Three-year clinical follow-up of 5 patients treated with suicide gene modified donor lymphocyte infusion therapy in Japan

Suicide gene, herpes virus thymidine kinase gene (hsv-tk), modified donor T lymphocyte infusion (TK-DLI) is one of the promising approach to high risk leukemia patients who are going to have T cell depleted haploidentical hematopoietic stem cell transplantation (1). Despite that success of the T lymphocyte based gene therapy in haplo SCT setting to reduce relapse unrelated mortality with control of graft-versus-host disease is becoming clear, there remains some difficulties to be solved for inducing remission to patients with relapsed leukemia after SCT. The solutions would be 1) very early detection of leukemia relapse and enough reduction of leukemia burden before TK-DLI, 2) making a "niche", space for lymphocytes, for TK-T lymphocytes, and 3) maintaining T lymphocytes to have potentials of proliferation and survival such as naive and central memory T cells. A phase I/II clinical trial of TK-DLI have been performed in the Tsukuba University Hospital to 5 patients (2 AML, 2 ALL, and 1 MDS) since 2002. Actually our five patients for relapsed leukemia had one or more difficult points as listed above, and it results only temporal and insufficient clinical response in 4 of 5 patients. Different from the other patients in treatment failure, only one MDS patient survives more than 3 years after TK-DLI without any sign of relapse. He was in hematological remission at the time of TK-DLI and had been in immunosuppressive status of 6 month after SCT, suggests that he had been in ideal clinical conditions for TK-DLI. But TK-T cells disappeared within 4 month after TK-DLI same as the other patient, suggests TK-T cells lacked potentials of proliferation and survival in a patient. According to the result, we optimized clinical and manipulation protocols. They include 1) detection of molecular relapse and perform a TK-DLI at the level, 2) addition of lympho-depletion conditioning with Fludarabine and Cyclophosphamide before TK-DLI, and 3) usage of CD3/CD28 stimulation + low dose IL2, instead of OKT3 + high concentrated IL-2, to obtain suicide gene transduced central memory TK-T cells(2,3). Clinical outcome of five TK-DLI patients and result of protocol modification will be discussed in the meeting.