CAR-T cells in multiple myeloma: current status

Abstract

SummaryStarting with the approval of bortezomib, a proteasome-inhibiting drug, tremendous progress has been achieved in the treatment of multiple myeloma (MM) patients during the last 15 years. Due to a plethora of novel drugs such as second generation proteasome inhibitors, immunomodulating agents and monoclonal antibodies the 5‑year survival of MM patients has been extended from 33% at the turn of the millennium to approximately 60% in younger patients (<65–70 years) who were eligible for consolidation with high-dose chemotherapy and autologous stem cell transplantation. Unfortunately, virtually all patients suffer from relapse and ultimately succumb to the disease, indicating the need for additional treatment strategies. Currently there are two promising immunologic approaches. First, bispecific antibodies called BITE (bispecific T-cell enhancer), which act as fusion proteins with two single-chain variable fragments, target antigens on malignant cells and bind the CD3 receptor and thereby recruit T‑cells to the target cells. The second strategy is chimeric antigen receptor (CAR) engineered T‑cell therapy that attacks myeloma cells by recognizing specific targets such as CD138, BCMA (B-cell maturation antigen), light-chains, SLAM-F7 (signaling lymphocytic activation molecule family member 7) or the pan B‑cell antigen CD19.Several early phase clinical trials show encouraging results in patients who have relapsed after modern treatment including proteasome inhibitors, immunomodulating drugs and monoclonal antibodies. Here, we briefly summarize current clinical knowledge about CAR‑T cell treatment in multiple myeloma, including clinical data presented at the 61st American Society of Hematology annual meeting held in December 2019 in Orlando.

CAR T-cell therapy in multiple myeloma: more room for improvement

“…The underlying mechanisms for therapeutic resistance have remain largely unclear, but tumor heterogeneity, and antigen escape have been implicated 50 .…”

“…For BCMA antigen escape, one of the most well-described ways is the erroneous physiology of the BCMA antigen. BCMA can be inadvertently transferred from tumors to T cells in a process called trogocytosis, causing T-cell fatricide 3 , 50 or it can be shed into the blood circulation (now called serum BCMA (sBCMA)), mediated by γ-secretase 47 . Both can cause dampening of tumor cell recognition 38 , 54 .…”

CAR-T cells for the treatment of relapsed/refractory multiple myeloma in 2022: efficacy and toxicity

“…The exposure of BCMA-positive tumor cells to BCMA-directed CAR T-cells leads to selection of those tumor cells with lower expression of BCMA and therefore to resistance against CAR-T cells [66]. One of the possible explanations of BCMA antigen escape is the process called trogocytosis-BCMA can be transferred from tumors to T-cells causing T-cell fratricide [67]. Or it can be shed in the blood circulation which is mediated by -secretase [68].…”

Novel Therapies in BCMA-exposed Relapsed/Refractory Multiple Myeloma: The Anti-BCMA Therapy-refractory Patient

“…as two likely culprits. 8,9 Understanding these potential mechanisms can aid in physicians' decisions to initiate subsequent treatment with either a regimen that re-challenges anti-BCMA therapy or one that utilizes another target entirely.…”