Early immune reconstitution and abrogation of GvHD after infusion of HSV-TK engineered donor lymphocytes after haplo-identical hemopoietic stem cell transplantation

Abstract

6515 Background: Haplo-identical stem cell transplantation (haplo-SCT) is a therapeutic option for patients with high risk hematologic malignancies lacking an HLA matched donor. The full exploitation of haplo-SCT is limited by delayed immune recovery, resulting in prolonged risk of life-threatening infections. Infusion of small numbers of donor T cells, aimed at providing immune reconstitution, results in severe forms of graft-versus-host-disease (GvHD). We previously showed that infusion of donor lymphocytes (DLI) expressing the herpes simplex virus thymidine kinase (Tk) is an efficient tool for controlling GvHD and preserving anti-tumor activity. Methods: We designed a dose-finding clinical protocol of Tk-DLI for immune reconstitution and relapse prevention after haplo-SCT. Eight pts with high risk hematologic malignancies who underwent haplo-SCT received escalating doses (10e6–10e7/kg) of Tk-DLI from day +42. Results: Transduced cells were documented ex vivo in all evaluable pts. While no CD3+ cells were observed after infusion of 10e6/kg, the majority of pts who received 10e7/kg Tk-DLI reached 50 CD3+/μl by day 50, increasing steadily thereafter. Analysis on ex vivo PBLs showed Th1/Tc1 cells with a wide TCR repertoire able to proliferate, lyse and produce IFN-γ after stimulation with viral and allogeneic antigens. Immune reconstitution resulted in complete control of viral infections and complete remission of leukemia in the majority of patients. In 1 pt a grade II biopsy-proven acute GvHD, involving skin and liver was observed. Multiple doses of ganciclovir (10 mg/kg/die), in the absence of immunosuppressive drugs, quickly resulted in the complete resolution of all signs of GvHD. Ganciclovir-mediated abrogation of alloreactive T cells was confirmed by ex vivo ELISPOT analysis of host-reactivity. Conclusions: Tk-DLI at a dose of 10e7/kg is a promising tool for preventing disease relapse and promoting immune reconstitution after haplo-SCT while providing an effective and selective treatment for GvHD. A multicentric study aimed confirming these results on a larger cohort of patients recently started. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Molmed s.p.a.