Adoptive Transfer of Primed CD62L+ T Cells Mediate Selective GVL In a Murine Model of Pediatric ALL

While current upfront therapy will cure over 80% of patients with pediatric ALL, treating recurrence remains a major challenge. Blood or marrow transplantation (BMT) offers a curative option but approximately 50% of patients undergoing BMT will relapse. Donor lymphocyte infusions (DLIs) have demonstrated efficacy in myeloid leukemia but are much less effective for ALL. Strategies to improve the potency of DLI can result in GVHD and may compromise outcome. Thus, we explored strategies to improve on the potency and specificity of the graft versus leukemia response in a murine model of pediatric ALL.

A transplantable cell line was generated from E2a-PBX1 transgenic mice (that express a recurring translocation t(1;19) present in approximately 5% of all pediatric ALL). Lethally irradiated C57Bl/6 (H2b) mice received T-cell-depleted C3H.SW (H2b, minor histocompatibility antigen miHA mismatch allogeneic) or C57Bl/6 (syngeneic) bone marrow followed by E2aPBX1 IV on day +6. A purified T cell DLI was given on day +7. DLI donors were primed with irradiated cells as indicated intraperitoneally 14 days prior to harvest. In some experiments T cell subsets were purified using magnetic beads.

E2a-PBX1 is a pre-B cell ALL that expresses B220, BP-1, CD43 and the alpha chain of the IL-7 receptor. The distribution of leukemia is similar to that observed in humans with bone marrow, lymph node, liver, spleen and central nervous system involvement confirmed by necropsy and imaging following injection of luciferase-expressing cells. Administration of naive T cells (6×10⁶) following syngeneic or allogeneic BMT was not effective at treating E2a-PBX1 indicating that the presence of miHA did not increase the efficacy of naïve T cells consistent with the poor response rate to DLI in patients with ALL. However, primed T cell DLI (6×10ee6) from a donor immunized by irradiated E2a-PBX1 resulted in a statistically significant prolongation of survival in syngeneic (and cure in allogeneic BMT models suggesting the presence of tumor-specific antigens as well as a contribution from miHA. However, mice receiving sufficient primed allogeneic T cells for cure developed GVHD-associated weight loss and 40% late mortality (after 30 days). While purified, primed CD4 or CD8 T cells prevented GVHD associated mortality, 40–60% of mice developed leukemia. Remarkably, mice receiving magnetic-bead purified CD62L+ T cells from primed allogeneic donors were cured of leukemia with no GVHD-associated weight loss or mortality.

Naïve T cells (analogous to DLI given post-relapse in the clinic) were ineffective at treating ALL our model. However, priming of allogeneic DLI donors with whole tumor cells results in cure but with the development of GVHD. CD62L+ expressing T cells from primed donors mediate curative GVL without GVHD.

No relevant conflicts of interest to declare.