Voor een goede vergelijking met Atir hier nog scores met de Zalmoxis methode. Als ik de non-relapse mortality (NRM) en relapse mortality optel kom ik voor Zalmoxis uit op een overall survival van slechts 39% na 3 jaar. Dit is nauwelijks beter dan de Cyclophosphamide variant. De laatse variant zal (net als Zalmoxis) met Atir worden vergeleken in de fase 3 trial van Kiadis.
In the TK007 multicentric phase I-II clinical trial, 50 adult patients were enrolled to receive a TCD haploidentical HSCT followed by the infusion of TK cells, for high-risk hematologic malignancies. Again TK cells proved safe, with no documented adverse event related to the genetic modification. In this study, 28 adult patients were treated with multiple infusions of TK cells starting 1 month after haploidentical HSCT, in the absence of pharmacologic prophylaxis for GvHD; 22 patients obtained immune reconstitution at a median of 75 days (range 34–127) from HSCT and 23 days (13–42) from TK-cell infusion. Twelve patients developed acute GvHD, and one developed chronic GvHD. Direct association of TK-cells and GvHD was confirmed by vector-encoded protein immunostaining of lymphocytes infiltrating affected lesions. In all cases the TK/GCV machinery proved effective, leading to a rapid and complete resolution of all clinical symptoms and providing a long-term immunosuppressive therapy free survival, in absence of GvHD related deaths or long-term complications (Lupo Stanghellini et al., 2014). Beside the efficient control of donor T-cell alloreactivity, the infusion of TK cells granted a rapid and wide immune reconstitution, which was instrumental for the abrogation of the late TRM, reported for TCD haploidentical HSCT. In immune reconstituted patients, progressive normalization of antiviral responses was associated with a decline in the number of infectious events, while patients who failed immune reconstitution continued to have frequent infectious complications. At 3 years, intention to treat NRM was ˜40%, with all events occurring in the first 6 months after HSCT. For patients with primary acute leukemia, transplanted in complete remission, relapse mortality at 3 years was 19% (Ciceri et al., 2009). All patients in complete remission 3 years after transplant remained so in the following years (longest follow-up 11 years; Oliveira et al., 2012).
The HSV-TK strategy is currently under evaluation in a phase III clinical trial in patients undergoing haploidentical HSCT for high-risk acute leukemia. In this pivotal, ongoing phase III trial (TK008, NCT00914628), up to 4 monthly infusions of TK cells are given at 1x107 for kg of patient body weight, starting 21–49 days after TCD haploidentical HSCT in the experimental arm. Control arm consists of either TCD or post-transplant cyclophosphamide haploidentical HSCT, at physician discretion. So far, 34 patients have been enrolled from eight EU and US sites. Preliminary results of this ongoing trial (median follow-up is 1.2 years) confirm the potential clinical benefit of T-cell gene transfer technology integrated with TCD haploidentical HSCT, and highlight the role of early IR as surrogate endpoint for survival outcomes and the dose-related antileukemic effects of TK (Bonini et al., 2014).