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Specificità della clinica: la ricostituzione immunologica, la GVHD e le complicanze infettive

Specificità della clinica: la ricostituzione immunologica, la GVHD e le complicanze infettive F. Narni. No immune suppression after transplantation!!!. Delayed immune reconstitution is the main limitation of T-cell depleted Haplo-HCT. 1st. 2nd. Add-back of donor T cells. risk of severe GvHD.

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Specificità della clinica: la ricostituzione immunologica, la GVHD e le complicanze infettive

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  1. Specificità della clinica: la ricostituzione immunologica, la GVHD e le complicanze infettive F. Narni

  2. No immune suppression after transplantation!!!

  3. Delayed immune reconstitution is the main limitation of T-cell depleted Haplo-HCT

  4. 1st 2nd

  5. Add-back of donor T cells risk of severe GvHD

  6. TK cells = donor lymphocytes genetically engineered to express HSV-thymidine kinase gene GMP lab Selection Transduction Drug product

  7. HSV-thymidine kinase gene= suicide gene:once integrated into donor lymphocytes DNA, makes them sensitive to Ganciclovir (GCV).

  8. GVHD ganciclovir administration GCV is phosphorylated by HSV thymidine kinase blockage of DNA synthesis death of proliferating cells.

  9. Objective:

  10. Infectious adverse events

  11. GVHD Ganciclovir

  12. Any of the following conditions: • AML and ALL in 1st CR at high-risk of relapse based on negative prognostic factors • AML and ALL in 2nd or subsequent CR • Secondary AML in CR • Absence of fully HLA matched family or unrelated donor

  13. Phase III study, Double arm, open label, randomized (3:1) • Multicentre, Multinational • 152 patients to be enrolled (114 in the experimental arm and 38 in the control arm)

  14. in patients of both arm A and B • The graft composition should be adjusted to contain a minimum of 7x106 CD34+/kg stem cells • and a dose of 1x104 CD3+/kg lymphocytes

  15. Experimental arm Weekly Immunophenotype • two consecutive findings of circulating CD3+ cells < 100/μl: • 1st Infusion between day + 21 to days +49 after HCT (1 x 107 cells/kg) • 2nd Infusion +30 days after 1st INFUSION (1 x 107 cells/kg) • 3rd Infusion +30 days after 2nd INFUSION (1 x 107 cells/kg) • 4th Infusion +30 days after 3rd INFUSION (1 x 107 cells/kg)

  16. In case of GvHD • the patients will be treated with • ganciclovir at a dose of 10 mg/Kg/day i.v. divided into 2 administrations • or • val-ganciclovir 900 mg bid p.o. for 14 days

  17. Primary endpoint: Disease-free survival • Secondary endpoints • Overall Survival (OS) • Non-relapse mortality (NRM) • Time to immune reconstitution (IR) • Engraftment rate • Cumulative incidence of aGvHD • Cumulative incidence of extensive cGvHD • Cumulative incidence of relapse (CIR)

  18. despite the preferential integration of the retroviral vector within or in the proximity of transcriptionally active genes, transduced T cell population maintained a stable gene profile expression, phenotype and biological functions. A comparison of the integration site in transduced T cells before and after infusion showed that vector integration within genes involved in cell cycle control or in other physiological T cellfunctions were counter-selected in vivo. Furthermore, no clonal selection or expansion could be observed during the follow up. Therefore, the results obtained clearly point out that retroviral integration in SFCMM-3 transduced T cells are not associated to a measurable risk of insertional oncogenesis.

  19. Long term follow-up period of 15 years For the first 5 years a general health evaluation with a physician and collection of blood samples (about 10 ml) on an annual basis, for detection of late clinical outcomes suggestive of retroviral disease, including new/recurrent malignancies, neurologic disorders, hematologic disorders, autoimmune disorders, unexpected medical problems and hospitalizations For the subsequent 10 years, only a specific questionnaire will be filled in by the patients

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