Immunotherapy of multi-drug resistant hematologic malignancies with IL-2-activated intentionally mismatched lymphocytes

Abstract: Donor lymphocyte infusion using IL-2 activated donor lymphocytes following allogeneic stem cell transplantation (SCT) can sometimes eliminate multi-drug resistant (MDR) cancer cells and result in a cure. We hypothesized that more effective and faster immunotherapy could be accomplished by non-engrafting Intentionally Mismatched IL-2 Activated Killer cells (IMAK) with no prior SCT, avoiding the risks of GVHD due to consistent spontaneous rejection of killer cells after induction of cancer cytotoxicity. IMAK was applied for the compassionate treatment of 33 patients with MDR hematological malignancies following mild immunosuppressive conditioning. IMAK infusion was followed by low-dose subcutaneous IL-2 injections for ≤ 5 days for in vivo activation of donors’ and patients’ lymphocytes. Cumulative experience confirmed major anti-cancer responses following treatment with IMAK including in patients relapsing after myeloablative SCT. Treatment of relatively low tumor burden resulted in cure (> 5 to > 28 years unmaintained disease-free survival). Treatment was reasonably well-tolerated or manageable with no grade IV toxicity. Circulating donor lymphocytes were undetected beyond day + 6, confirming that early spontaneous rejection prevented the risk of GVHD-like toxicity. Immunotherapy potentially resulting in cure could be accomplished in patients with resistant hematologic malignancies when treated with relatively low tumor burden by transient circulation of IMAK. Since MRD can be accomplished in most patients with hematologic malignancies following successful first-line or high-dose chemotherapy, eradication of MRD in otherwise incurable patients could possibly be accomplished by IMAK. Prospective randomized clinical trials are indicated to confirm our working hypothesis.