Myeloid leukemia switch as immune escape from CD19 chimeric antigen receptor (CAR) therapy

Gardner et al. recently reported on two cases of mixed lineage leukemia (MLL) + acute myeloid leukemia (AML) occurring after CD19 chimeric antigen receptor (CAR) therapy for MLL + B-acute lymphoblastic leukemia (ALL) (1).This report provides new insights into mechanisms of immune escape from targeted immunotherapy and strategies to prevent their occurrence with adapted immune interventions.Adoptive cell therapy utilizing genetically engineered T cells expressing second generation CARs specific for CD19 has shown remarkable efficacy against a range of chemo-refractory and relapsed B cell malignancies, most remarkably in ALL (2).A single infusion of CD19 CAR T cells may induce a complete remission in subjects whose leukemia has developed drug resistance and is unlikely to respond to allogeneic stem cell transplantation.This novel cell-based immunotherapy was highlighted, together with checkpoint blockade, as the basis for selecting cancer immunotherapy as the scientific breakthrough of the year in 2013 (3).CARs recognize tumor antigens irrespective of human leukocyte antigen (HLA) and can thus target tumor cells that have down-regulated HLA expression or proteasomal antigen processing, two mechanisms that contribute to tumor escape from T cell receptor (TCR)mediated immunity (4).The advent of second generation CARs not only enables to retarget T cells but also to augment their functional capabilities (5).The two cases recently reported by Gardner et al. include a 52-yo woman and an 18-mo girl with an initial diagnosis of MLL-rearranged B-ALL, who presented a lineage switch at relapse after CAR therapy.Several facets of leukemia biology and resistance to CAR therapy need to be taken into account in analyzing these observations.The MLL gene is frequently involved in chromosomal translocations found in human acute leukemias characterized as AML, ALL or biphenotypic (mixed lineage) leukemia (6-8).MLL rearrangements are found in >70% of infant leukemias, whether the immunophenotype is that of ALL or AML (9).MLL translocations are also found in about 10% of AML in adults, and in therapy-related leukemias that develop in patients previously treated with