scholarly journals Keeping Myeloma in Check: The Past, Present and Future of Immunotherapy in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4787
Author(s):  
James Ackley ◽  
Miguel Armenta Ochoa ◽  
Delta Ghoshal ◽  
Krishnendu Roy ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Biology ◽  
Plasma Cells ◽  
Immune Therapy ◽  
Adoptive Cell Transfer ◽  
Cell Therapies ◽  
Chemical Structures ◽  
Drug Conjugates ◽  
Incurable Disease ◽  
Car T

Multiple myeloma is an incurable disease of malignant plasma cells and an ideal target for modern immune therapy. The unique plasma cell biology maintained in multiple myeloma, coupled with its hematological nature and unique bone marrow microenvironment, provide an opportunity to design specifically targeted immunotherapies that selectively kill transformed cells with limited on-target off-tumor effects. Broadly defined, immune therapy is the utilization of the immune system and immune agents to treat a disease. In the context of multiple myeloma, immune therapy can be subdivided into four main categories: immune modulatory imide drugs, targeted antibodies, adoptive cell transfer therapies, and vaccines. In recent years, advances in all four of these categories have led to improved therapies with enhanced antitumor activity and specificity. In IMiDs, modified chemical structures have been developed that improve drug potency while reducing dose limiting side effects. Targeted antibody therapies have resulted from the development of new selectively expressed targets as well as the development of antibody drug conjugates and bispecific antibodies. Adoptive cell therapies, particularly CAR-T therapies, have been enhanced through improvements in the manufacturing process, as well as through the development of CAR constructs that enhance CAR-T activation and provide protection from a suppressive immune microenvironment. This review will first cover in-class breakthrough therapies for each of these categories, as well as therapies currently utilized in the clinic. Additionally, this review will explore up and coming therapeutics in the preclinical and clinical trial stage.

scholarly journals Boosting Immunity against Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1221
Author(s):  
Raquel Lopes ◽  
Bruna Velosa Ferreira ◽  
Joana Caetano ◽  
Filipa Barahona ◽  
Emilie Arnault Carneiro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Proteasome Inhibitors ◽  
Treatment Strategies ◽  
Complete Response ◽  
Drug Conjugates ◽  
Incurable Disease ◽  
Car T ◽  
Patient’S Outcome ◽  
The Impact

Despite the improvement of patient’s outcome obtained by the current use of immunomodulatory drugs, proteasome inhibitors or anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. More recently, the testing in clinical trials of novel drugs such as anti-BCMA CAR-T cells, antibody–drug conjugates or bispecific antibodies broadened the possibility of improving patients’ survival. However, thus far, these treatment strategies have not been able to steadily eliminate all malignant cells, and the aim has been to induce a long-term complete response with minimal residual disease (MRD)-negative status. In this sense, approaches that target not only myeloma cells but also the surrounding microenvironment are promising strategies to achieve a sustained MRD negativity with prolonged survival. This review provides an overview of current and future strategies used for immunomodulation of MM focusing on the impact on bone marrow (BM) immunome.

scholarly journals Antibody-drug conjugates in clinical trials for lymphoid malignancies and multiple myeloma

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Bo Yu ◽  
Delong Liu
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Plasma Cells ◽  
Immune Therapy ◽  
Brentuximab Vedotin ◽  
Antibody Drug Conjugates ◽  
Lymphoid Malignancies ◽  
Drug Conjugates ◽  
Promising Treatment ◽  
Antibody Drug

Abstract Antibody-drug conjugates (ADC) represent a distinct family of chemoimmunotherapy agents. ADCs are composed of monoclonal antibodies conjugated to cytotoxic payloads via specialized chemical linkers. ADCs therefore combine the immune therapy with targeted chemotherapy. Due to the distinct biomarkers associated with lymphocytes and plasma cells, ADCs have emerged as a promising treatment option for lymphoid malignancies and multiple myeloma. Several ADCs have been approved for clinical applications: brentuximab vedotin, inotuzumab ozogamicin, moxetumomab pasudotox, and polatuzumab vedotin. More novel ADCs are under clinical development. In this article, we summarized the general principles for ADC design, and updated novel ADCs under various stages of clinical trials for lymphoid malignancies and multiple myeloma.

The emergence of b-cell maturation antigen (BCMA) targeting immunotherapy in multiple myeloma

2022 ◽  
pp. 107815522110735
Author(s):  
James A. Davis ◽  
Abigail Shockley ◽  
Hamza Hashmi
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Efficacy And Safety ◽  
Cell Therapies ◽  
Antibody Drug Conjugates ◽  
Car T Cell ◽  
Drug Conjugates ◽  
B Cell Maturation ◽  
Car T ◽  
Antibody Drug

Objective Multiple myeloma, a plasma cell neoplasm is the second most common hematological malignancy in the United States. Despite significant advances in treatment armamentarium over the last decade, multiple myeloma remains an incurable malignancy. B-cell maturation antigen (BCMA) is an antigen expressed on the surface on plasma cells that can be targeted by novel mechanisms of action including antibody-drug conjugates (ADCs), bispecific T-cell engagers, and chimeric antigen receptor (CAR) T-cell therapy. This review summarizes the clinical application and development of approved and investigational immunotherapies targeting BCMA. Data Sources A search of the PubMed database was conducted using the following search terms: BCMA, CAR T, myeloma, belantamab mafodotin, and bispecific. Ongoing clinical trials, as well as abstracts from ASH and ASCO evaluating the efficacy and safety of novel agents targeting BCMA were evaluated. Prescribing information was also reviewed. Data Summary Since the discovery of BCMA as a target for myeloma, researchers have developed antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies as novel treatment modalities for myeloma patients. Belantamab mafodotin and idecabtagene vicleucel represent currently available therapies and ongoing trials have demonstrated the efficacy and safety of bispecifics and other BCMA targeting therapies. Conclusion BCMA targeting antibody drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies have demonstrated clinical activity in myeloma patients and represent novel therapies in multiple myeloma treatment paradigm.

scholarly journals Decades of Progress in Allogeneic Stem Cell Transplantation for Multiple Myeloma

Hemato ◽  
2021 ◽  
Vol 2 (1) ◽  
pp. 89-102
Author(s):  
Benedetto Bruno ◽  
Giuseppe Lia ◽  
Francesca Bonifazi ◽  
Luisa Giaccone
Keyword(s):  
Multiple Myeloma ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Long Term Outcomes ◽  
Cell Therapies ◽  
Car T Cells ◽  
Incurable Disease ◽  
Car T ◽  
Risk Patients

Allogeneic hematopoietic cell transplantation in multiple myeloma has evolved over the decades. Myeloablative regimens have been replaced by the reduced intensity and non-myeloablative conditionings to reduce treatment-related toxicity and mortality while sparing graft-vs.-myeloma effects. Newer agents with potent anti-myeloma activity are not mutually exclusive and the combination with an allograft may improve long-term outcomes in this incurable disease especially in high-risk patients. Allografting may also be a platform for other promising new cell therapies such as CAR T-cells, NK-, and CAR NK-cells. These studies are warranted in the context of clinical trials. This review highlights the progress that has been made over the decades and possible future roles of allografting in the treatment landscape of multiple myeloma.

Emerging immunotherapies in multiple myeloma

BMJ ◽  
2020 ◽  
pp. m3176
Author(s):  
Urvi A Shah ◽  
Sham Mailankody
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell Transplant ◽  
Plasma Cells ◽  
Checkpoint Inhibitors ◽  
Cell Transplant ◽  
The Past ◽  
Drug Conjugates ◽  
Incurable Disease ◽  
B Cell Maturation ◽  
Emerging Treatments

ABSTRACT Despite considerable advances in treatment approaches in the past two decades, multiple myeloma remains an incurable disease. Treatments for myeloma continue to evolve with many emerging immunotherapies. The first immunotherapy used to treat hematologic cancers, including multiple myeloma, was an allogeneic stem cell transplant. In the mid-2000s, immunomodulatory drugs thalidomide, lenalidomide, and subsequently pomalidomide were proven to be effective in multiple myeloma and substantially improved survival. The next wave of immunotherapies for multiple myeloma included the monoclonal antibodies daratumumab and elotuzumab, which were approved by the Food and Drug Administration in 2015. Subsequently, a variety of immunotherapies have been developed for multiple myeloma, including chimeric antigen receptor T cells, bispecific antibodies, antibody drug conjugates, and checkpoint inhibitors. Many of these emerging treatments target the B cell maturation antigen, which is expressed on plasma cells, although several other novel receptors are also being studied. This review summarizes the evidence of these various immunotherapies, their mechanism of action, and data from clinical trials regarding the treatments’ safety and efficacy.

scholarly journals Chimeric antigen receptor T-cell therapies for multiple myeloma

Blood ◽  
2017 ◽  
Vol 130 (24) ◽  
pp. 2594-2602 ◽  
Author(s):  
Lekha Mikkilineni ◽  
James N. Kochenderfer
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Maturation ◽  
Cell Therapies ◽  
B Cell Maturation ◽  
Car T ◽  
B Cell Maturation Antigen

Abstract Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR-T cells (CAR-Ts) against leukemia and lymphoma has encouraged development of CAR-T therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen is expressed by normal and malignant plasma cells. CAR-Ts targeting B-cell maturation antigen have demonstrated significant antimyeloma activity in early clinical trials. Toxicities in these trials, including cytokine release syndrome, have been similar to toxicities observed in CAR-T trials for leukemia. Targeting postulated CD19+ myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte–activating molecule 7, and κ light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of >1 antigen might often be required for effective treatment of MM with CAR-Ts. Integration of CAR-Ts with other myeloma therapies is an important area of future research. CAR-T therapies for MM are at an early stage of development but have great promise to improve MM treatment.

scholarly journals BCMA-targeted immunotherapy for multiple myeloma

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Bo Yu ◽  
Tianbo Jiang ◽  
Delong Liu
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Targeted Therapeutics ◽  
Treatment Target ◽  
Drug Conjugates ◽  
B Cell Maturation ◽  
Novel Treatment ◽  
Physiological Properties ◽  
Car T ◽  
Selective Expression

Abstract B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development.

scholarly journals An Overview of CAR T Cell Mediated B Cell Maturation Antigen Therapy

2021 ◽  
Author(s):  
Sameer Quazi
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
T Cell ◽  
Bispecific Antibody ◽  
Plasma Cells ◽  
Car T Cell ◽  
B Cell Maturation ◽  
Car T ◽  
Value Association ◽  
Made In

Multiple Myeloma (MM) is one of the incurable types of cancer in plasma cells. While immense progress has been made in the treatment of this malignancy, a large percentage of patients were unable to adapt to such therapy. Additionally, these therapies might be associated with significant diseases and are not always tolerated well in all patients. Since cancer in plasma cells has no cure, patients develop resistance to treatments, resulting in R/R MM. BCMA is primarily produced on mature B cells. Its up-regulation and activation are associated with multiple myeloma in both murine and human models, indicating that this might be an effective therapeutic target for this type of malignancy. Additionally, BCMA's predictive value, association with effective clinical trials, and capacity to be utilized in previously difficult to observe patient populations, imply that it might be used as a biomarker for multiple myeloma. Numerous kinds of BCMA-targeting medicines have demonstrated antimyeloma efficacy in individuals with refractory/relapsed MM, including CAR T-cell treatments, ADCs, bispecific antibody constructs. Among these medications, CART cell-mediated BCMA therapy has shown significant outcomes in multiple myeloma clinical trials. This review article outlines CAR T cell mediated BCMA medicines have the efficiency to change the therapeutic pattern for multiple myeloma significantly.

scholarly journals Enhancing co-stimulation of CAR T cells to improve treatment outcomes in solid cancers

2021 ◽  
Author(s):  
Aaron J Harrison ◽  
Xin Du ◽  
Bianca von Scheidt ◽  
Michael H Kershaw ◽  
Clare Y Slaney
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
Tumour Microenvironment ◽  
Solid Tumours ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Co-stimulation is a fundamental component of T cell biology and plays a key role in determining the quality of T cell proliferation, differentiation and memory formation. T cell-based immunotherapies, such as chimeric antigen receptor (CAR) T cell immunotherapy, are no exception. Solid tumours have largely been refractory to CAR T cell therapy owing to an immunosuppressive microenvironment which limits CAR T cell persistence and effector function. In order to eradicate solid cancers, increasingly sophisticated strategies are being developed to deliver these vital co-stimulatory signals to CAR T cells, often specifically within the tumour microenvironment. These include designing novel co-stimulatory domains within the CAR or other synthetic receptors, arming CAR T cells with cytokines or using CAR T cells in combination with agonist antibodies. This review discusses the evolving role of co-stimulation in CAR T cell therapies and the strategies employed to target co-stimulatory pathways in CAR T cells, with a view to improve responses in solid tumours.

scholarly journals Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 15 ◽  
Author(s):  
Francesca Bonello ◽  
Roberto Mina ◽  
Mario Boccadoro ◽  
Francesca Gay
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Plasma Cells ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Promising Target ◽  
Therapeutic Monoclonal Antibodies ◽  
Antibody Drug

Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs®), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation.

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