Failure of ALL recognition by CAR T cells: a review of CD 19-negative relapses after anti-CD 19 CAR-T treatment in B-ALL

Abstract

The use of chimeric antigen receptor (CAR) T lymphocytes in the treatment of refractory or relapsed (R/R) B cell acute lymphoblastic leukemia (B-ALL) has meant a radical change in the prognosis of these patients, whose chances of survival with conventional treatment are very low. The current probability of event-free survival by R/R B-ALL patients treated using anti-CD 19 CART cell therapy is as high as 50-60% at 1.5 years, which is a very important advance for this group of very ill patients. Although most patients (70 to 94%) achieve complete remission (CR), the main problem continues to be relapse of the disease. Most relapses, both in clinical trials and real-world evidence, are due to failure of CAR-T cell expansion or limited CAR-T persistence. However, despite the adequate functioning of infused CART lymphocytes, the tumor cells of an important group of patients manage to evade CAR-T attack, resulting in a CD 19-negative relapse. Several mechanisms have been described that may be able to produce the escape of leukemic cells, such as acquired mutations and alternative splicing of the CD19 antigen, CD19 epitope loss or masking, leukemia lineage switching, and trogocytosis. In the present review, we comprehensively analyze the leukemic cell escape mechanisms, the incidence of CD19-negative relapse reported in clinical trials and real-world evidence (outside clinical trials), and provide an update on the main lines of current research into the prevention of leukemia evasion.

Clinicopathologic features of relapsed CD19(−) B‐ALL in CD19‐targeted immunotherapy: Biological insights into relapse and LILRB1 as a novel B‐cell marker for CD19(−) B lymphoblasts

“…10,[14][15][16][17][18][19][20] CD19 negativity may result from alternatively spliced CD19 isoforms with the compromise or loss of CART-19 epitope and reduced mRNA transcription. 17,18,12,30 Lineage switch from B-ALL to post-CART myeloid leukemia has been reported in patients with KMT2A or ZNF384 rearrangement under anti-CD19 immunotherapy pressure. 20,31 No case in our cohort had a myeloid lineage switch or carried KMT2A or ZNF384 rearrangement.…”

“…Several mechanisms have been described, including loss of CD19 expression, lineage switch, and selective expansions of preexisting non‐targeted tumor cells 10,14–20 . CD19 negativity may result from alternatively spliced CD19 isoforms with the compromise or loss of CART‐19 epitope and reduced mRNA transcription 17,18,12,30 . Lineage switch from B‐ALL to post‐CART myeloid leukemia has been reported in patients with KMT2A or ZNF384 rearrangement under anti‐CD19 immunotherapy pressure 20,31 .…”

“…Despite a high initial response rate, approximately 50% of patients ultimately relapse with either CD19(+) B‐ALL or CD19(−) B‐ALL 8–10 . The CD19(+) relapses are thought to be inherent to the CART‐cells' inability to expand and/or persist in circulation, whereas CD19(−) relapses are thought to be caused by evasive mechanisms inherent to leukemia typically occurring in the presence of functioning CART‐cells 11–13 . CD19(−) relapses carry a worse prognosis, and the mechanism for emergence of CD19(−) B‐ALL relapse has been a topic of active investigation.…”

“…CART-cells' inability to expand and/or persist in circulation, whereas CD19(À) relapses are thought to be caused by evasive mechanisms inherent to leukemia typically occurring in the presence of functioning CART-cells. [11][12][13] CD19(À) relapses carry a worse prognosis, and the mechanism for emergence of CD19(À) B-ALL relapse has been a topic of active investigation. Several mechanisms have been proposed, including loss of CD19 expression, lineage switch, and selective expansions of preexisting non-targeted tumor cells.…”

Enhanced potency of immunotherapy against B‐cell precursor acute lymphoblastic leukemia by combination of an Fc‐engineered CD19 antibody and CD47 blockade

“…However, CD19-targeted therapy also has limitations, including a substantial amount of patients nonresponding despite CD19-positivity, 6 nonsustained remission phases, 7 and antigen escape leading to CD19-negative relapse. 8 There are specific patient subgroups particularly prone to these phenomena, for example, patients with KMT2A-rearranged leukemias, which may acquire resistance to CD19-targeted therapies by lineage switch. 9 Some of these barriers can potentially be tackled by making CD19directed antibody therapy more efficient and thereby causing deeper levels of remission in shorter amounts of time.…”