Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK in Patients With Haematological Malignancies

A Phase I-II Study: Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK, After Transplantation of Allogeneic T-depleted Stem Cells From a Haploidentical Donor in Patients With Haematological Malignancies

The aim of the study is to obtain immune reconsitutuion as well as reduction of infective episodes and disease relapse in patient with haematological malignancies who underwent SCT(and subsequent T lymphocytes infusions) and selectively controlling GvHD.

Study Overview

• Status: Completed
• Conditions: Hematological Malignancies
• Intervention / Treatment: Genetic: HSV-TK

Detailed Description

Delayed immune-reconstitution remains one of the main limitation of haploidentical stem cell transplantation. The risk of severe infections remains high for several months and CD4+ reconstitution could take more than 10 months. The low number of lymphocytes infused with the graft, the degree of HLA disparity, and a reduced thymic function in adults and differences in host/donor antigen presenting cells are contributing causes.

The infusions of HSV-TK engineered lymphocytes may represent a significant therapeutic improvement in haploidentical haplo-HCT, because it remarkably may enhance both GvL activity, thus reducing the occurrence of disease relapse, and post-transplant immune reconstitution in the absence of chronic immune suppression, thus decreasing the rate of both post-transplant opportunistic infections and transplant-related mortality. Furthermore, the efficient control of GvHD achieved via the suicide mechanism allows also the multiple infusion of HSV-TK-treated donor lymphocytes, when needed, that might further improve post-transplant host immune reconstitution, and, eventually, survival in patients receiving haplo-HCT. Finally, this therapeutic approach, which allows the safe infusion of escalating doses of donor lymphocytes, can become a valuable option for all candidates, including patients with advanced disease and older age.

The proposed clinical trial represents an innovative therapeutic treatment for patients affected by hematological malignancies, who have undergone haploidentical stem cell transplantation.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Hannover, Germany
    • Medizinische Hoschule Hannover
• Greece
  • Thessaloniki, Greece
    • G. Papanicolau
• Israel
  • Jerusalem, Israel
    • Hadassah University Hospital
• Italy
  • Milan, Italy
    • Istituto Clinico Humanitas
  • Milan, Italy
    • Fondazione San Raffaele
  • Perugia, Italy
    • Policlinico Monteluce
  • Pescara, Italy
    • Ospedale Civile
• United Kingdom
  • London, United Kingdom
    • Hammersmith Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients >=18 years old affected by hematological malignancies at high risk of relapse based on disease progression or presence of negative prognostic factors, who have received a HCT from donor HLA mismatched (haploidentical) for 2 or 3 loci
• Engraftment documented by >500 neutrophils/µl for three consecutive days in the absence of growth factors
• Mixed chimerism or full donor chimerism confirmed
• AML in 1st or 2nd relapse or primary refractory
• High-risk AML in 1st or subsequent remission
• RAEB and RAEB-T
• CML in 2nd chronic phase, blast crisis or accelerated phase
• Poor prognosis ALL in 1st or subsequent remission
• High grade lymphomas in 3rd or subsequent remission
• Multiple myeloma in advanced stage relapsing or progressing after high dose chemotherapy
• Absence of fully HLA matched or one HLA locus mismatched family donor
• Stable clinical conditions and life expectancy >3 months
• PS Karnofsky >70
• Written donor/patient informed consent

Exclusion Criteria:

• Infection with cytomegalovirus being treated with ganciclovir
• Presence of GvHD grade > I that requires systemic immunosuppressive therapy (at baseline)
• Ongoing systemic immunosuppressive therapy
• Ongoing acyclovir administration
• Administration after haplo-HCT of G-CSF and cyclosporine A
• CD3+ lymphocytes >100/µl before day +42 after haplo-HCT
• Life-threatening condition or complication other than their basic disease
• CNS disease
• Pregnant or lactating women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A	Genetic: HSV-TK; Infusion of genetically modified lymphocytes (1x10^6-1x10^7 c/kg): first at +21-+49 days after HSCT; in absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Evaluation of clinical activity in terms of immune-reconstitution, provided by the add- back of the transduced T-cells after haplo-HCT	during the study
Evaluation of the "in vivo" control of GvHD after administration of ganciclovir in patients treated with HSV-TK transduced T-cells	during the study
Evaluation of GvL effect	during the study

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to relapse, time to death (evaluated by disease free survival and overall survival)	during the study
Incidence of infectious events (measured by number of infectious events)	during the study
Acute and long term toxicity related to the infusions (measured by incidence of adverse events)	during the study and study follow up

Collaborators and Investigators

• Sponsor: AGC Biologics S.p.A.
• Investigators: Principal Investigator: Fabio Ciceri, MD, Hematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy

Publications and helpful links

General Publications

• Stornaiuolo A, Valentinis B, Sirini C, Scavullo C, Asperti C, Zhou D, Martinez De La Torre Y, Corna S, Casucci M, Porcellini S, Traversari C. Characterization and Functional Analysis of CD44v6.CAR T Cells Endowed with a New Low-Affinity Nerve Growth Factor Receptor-Based Spacer. Hum Gene Ther. 2021 Jul;32(13-14):744-760. doi: 10.1089/hum.2020.216. Epub 2021 May 5.
• Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, Salomoni M, Turchetto L, Colombi S, Bernardi M, Peccatori J, Pescarollo A, Servida P, Magnani Z, Perna SK, Valtolina V, Crippa F, Callegaro L, Spoldi E, Crocchiolo R, Fleischhauer K, Ponzoni M, Vago L, Rossini S, Santoro A, Todisco E, Apperley J, Olavarria E, Slavin S, Weissinger EM, Ganser A, Stadler M, Yannaki E, Fassas A, Anagnostopoulos A, Bregni M, Stampino CG, Bruzzi P, Bordignon C. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. Lancet Oncol. 2009 May;10(5):489-500. doi: 10.1016/S1470-2045(09)70074-9. Epub 2009 Apr 1.

Study record dates

Study Major Dates

• Study Start: July 1, 2002
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: January 16, 2007
• First Submitted That Met QC Criteria: January 16, 2007
• First Posted (Estimate): January 17, 2007

Study Record Updates

• Last Update Posted (Estimate): May 30, 2014
• Last Update Submitted That Met QC Criteria: May 29, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: GvHD; Hematological malignancies; HSV-TK; Haploidentical HCT; GvL
• Additional Relevant MeSH Terms: Behavioral Symptoms; Neoplasms by Site; Hematologic Diseases; Self-Injurious Behavior; Neoplasms; Hematologic Neoplasms; Suicide
• Other Study ID Numbers: TK007; 2005-003587-34 (EudraCT Number)