Chimeric antigen receptor T-cell therapy in multiple myeloma: A comprehensive review of current data and implications for clinical practice.

Multiple myeloma (MM) is a hematologic malignancy defined by the clonal proliferation of transformed plasma cells. Despite tremendous advances in the treatment paradigm of MM, a cure remains elusive for most patients. Although long-term disease control can be achieved in a very large number of patients, the acquisition of tumor resistance leads to disease relapse, especially in patients with triple-class refractory MM (defined as resistance to immunomodulatory agents, proteosome inhibitors, and monoclonal antibodies). There is an unmet need for effective treatment options in these patients. Chimeric antigen receptor (CAR) T-cell therapy is a novel approach that has demonstrated promising efficacy in the treatment of relapsed, refractory MM (RRMM). These genetically modified cellular 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 demonstrated remarkable response rates with CAR T-cell therapy in RRMM; however, durable responses with CAR T-cell therapies in myeloma have yet to be realized. In this comprehensive review, the authors describe the development of CAR T-cell therapies in myeloma, the outcomes of notable clinical trials, the toxicities and limitations of CAR T-cell therapies, and the strategies to overcome therapeutic challenges of CAR T cells in the hope of achieving a cure for multiple myeloma.

Discovery of a highly specific radiolabeled antibody targeting B-cell maturation antigen: Applications in PET imaging of multiple myeloma.

PURPOSE: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM. EXPERIMENTAL DESIGN: Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential. RESULTS: The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430. CONCLUSIONS: Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy.

Safety outcomes of teclistamab accelerated dose escalation.

INTRODUCTION: Teclistamab, a bispecific T-cell engaging antibody targeting B-cell maturation antigen (BCMA), is indicated for the treatment of relapsed or refractory multiple myeloma after at least four lines of therapy. It has boxed warnings for life threatening cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). To mitigate these risks, teclistamab is initiated using step-up doses. This article examines safety event rates following the implementation of a 2-day separation between step-up doses at one institution to streamline patient care. METHODS: This was a retrospective, single-center study encompassing all patients who received teclistamab within a 1-year period. The primary endpoint was the overall incidence of CRS and ICANS. Secondary endpoints included hospital length of stay, hematological toxicities, infection rates, among other adverse events. RESULTS: A total of 27 patients were included in the analysis and stratified into accelerated (days 1,3,5) or standard (days 1,4,7) dosing groups. CRS occurred in 48% (11) of patients for the accelerated dosing and 50% (2) for the standard dosing group. ICANS was seen in 17% (4) of patients in the accelerated dosing group and none in the standard dosing group. Average length of stay in the accelerated dose was 7.6 days versus 9.2 days in the standard dose group. CONCLUSION: Accelerated dose escalation of teclistamab yielded safety event rates comparable to those in the literature. These findings may support outpatient administration for teclistamab. Accelerated dose escalation strategy allowed for the optimization of hospitalization and resources.

In Vitro Functionality and Endurance of GMP-Compliant Point-of-Care BCMA.CAR-T Cells at Different Timepoints of Cryopreservation.

The search for target antigens for CAR-T cell therapy against multiple myeloma defined the B-cell maturation antigen (BCMA) as an interesting candidate. Several studies with BCMA-directed CAR-T cell therapy showed promising results. Second-generation point-of-care BCMA.CAR-T cells were manufactured to be of a GMP (good manufacturing practice) standard using the CliniMACS Prodigy® device. Cytokine release in BCMA.CAR-T cells after stimulation with BCMA positive versus negative myeloma cell lines, U266/HL60, was assessed via intracellular staining and flow cytometry. The short-term cytotoxic potency of CAR-T cells was evaluated by chromium-51 release, while the long-term potency used co-culture (3 days/round) at effector/target cell ratios of 1:1 and 1:4. To evaluate the activation and exhaustion of CAR-T cells, exhaustion markers were assessed via flow cytometry. Stability was tested through a comparison of these evaluations at different timepoints: d0 as well as d + 14, d + 90 and d + 365 of cryopreservation. As results, (1) Killing efficiency of U266 cells correlated with the dose of CAR-T cells in a classical 4 h chromium-release assay. There was no significant difference after cryopreservation on different timepoints. (2) In terms of endurance of BCMA.CAR-T cell function, BCMA.CAR-T cells kept their ability to kill all tumor cells over six rounds of co-culture. (3) BCMA.CAR-T cells released high amounts of cytokines upon stimulation with tumor cells. There was no significant difference in cytokine release after cryopreservation. According to the results, BCMA.CAR-T cells manufactured under GMP conditions exerted robust and specific killing of target tumor cells with a high release of cytokines. Even after 1 year of cryopreservation, cytotoxic functions were maintained at the same level. This gives clinicians sufficient time to adjust the timepoint of BCMA.CAR-T cell application to the patient's course of the underlying disease.

sBCMA Plasma Level Dynamics and Anti-BCMA CAR-T-Cell Treatment in Relapsed Multiple Myeloma.

BACKGROUND: Novel chimeric antigen receptor T-cells (CAR-T) target the B-cell maturation antigen (BCMA) expressed on multiple myeloma cells. Assays monitoring CAR-T cell expansion and treatment response are being implemented in clinical routine. METHODS: Plasma levels of soluble BCMA (sBCMA) and anti-BCMA CAR-T cell copy numbers were monitored in the blood, following CAR-T cell infusion in patients with relapsed multiple myeloma. sBCMA peptide concentration was determined in the plasma, applying a human BCMA/TNFRS17 ELISA. ddPCR was performed using probes targeting the intracellular signaling domains 4-1BB und CD3zeta of the anti-BCMA CAR-T construct. RESULTS: We report responses in the first five patients who received anti-BCMA CAR- T cell therapy at our center. Four patients achieved a complete remission (CR) in the bone marrow one month after CAR-T infusion, with three patients achieving stringent CR, determined by flow cytometry techniques. Anti-BCMA CAR-T cells were detectable in the peripheral blood for up to 300 days, with copy numbers peaking 7 to 14 days post-infusion. sBCMA plasma levels started declining one to ten days post infusion, reaching minimal levels 30 to 60 days post infusion, before rebounding to normal levels. CONCLUSIONS: Our data confirm a favorable response to treatment in four of the first five patients receiving anti-BCMA CAR-T at our hospital. Anti-BCMA CAR-T cell expansion seems to peak in the peripheral blood in a similar pattern compared to the CAR-T cell products already approved for lymphoma treatment. sBCMA plasma level may be a valid biomarker in assessing response to BCMA-targeting therapies in myeloma patients.

A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy.

IgA nephropathy (IgAN) is the most prevalent primary chronic glomerular disease for which no safe disease-specific therapies currently exist. IgAN is an autoimmune disease involving the production of autoantigenic, aberrantly O-glycosylated IgA1 and ensuing deposition of nephritogenic immune complexes in the kidney. A Proliferation Inducing Ligand (APRIL) has emerged as a key B-cell-modulating factor in this pathogenesis. Using a mouse anti-APRIL monoclonal antibody (4540), we confirm both the pathogenic role of APRIL in IgAN and the therapeutic efficacy of antibody-directed neutralization of APRIL in the grouped mouse ddY disease model. Treatment with 4540 directly translated to a reduction in relevant pathogenic mechanisms including suppressed serum IgA levels, reduced circulating immune complexes, significantly lower kidney deposits of IgA, IgG and C3, and suppression of proteinuria compared to mice receiving vehicle or isotype control antibodies. Furthermore, we translated these findings to the pharmacological characterization of VIS649, a highly potent, humanized IgG2κ antibody targeting and neutralizing human APRIL through unique epitope engagement, leading to inhibition of APRIL-mediated B-cell activities. VIS649 treatment of non-human primates showed dose-dependent reduction of serum IgA levels of up to 70%. A reduction of IgA+, IgM+, and IgG+ B cells was noted in the gut-associated mucosa of VIS649-treated animals. Population-based modeling predicted a favorable therapeutic dosing profile for subcutaneous administration of VIS649 in the clinical setting. Thus, our data highlight the potential therapeutic benefit of VIS649 for the treatment of IgAN.

TACI-dependent APRIL signaling maintains autoreactive B cells in a mouse model of systemic lupus erythematosus.

Autoantibodies contribute to the development of systemic lupus erythematosus (SLE). APRIL (a proliferation-inducing ligand), a member of the TNF superfamily, regulates plasma-cell survival and binds to TACI (transmembrane activator CAML interactor) and BCMA (B-cell maturation antigen). We previously showed that APRIL blockade delayed disease onset in lupus-prone mice. In order to evaluate the role of APRIL receptors in the development of SLE, APRIL, TACI, BCMA, or double TACI.BCMA null mutations were introduced into the Nba2.Yaa (Y-linked autoimmune acceleration) spontaneous lupus mouse model. Mortality as a consequence of glomerulonephritis (GN) was reduced in Nba2.APRIL-/- .Yaa, Nba2.TACI-/- .Yaa and double-KO mice compared with Nba2.Yaa mice and correlated with lower levels of circulating antibodies, while splenic populations remained unchanged. In contrast, the appearance of symptoms was accelerated in BCMA-deficient mice, in which TACI signaling was increased. Finally, lupus-prone mice deficient for the APRIL-TACI axis produced less pathogenic antibodies and developed less GN. Disease reduction was attributed to impaired T-independent type 2 responses when the APRIL-TACI signaling axis was disrupted. Collectively, our results have identified and confirmed APRIL as a new target involved in B-cell activation, in the maintenance of plasma cell survival and subsequent increased autoantibody production that sustains lupus development in mice.

Binding of B-cell maturation antigen to B-cell activating factor induces survival of multiple myeloma cells by activating Akt and JNK signaling pathways.

B-cell maturation antigen (BCMA) is expressed on normal and malignant plasma cells and represents a potential target for therapeutic intervention. In this study, we characterized the mechanism underlying the protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) pathways and BCMA interactions in regulating multiple myeloma (MM) cell survival. It was found that the expression levels of B cell-activating factor (BAFF) and BCMA were increased in MM cells as compared with those in normal controls. The proliferation of U266 cells was induced by recombinant human BAFF (rhBAFF) and could also be decreased by BCMA siRNA. The expression of Bcl-2 protein was up-regulated, and Bax protein was down-regulated after rhBAFF treatment, which could be reversed by BCMA siRNA. Similarly, the protein p-JNK and p-Akt were activated by rhBAFF and could be changed by BCMA siRNA. In addition, the BCMA mRNA and protein expression levels were decreased after treatment with Akt and JNK pathway inhibitors. These results suggest that Akt and JNK pathways are involved in the regulation of BCMA. A novel BAFF/BCMA signalling pathway in MM may be a new therapeutic target for MM.

Targeting B-cell maturation antigen for treatment and monitoring of relapsed/refractory multiple myeloma patients: a comprehensive review.

Despite major therapeutic advancements in recent years, multiple myeloma (MM) remains an incurable disease with nearly all patients experiencing relapsed and refractory disease over the course of treatment. Extending the duration and durability of clinical responses will necessitate the development of therapeutics with novel targets that are capable of robustly and specifically eliminating myeloma cells. B-cell maturation antigen (BCMA) is a membrane-bound protein expressed predominantly on malignant plasma cells and has recently been the target of several novel therapeutics to treat MM patients. This review will focus on recently approved and currently in development agents that target this protein, including bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cell therapies. In addition, this protein also serves as a novel serum biomarker to predict outcomes and monitor disease status for MM patients; the studies demonstrating this use of BCMA will be discussed in detail.

CAR NK92 Cells Targeting BCMA Can Effectively Kill Multiple Myeloma Cells Both In Vitro and In Vivo.

Multiple myeloma (MM) is a hematological malignancy caused by malignant proliferation of plasma cells in bone marrow. Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents. However, MM remains an incurable neoplastic plasma cell disorder. In addition, almost all MM patients inevitably relapse due to drug resistance. Chimeric antigen receptor (CAR)-modified NK cells represent a promising immunotherapeutic modality for cancer treatment. In this study, NK92 cells were engineered to express the third generation of BCMA CAR. In vitro, BCMA CAR-engineered NK92 cells displayed higher cytotoxicity and produced more cytokines such as IFN-γ and granzyme B than NK92 cells when they were co-cultured with MM cell lines. Furthermore, BCMA CAR-engineered NK92 cells released significantly higher amounts of cytokines and showed higher cytotoxicity when they were exposed to primary cells isolated from MM patients. The cytotoxicity of BCMA CAR NK92 cells was enhanced after MM cells were treated with bortezomib. Additionally, BCMA CAR NK92 cells exhibited potent antitumor activities in subcutaneous tumor models of MM. These results demonstrate that regional administration of BCMA CAR NK92 cells is a potentially promising strategy for treating MM.

T-cell redirecting bispecific antibody treatment in multiple myeloma: current knowledge and future strategies for sustained T-cell engagement.

INTRODUCTION: T-cell redirecting bispecific antibodies (BsAbs), targeting B-cell maturation antigen (BCMA) or G-protein - coupled receptor class C group 5 member D (GPRC5D), are efficacious new agents for the treatment of patients with relapsed or refractory MM. AREAS COVERED: This review discusses the pharmacokinetic properties, efficacy, and safety profile of T-cell redirecting BsAbs in MM, with a special focus on their optimal dosing schedule, resistance mechanisms and future strategies to enhance efficacy, reduce toxicity, and maximize duration of response. EXPERT OPINION: To further improve the efficacy of BsAbs, ongoing studies are investigating whether combination therapy can enhance depth and duration of response. An important open question is also to what extent response to BsAbs can be improved when these agents are used in earlier lines of therapy. In addition, more evidence is needed on rational de-intensification strategies of BsAb dosing upon achieving a sufficient response, and if (temporary) treatment cessation is possible in patients who have achieved a deep remission (e.g. complete response or minimal residual disease-negative status).

Multiple Myeloma: A Personal Account of My Journey With the Disease and Response to Teclistamab.

Multiple myeloma (MM) remains an incurable hematologic cancer leading to damage to the bone marrow that causes destructive bone lesions in addition to many other effects. I am a patient with MM who has undergone treatment to date since the diagnosis of this disease in December 2019. This paper reviews the treatments and observations made throughout this period. The salient results of such treatments are discussed in chronological order. During this period, my MM relapsed and then I was introduced to teclistamab treatment. The outcome of teclistamab treatment is quite promising, and I anticipate a longer life at a maintenance dose of this drug with a better quality of life. When writing this article, I am still receiving the teclistamab treatment cycles that maintain a constant normal level of my kappa-free light chain (FLC) and kappa/lambda ratio, with no significant side effects.

Cilta-cel, a BCMA-targeting CAR-T therapy for patients with multiple myeloma.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy, is approved in the United States and Europe for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy (LOT), including a proteasome inhibitor and an immunomodulatory drug, and are lenalidomide refractory. AREAS COVERED: We examine recent long-term data in heavily pretreated RRMM (LEGEND-2, CARTITUDE-1) and earlier LOTs (CARTITUDE-4) compared with standard therapy and discuss the rationale for investigating cilta-cel as frontline therapy for transplant-eligible and transplant-ineligible patients (CARTITUDE-5, CARTITUDE-6). EXPERT OPINION: CAR-T therapies can improve outcomes for patients with MM across different LOTs. CARTITUDE-1 and CARTITUDE-4 have set a new bar for efficacy, with median PFS of 34.9 months in heavily pretreated patients (CARTITUDE-1) and a 74% relative risk reduction for progression/death versus standard care in patients with 1-3 prior LOTs (CARTITUDE-4), with manageable safety. Response rates were consistent between the two studies: 98% in CARTITUDE-1 and approaching 100% for infused patients in CARTITUDE-4. Cilta-cel could be a key treatment choice for patients with RRMM after first LOT. Clinical trials investigating frontline cilta-cel therapy will provide valuable insights into optimizing treatment pathways with the aim to potentially cure MM.

Chimeric Antigen Receptor T Cells in the Treatment of Multiple Myeloma.

Chimeric antigen receptor T cells (CARTs) represent another powerful way to leverage the immune system to fight malignancy. Indeed, in multiple myeloma, the high response rate and duration of response to B cell maturation antigen-targeted therapies in later lines of disease has led to 2 Food and Drug Administration (FDA) drug approvals and opened the door to the development of this drug class. This review aims to provide an update on the 2 FDA-approved products, summarize the data for the most promising next-generation multiple myeloma CARTs, and outline current challenges in the field and potential solutions.

The preclinical discovery and clinical development of ciltacabtagene autoleucel (Cilta-cel) for the treatment of multiple myeloma.

INTRODUCTION: Despite remarkable therapeutic advances over the last two decades, which have resulted in dramatic improvements in patient survival, multiple myeloma (MM) is still considered an incurable disease. Therefore, there is a high need for new treatment strategies. Genetically engineered/redirected chimeric antigen receptor (CAR) T cells may represent the most compelling modality of immunotherapy for cancer treatment in general, and MM in particular. Indeed, unprecedented response rates have led to the recent approvals of the first two BCMA-targeted CAR T cell products idecabtagene-vicleucel ('Ide-cel') and ciltacabtagene-autoleucel ('Cilta-Cel') for the treatment of heavily pretreated MM patients. In addition, both are emerging as a new standard-of-care also in earlier lines of therapy. AREAS COVERED: This article briefly reviews the history of the preclinical development of CAR T cells, with a particular focus on Cilta-cel. Moreover, it summarizes the newest clinical data on Cilta-cel and discusses strategies to further improve its activity and reduce its toxicity. EXPERT OPINION: Modern next-generation immunotherapy is continuously transforming the MM treatment landscape. Despite several caveats of CAR T cell therapy, including its toxicity, costs, and limited access, prolonged disease-free survival and potential cure of MM are finally within reach.

CAR-T-Cell Therapy in Multiple Myeloma: B-Cell Maturation Antigen (BCMA) and Beyond.

Significant progress has been achieved in the realm of therapeutic interventions for multiple myeloma (MM), leading to transformative shifts in its clinical management. While conventional modalities such as surgery, radiotherapy, and chemotherapy have improved the clinical outcomes, the overarching challenge of effecting a comprehensive cure for patients afflicted with relapsed and refractory MM (RRMM) endures. Notably, adoptive cellular therapy, especially chimeric antigen receptor T-cell (CAR-T) therapy, has exhibited efficacy in patients with refractory or resistant B-cell malignancies and is now also being tested in patients with MM. Within this context, the B-cell maturation antigen (BCMA) has emerged as a promising candidate for CAR-T-cell antigen targeting in MM. Alternative targets include SLAMF7, CD38, CD19, the signaling lymphocyte activation molecule CS1, NKG2D, and CD138. Numerous clinical studies have demonstrated the clinical efficacy of these CAR-T-cell therapies, although longitudinal follow-up reveals some degree of antigenic escape. The widespread implementation of CAR-T-cell therapy is encumbered by several barriers, including antigenic evasion, uneven intratumoral infiltration in solid cancers, cytokine release syndrome, neurotoxicity, logistical implementation, and financial burden. This article provides an overview of CAR-T-cell therapy in MM and the utilization of BCMA as the target antigen, as well as an overview of other potential target moieties.

Chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma.

Although treatment outcomes of multiple myeloma patients have improved significantly during the last two decades, myeloma is still an incurable disease. There are newly emerging immunotherapies to treat multiple myeloma including monoclonal antibodies, antibody-drug conjugate, bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapy. Impressive response rate and clinical efficacy in heavily pretreated myeloma patients led to the FDA approval of the first myeloma CAR-T therapy in March 2021. Among many different targets for myeloma CAR-T therapies, B Cell Maturation Antigen (BCMA) has been the most successful target so far, but other targets which can be used either for single-target or dual-target CAR-T's are actively being explored. Clinical efficacy and safety of current myeloma CAR-T therapies will be presented here. Potential mechanisms leading to resistance include clearance of CAR-T cells, antigenic escape, and immunosuppressive tumor microenvironment. Novel strategies to enhance myeloma CAR-T will also be described. In this article, we provide a comprehensive review of the current data and the future directions of myeloma CAR-T therapies.

A comparative study of adjuvants effects on neonatal plasma cell survival niche in bone marrow and persistence of humoral immune responses.

The neonatal immune system is distinct from the immune system of older individuals rendering neonates vulnerable to infections and poor responders to vaccination. Adjuvants can be used as tools to enhance immune responses to co-administered antigens. Antibody (Ab) persistence is mediated by long-lived plasma cells that reside in specialized survival niches in the bone marrow, and transient Ab responses in early life have been associated with decreased survival of plasma cells, possibly due to lack of survival factors. Various cells can secrete these factors and which cells are the main producers is still up for debate, especially in early life where this has not been fully addressed. The receptor BCMA and its ligand APRIL have been shown to be important in the maintenance of plasma cells and Abs. Herein, we assessed age-dependent maturation of a broad range of bone marrow accessory cells and their expression of the survival factors APRIL and IL-6. Furthermore, we performed a comparative analysis of the potential of 5 different adjuvants; LT-K63, mmCT, MF59, IC31 and alum, to enhance expression of survival factors and BCMA following immunization of neonatal mice with tetanus toxoid (TT) vaccine. We found that APRIL expression was reduced in the bone marrow of young mice whereas IL-6 expression was higher. Eosinophils, macrophages, megakaryocytes, monocytes and lymphocytes were important secretors of survival factors in early life but undefined cells also constituted a large fraction of secretors. Immunization and adjuvants enhanced APRIL expression but decreased IL-6 expression in bone marrow cells early after immunization. Furthermore, neonatal immunization with adjuvants enhanced the proportion of plasmablasts and plasma cells that expressed BCMA both in spleen and bone marrow. Enhanced BCMA expression correlated with enhanced vaccine-specific humoral responses, even though the effect of alum on BCMA was less pronounced than those of the other adjuvants at later time points. We propose that low APRIL expression in bone marrow as well as low BCMA expression of plasmablasts/plasma cells in early life together cause transient Ab responses and could represent targets to be triggered by vaccine adjuvants to induce persistent humoral immune responses in this age group.

Idecabtagene vicleucel for relapsed/refractory multiple myeloma: a review of recent advances.

The introduction of new classes of drugs for the treatment of multiple myeloma (MM) in the past 2 decades, such as proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies, coupled with autologous stem cell transplantation, has approximately doubled the 5-year survival rate of MM patients. However, the patients eventually relapse and/or become resistant to the drugs and treatment. The recent emergence of anti-B-cell maturation antigen (BCMA) therapies, especially chimeric antigen receptor T-cell (CAR-T) immunotherapy targeting BCMA, holds great prospect in MM treatment. In this article, we review in detail the advances of idecabtagene vicleucel (ide-cel, bb-2121), the first CAR-T therapy targeting BCMA for treating relapse or refractory MM approved by the U.S. Food and Drug Administration (FDA) in 2021, including the preclinical study and phase I and II clinical trials. Also, it is predicted in this review that despite its amazing clinical efficacy and relatively lower toxicity, a lot of challenges and unsolved problems for ide-cel therapy remain in the way ahead.

Perspectives for the Use of CAR-T Cells for the Treatment of Multiple Myeloma.

During recent years considerable progress has been made in the treatment of multiple myeloma. However, despite the current improvements in the prognosis of this malignancy, it always ends with relapse, and therefore new therapy approaches for destroying resistant cancer cells are needed. Presently, there is great hope being placed in the use of immunotherapy against refractory/relapsed multiple myeloma which is unresponsive to any other currently known drugs. The most promising one is CAR-T cell therapy which has already shown tremendous success in treating other malignancies such as acute lymphoblastic leukaemia (ALL) and could potentially be administered to multiple myeloma patients. CAR-T cells equipped with receptors against BCMA (B-cell maturation antigen), which is a surface antigen that is highly expressed on malignant cells, are now of great interest in this field with significant results in clinical trials. Furthermore, CAR-T cells with other receptors and combinations of different strategies are being intensively studied. However, even with CAR-T cell therapy, the majority of patients eventually relapse, which is the greatest limitation of this therapy. Serious adverse events such as cytokine release syndrome or neurotoxicity should also be considered as possible side effects of CAR-T cell therapy. Here, we discuss the results of CAR-T cell therapy in the treatment of multiple myeloma, where we describe its main advantages and disadvantages. Additionally, we also describe the current results that have been obtained on using combinations of CAR-T cell therapies with other drugs for the treatment of multiple myeloma.