14 days after initiation of antiviral treatment OR increasing CMV viral load 7 days after initiation of antiviral treatment 4) Informed consent given
• Donor:

1. Is identical to donor of the previous stem cell transplant

2. The donor will be pre-screened for the presence of sufficient numbers of CMV-specific T cells:

• IFNgamma producing T cells upon CMVpp65 stimulation are at least twice the background level (unstimulated cells)
• At least 10 events of IFNgamma positive T cells are measured
• IFNgamma producing T cells upon CMVpp65 stimulation are equal or higher than 0,1% of the viable CD4+ and CD8+ cell population If the donor shows sufficient number of circulating CMV-specific cells, according to the test described in 2 3) Only if the donor shows sufficient number of circulating CMV-specific cells, according to the test described in 2:
• Donor has positive IgG serology for CMV, IgM negative or positive
• Donor has signed informed consent for the donation of donor lymphocyte cells
• Donor is found fit for donation by a medical doctor according to selection criteria conform KB annex II (C-2009/18414)
• Donor is negative for infectious disease markers including HCV, HBV and HIV-NAT testing: HBs antigen, HBc/HBs antibodies, Syphilis (TPHA or equivalent), HVC and HIV antibodies.
• Additional testing should be performed and negative when relevant: malaria, west nile virus, trypanosomiasis, HTLV conform KB annex II (C-2009/18414)
• HCG negative within 7 days of apheresis

• Donor:

Exclusion Criteria

• Patients:

1. HIV, HCV, HBV positive (HbSAg positivity after vaccination is allowed)

2. Life expectancy severely limited by disease other than malignancy or viral infection

3. Administration of cytotoxic agent(s) for cytoreduction within three weeks prior to initiation of the treatment or to be expected within 8 weeks after administration of the treatment

4. Terminal organ failure except for renal failure (dialysis acceptable)

5. Uncontrolled other infection than the one being treated

6. Karnofsky performance score < 60%

7. Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment

8. Patient is a female who is pregnant or breastfeeding

9. Patient with active aGVHD grade 3 or more

10. Patient with severe chronic GVHD

11. Patient on corticosteroids > 0.5mg/kg. Patient can still be on therapeutic doses of immunosuppressive therapy, but these will be tapered to the lowest possible dose, as is part of standard care in case of CMV reactivation.

12. Patient that has received ATG < 1 month prior to infusion or Campath < 1 year prior to infusion

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Ghent

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Tessa Kerre, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Ghent

Locations

Universitair Ziekenhuis Gent

Ghent, Oost-Vlaanderen, Belgium

ZNA Stuivenberg

Antwerp, , Belgium

AZ Sint-Jan Brugge

Bruges, , Belgium

Institut Jules Bordet

Brussels, , Belgium

Universitair Ziekenhuis Brussel

Brussels, , Belgium

Cliniques Universitaires Saint Luc

Brussels, , Belgium

Université de Liège

Liège, , Belgium

Heilig Hart Ziekenhuis Roeselare

Roeselare, , Belgium

Countries

Belgium

References

Geurten C, Ghinai R, Munford H, Lawson S. Efficacy of Cytomegalovirus Specific Immunoglobulins to Reduce CMV Reactivation in Pediatric Hematopoietic Stem Cell Transplant Recipients. J Pediatr Hematol Oncol. 2023 Jan 1;45(1):e82-e86. doi: 10.1097/MPH.0000000000002553. Epub 2022 Sep 22.

Reference Type: DERIVED

PMID: 36162011 (View on PubMed)

Other Identifiers

2013-004953-26

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

BHS-TC13

Identifier Type: OTHER

Identifier Source: secondary_id

BHS-TJT1401

Identifier Type: -

Identifier Source: org_study_id