Clinical trial NCT00423124: Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK in Patients With Haematological Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hematological Malignancies
Keywords: Hematological malignancies
HSV-TK
Haploidentical HCT
GvHD
GvL
Lead sponsor: AGC Biologics S.p.A.
Sponsor class: INDUSTRY
First posted: 2007-01-17
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Evaluation of clinical activity in terms of immune-reconstitution, provided by the add- back of the transduced T-cells after haplo-HCT
timeFrame: during the study
measure: Evaluation of the "in vivo" control of GvHD after administration of ganciclovir in patients treated with HSV-TK transduced T-cells
timeFrame: during the study
measure: Evaluation of GvL effect
timeFrame: during the study
Secondary outcomes:
measure: Time to relapse, time to death (evaluated by disease free survival and overall survival)
timeFrame: during the study
measure: Incidence of infectious events (measured by number of infectious events)
timeFrame: during the study
measure: Acute and long term toxicity related to the infusions (measured by incidence of adverse events)
timeFrame: during the study and study follow up
Other outcomes:
Locations:
city: Hannover
country: Germany
facility: Medizinische Hoschule Hannover
city: Thessaloniki
country: Greece
facility: G. Papanicolau
city: Jerusalem
country: Israel
facility: Hadassah University Hospital
city: Milan
country: Italy
facility: Fondazione San Raffaele
city: Milan
country: Italy
facility: Istituto Clinico Humanitas
city: Perugia
country: Italy
facility: Policlinico Monteluce
city: Pescara
country: Italy
facility: Ospedale Civile
city: London
country: United Kingdom
facility: Hammersmith Hospital
Study officials:
affiliation: Hematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy
name: Fabio Ciceri, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.