Immunotherapy with cure potential of multi-drug resistant hematologic malignancies using IL-2 preactivated intentionally mismatched donor lymphocytes

Purpose: Unfortunately, cure of multi-drug resistant (MDR) hematologic malignancies remains an unmet need. Donor lymphocyte infusion (DLI) following allogeneic stem cell transplantation (SCT) can sometimes eliminate multi-drug resistant leukemia but at a risk of acute and chronic graft-vs-host disease (GVHD) and procedure-related toxicity. Supported by pre-clinical experiments in animal models, we hypothesized that immunotherapy induced by non-engrafting intentionally mismatched IL-2 activated killers (IMAK) including both T & NK cells could induce safer, faster and much more effective immunotherapy while avoiding the need for SCT and the risks of GVHD. Methods: IMAK treatment was applied in 33 patients with MDR hematologic malignancies conditioned with cyclophosphamide 1,000mg/m^2 based protocol. Haploidentical or unrelated donor lymphocytes were preactivated with IL-2 6,000 IU/ml for 4 days. IMAK was combined with Rituximab in 12/23 patients with CD20 + B cells. Results: A total of 23/33 patients with MDR (4 failing SCT) achieved complete remission (CR). First patient currently 30 years with no further treatment and 5 observed for >5 years (2 AML; 2 multiple myeloma, 1 ALL & 1 NHL) can be considered cured. No patient developed >grade 3 toxicity or GVHD. No residual male cells were detectable among 6 females treated with male cells beyond day +6, confirming that GVHD was prevented by consistent early rejection of donor lymphocytes. Conclusions: We hypothesize that safe and superior immunotherapy of MDR with cure potential may be accomplished by IMAK, most probably in patients with low tumor burden, but that remains to be confirmed by future clinical trials.