CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity

Abstract

Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.

Repeated loss of target surface antigen after immunotherapy in primary mediastinal large B cell lymphoma

“…None of the previously described alternative isoforms of CD19 were found in the patient's tumor. CAR treatment pressure can differentiation of CLL to a CD19-negative plasmablastic lymphoma [7] or B-ALL to CD19-negative leukemia with myeloid phenotype [8]. Our case is the first report of CD19 membrane negative (but dim cytoplasmic expression) relapse after CART-19 therapy in PMLBCL.…”

Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma

“…However, as seen in patients with leukemia who receive CD19 directed immunotherapy, antigen loss may prevent durable remissions (11,12). In this case, re-biopsy of the target lesions was instrumental in guiding further management.…”

Hematopoietic stem cell involvement in BCR-ABL1–positive ALL as a potential mechanism of resistance to blinatumomab therapy

“…In 13 (52%) of 25 patients, a second predominant pattern, referred to as "B-lineage-pattern," was identified in which BCR-ABL1 positivity was restricted to the B-lineage-determined CD34 are not a consequence of dedifferentiation or reprogramming. Jacoby et al 13 did not identify myeloid leukemic clones prior to therapy when they induced CD19…”