Donor-derived Anti-leukemia Cytotoxic T Lymphocytes(Fondazione IRCCS Policlinico San Matteo)

The prognosis for children affected by acute leukemia and transplanted in an advanced disease stage, in the presence of MRD or with unfavorable cytogenetic abnormalities, is still poor. Optimizing post-transplant management to maintain durable remission represents the greatest challenge to improve the outcome of pediatric patients with acute leukemia given an allogeneic HSCT.
The pivotal therapeutic role of immunity against acute leukemia has been highlighted by the immunological effect of donor T cells (GVL) observed following allogeneic HSCT, which is considered the only curative strategy for this type of cancer. Moreover, circulating leukemia-specific CTLs have been detected in patients with different forms of acute leukemia, and the presence of these specific T-cell responses in peripheral blood and bone marrow samples of leukemic patients has been associated with improved disease control and longer survival. This body of data suggests that immunological interventions could have an effect in preventing relapse and improving transplant outcome.
Unmanipulated donor lymphocyte infusion (DLI) is used after stem cell transplantation to treat and prevent relapse, to prevent infections and to establish full donor chimerism. However, an expected side effect of the presence of mature T cells is the potential occurrence of acute GvHD. Evidence has emerged that escalating DLI has achieved higher clinical response rates with lower GvHD occurrence. Optimization of DLI dose and schedule as well as strategies of donor T-cell manipulation may lead to the consistent ability to separate GvHD from GvL activity and improve the safety of DLI treatment. One way to manipulate donor lymphocytes to reduce GVHD is leukemia antigen stimulation, in order to increase antileukemia activity while reducing the number of alloreactive T cells by specific culture.
The aim of this study is to enhance the GVL effect, and reduce the rate of post-transplant relapse, with preventive post-HSCT infusions of donor anti-leukemia CTLs specifically directed to patient's leukemic blasts. The leukemia-reactive CTLs obtained by stimulation with patients' leukemia blasts are specific for each individual blast signature, and, due to their physiological recognition and effector mechanism through their natural T cell receptor, exert leukemia-specific killing with less severe adverse reactions than CAR-T cells. Moreover, due to their potential to recognize multiple leukemia-associated antigens present on the blast surface, they should be less prone to immune evasion strategies exerted by leukemic stem cells. Additionally, the risk of GVHD should be reduced by the culture procedure, which decreases the number of alloreactive T cells. For the reasons stated, the use of these T cells after HSCT in a highly personalized approach may be a safer and more efficient option than unmanipulated donor lymphocyte infusions (DLIs) to prevent leukemia relapse after HSCT.