Allogeneic cell therapy as potential cure of hematologic malignancies
Author(s): Shimon Slavin
In sharp contrast to existing immunotherapy procedures based on activation of patient’s own immune system, our working hypothesis was that optimal induction of immunotherapy may be accomplished using intentionally mismatched activated donor lymphocytes as the most effective approach for elimination of fully resistant malignant cells by a mechanism resembling rejection of an allograft. Using murine B cell leukemia (BCL1) and based on their pilot clinical experience, they proved that effective graft-vs-leukemia (GVL) effects following SCT and durable engraftment of donor lymphocytes could eliminate otherwise incurable heavy tumor burden but at the risk of severe GVHD. Accordingly, they developed an immunotherapy protocol based on the use of non-engrafting, Intentionally mismatched activated Killers (IMAK) activated in vitro for five days with IL-2 prior to cell infusion with five days activation in vivo following cell infusion with no prior SCT. They confirmed that curative GVL was induced by IMAK with no risk of GVHD due to consistent rejection of mismatched donor lymphocytes treated at the stage of minimal residual disease (MRD), elimination of leukemia and cure were accomplished by transient circulation of alloreactive donor lymphocytes consisting of T & NK cells combined, indicating that “the last” cancer cell was eliminated since even residual of 10 BCL1 cells can result in lethal leukemia. Using IMAK following non-myeloablative conditioning in parallel with suppression of regulatory T cells by cyclophosphamide and using alpha interferon for induced expression of cancer antigens, their first multiple myeloma patients as well as our first patient with AML and two with NHL remain disease free >25 years. Long-term progression-free survival was also reported in other patients with hematologic malignancies and even solid tumors since then but cure of cancer by IMAK depends exclusively on clinical application of successful immunotherapy at the stage of minimal residual disease.