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iNature
Multiple myeloma (MM) is a hematologic malignancy
defined by clonal proliferation of transformed plasma cells.
Despite tremendous advances in treatment models for MM, a cure remains elusive for most patients
.
While long-term disease control can be achieved in a very large number of patients, acquiring tumor resistance can lead to disease recurrence, particularly in patients
with three classes of refractory MM, defined as resistance to immunomodulators, proteosome inhibitors, and monoclonal antibodies.
The need for effective treatment options in these patients has not been met
.
Chimeric antigen receptor (CAR) T cell therapy is a new treatment that has shown good efficacy
in the treatment of refractory MM (RRMM).
These transgenic cell therapies have demonstrated deep and durable remissions in other B-cell malignancies, and current efforts aim to achieve similar results
in patients with RRMM.
Early studies have shown that CAR-T cell therapy has a significant efficacy rate in RRMM
.
However, the long-lasting efficacy of CAR-T cell therapy in myeloma has not been achieved
.
On January 10, 2023, Rujul H.
Parikh's research group at Emory University published an online report entitled " Chimeric antigen receptor T-cell therapy in multiple myeloma: A comprehensive review of current data and implications for clinical practice In this comprehensive review, the authors describe the development of CAR-T cell therapy for myeloma, significant clinical trial results, toxicity and limitations of CAR T cell therapy, and strategies to overcome CAR-T cell therapy challenges in hopes of curing multiple myeloma
.
.
In the United States, the 5-year survival rate is 56%, and increased understanding of disease biology, combined with advances in treatment, has led to improvements
in disease control and survival over the past decade.
Induction therapy with novel proteosome inhibitors such as bortezomib, immunomodulators such as lenalidomide, and monoclonal antibodies (MoAbs) such as daratumumab has improved survival and quality of life
in patients with newly diagnosed MM.
Follow-up therapy autologous stem cell transplantation (ASCT) and maintenance therapy further deepened the response and prolonged survival
.
In the real-world setting, induction with lenalidomide, bortezomib, and dexamethasone (RVd) triple therapy, followed by ASCT and risk adaptation maintenance, showed an impressive strict complete response (sCR) rate of approximately 33%.
However, for many patients, MM eventually progresses with
standard care.
Patients receiving multiple combination regimens develop drug resistance, which eventually leads to disease recurrence
.
The treatment of relapsed refractory MM (RRMM), particularly in patients with high-risk disease, remains a clinical challenge, and new immunotherapies have been shown to be effective in patients who do not respond to
standard therapies.
Engineered chimeric antigen receptor (CAR) T-cell therapies offer promising results for RRMM, improving patient survival and remission
even after standard therapy failure.
However, the plateau of the PFS curve remains elusive
.
This review summarizes the principles of CAR-T cell therapy, the current structure of CAR-T cells in multiple myeloma, the toxicity of CAR-T cell therapy, and overcoming CAR T cell therapy failures and resistance patterns.
Figure 1.
(left) for basic CAR-T cell structures, (right) for myeloma cells (CA-A Cancer Journal for Clinicians) Immunotherapy brings different prospects
for the treatment model of multiple myeloma 。 FDA-approved MoAbs daratumumab, elotuzumab, and isatuximab have changed the standard of care for myeloma treatment, even in frontline settings
.
The use of allogeneic stem cell transplantation shows modest potential
for immune system control of MM.
However, their efficacy is limited by excessive toxicity and a similar risk of recurrence to other therapies such as CAR-T cell therapy, antibody-drug conjugates, and bispecific T cell zygotes, which show great promise in altering the prospect of RRMM and that the use of CAR T cells in myeloma is influenced by their use in other B-cell lymphocytic malignancies such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL)) Inspired
by remarkable success.
In a phase I trial of 51 patients with relapsed B-cell ALL, CD19-targeted CAR-T cell therapy achieved a complete response rate of 83%, median event-free survival of 6.
1 months, median OS of 12.
9 months, and a median follow-up of 29 months Studies that detected CD19-directed CAR-T cell therapy in relapsed DLBCL10 and relapsed chronic lymphocytic leukemia saw equally impressive results
。 However, CAR-T cell therapy for myeloma is still in its early stages, but trials to date have replicated the promising early success
seen in other lymphoid malignancies.
Figure 2.
CAR - T cell manufacturing process, collecting PB leukocytes from patients by leukoplasma, enriching T lymphocytes, and performing genetic modifications to express the CAR of interest (CA-A Cancer Journal for Clinicians) Overall, innovative strategies to improve the efficacy, persistence, and mitigation of tumor cell resistance mechanisms in CAR cells are critical
to further improving outcomes.
The results of the ongoing study of novel CAR-T cell structures targeting other myeloma cell antigens are pending
.
The potential of allogeneic CAR-T cells to overcome many of the manufacturing and logistical limitations of traditional autologous CAR-T cell therapies is also promising
.
Original link: https://acsjournals.
onlinelibrary.
wiley.
com/doi/full/10.
3322/caac.
21771
—END—
The content is [iNature]
