ABSTRACTDespite 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.
This Viewpoint offers strategies to help shift to plant-based diets to reduce climate change and promote individual health by encouraging patients, incorporating the environmental impact of food ...choices in national dietary guidelines, and adding plant-based nutrition training in medical schools.
Summary
The B7‐CD28 family of ligands and receptors play important roles in T‐cell co‐stimulation and co‐inhibition. Phylogenetically they can be divided into three groups. The recent discovery of ...the new molecules (B7‐H3 CD276, B7x B7‐H4/B7S1, and HHLA2 B7H7/B7‐H5/TMIGD2 IGPR‐1/CD28H) of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure, and function of B7‐H3, B7x, HHLA2, and TMIGD2 in immune regulation. We also discuss their roles in important pathological states such as cancers, autoimmune diseases, transplantation, and infection. Various immunotherapeutical approaches are emerging including antagonistic monoclonal antibodies and agonistic fusion proteins to inhibit or potentiate these molecules and pathways in cancers and autoimmune diseases.
GPRC5D-Targeted CAR T Cells for Myeloma Mailankody, Sham; Devlin, Sean M.; Landa, Jonathan ...
The New England journal of medicine,
09/2022, Letnik:
387, Številka:
13
Journal Article
Recenzirano
In an early-phase study involving 17 patients with highly refractory multiple myeloma, CAR T-cell therapy with specificity for a G protein–coupled receptor that is expressed on myeloma cells produced ...a response in 71% of the patients.
CAR T and CAR NK cells in multiple myeloma: Expanding the targets Shah, Urvi A.; Mailankody, Sham
Baillière's best practice and research in clinical haematology/Baillière's best practice & research. Clinical haematology,
03/2020, Letnik:
33, Številka:
1
Journal Article
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Odprti dostop
Multiple myeloma (MM) is a haematologic malignancy with significant improvements in the overall survival over the last decade. However, patients still relapse and die due to a lack of treatment ...options. Ultimately, novel therapies with the potential for long term remissions are needed for patients with advanced MM. Research efforts for such immune therapies were not successful until recently when the first immunotherapies for MM were approved in 2015 and many more are under development. In this review, we focus on adoptive cell therapies including CAR T-cell and CAR NK-cell therapies for patients with MM. We will provide an update on clinical and translational advances with a focus on results from ongoing clinical trials with BCMA targeted cellular therapies and the development of other novel targets, changes in the manufacturing process, trials focusing on earlier lines of therapy and combinations with other therapies as well as off the shelf products.
Multiple myeloma (MM) remains an incurable plasma cell malignancy. Although little is known about the etiology of MM, several metabolic risk factors such as obesity, diabetes, poor nutrition, many of ...which are modifiable, have been linked to the pathogenesis of numerous neoplasms including MM. In this article, we provide a detailed summary of what is known about the impact of obesity on the pathogenesis of MM, its influence on outcomes in MM patients, and discuss potential mechanisms through which obesity is postulated to influence MM risk and prognosis. Along with advancements in treatment modalities to improve survival in MM patients, focused efforts are needed to prevent or intercept MM at its earliest stages. The consolidated findings presented in this review highlight the need for clinical trials to assess if lifestyle modifications can reduce the incidence and improve outcomes of MM in high-risk populations. Data generated from such studies can help formulate evidence-based lifestyle recommendations for the prevention and control of MM.
Adult T-cell leukemia lymphoma (ATLL) is a rare T cell neoplasm that is endemic in Japanese, Caribbean, and Latin American populations. Most North American ATLL patients are of Caribbean descent and ...are characterized by high rates of chemo-refractory disease and worse prognosis compared with Japanese ATLL. To determine genomic differences between these 2 cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results with the Japanese ATLL cases. Although the frequency of TP53 mutations was comparable, the mutation frequency in epigenetic and histone modifying genes (57%) was significantly higher, whereas the mutation frequency in JAK/STAT and T-cell receptor/NF-κB pathway genes was significantly lower. The most common type of epigenetic mutation is that affecting EP300 (20%). As a category, epigenetic mutations were associated with adverse prognosis. Dissimilarities with the Japanese cases were also revealed by RNA sequencing analysis of 9 primary patient samples. ATLL samples with a mutated EP300 gene have decreased total and acetyl p53 protein and a transcriptional signature reminiscent of p53-mutated cancers. Most importantly, decitabine has highly selective single-agent activity in the EP300-mutated ATLL samples, suggesting that decitabine treatment induces a synthetic lethal phenotype in EP300-mutated ATLL cells. In conclusion, we demonstrate that North American ATLL has a distinct genomic landscape that is characterized by frequent epigenetic mutations that are targetable preclinically with DNA methyltransferase inhibitors.
•North American ATLL has a distinct genomic landscape with a high frequency of prognostic epigenetic mutations, including EP300 mutations.•ATLL samples with mutated EP300 have compromised p53 function and are selectively sensitive to decitabine treatment.
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•In a cohort of 79 patients relapsing after BCMA-directed CAR T, multiple lines of salvage therapy led to a median overall survival of 17.9 months.•In 35 patients who received a subsequent ...T-cell-engaging therapy (CAR T or bispecific antibody), the response rate was 91.4% and median overall survival was not reached.
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B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and now there are two US Food and Drug Administration–approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied, and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions, who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post–CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T therapy was 17.9 months (95% confidence interval CI, 14.0 non-estimable). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five patients (44.3%) received a T-cell–engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients who received subsequent T-cell–engaging therapy was not reached after a median follow up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T-cell–engaging therapies appear to maintain pronounced clinical activity in this setting.
Targeting BCMA in Multiple Myeloma Tan, Carlyn Rose; Shah, Urvi A.
Current hematologic malignancy reports,
10/2021, Letnik:
16, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Purpose of Review
Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a significant number of patients still progress on current available therapies. Here, we ...review treatment modalities used to target BCMA in the treatment of MM, specifically antibody-drug conjugates (ADC), bispecific antibody constructs, and chimeric antibody receptor (CAR) modified T-cell therapies. We will provide an overview of therapies from these classes that have presented or published clinical data, as well as data on mechanisms of resistance to these novel agents.
Recent Findings
Clinical trials exploring different BCMA-targeting modalities to treat multiple myeloma are underway and demonstrate promising results. In relapsed/refractory multiple myeloma, anti-BCMA ADCs and bispecific antibody constructs are showing impressive efficacy with manageable side effect profiles. In parallel, adoptive cellular therapy has induced dramatic durable responses in multiply relapsed and refractory myeloma patients.
Summary
Therapeutic approaches targeting BCMA hold significant potential in the management of multiple myeloma and will soon be incorporated in combination with current standard therapies to improve outcomes for patients with multiple myeloma. In addition, novel approaches are being evaluated to overcome resistance mechanisms to anti-BCMA therapies.