Targeting B-cell maturation antigen with GSK2857916 antibody–drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial

Trudel, Suzanne; Lendvai, Nikoletta; Popat, Rakesh; Voorhees, Peter M.; Reeves, Brandi; Libby, Edward N.; Richardson, Paul G.; Anderson, Larry D.; Sutherland, Heather J.; Yong, Kwee; Hoos, Axel; Gorczyca, Michele; Lahiri, Soumi; He, Z.C.; Austin, Daren; Opalinska, Joanna; Cohen, Adam D.

doi:10.1016/s1470-2045(18)30576-x

Cited by 209 publications

(253 citation statements)

References 31 publications

(50 reference statements)

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“…Approval of anti‐BCMA CAR T cells for commercial use is expected and will address an unmet need, but CAR T cells will join a crowded field of existing and emerging agents for relapsed/refractory myeloma. For example, targeting BCMA with antibody‐drug conjugates and BiTEs is also effective. It is uncertain whether CAR T cells are superior to these alternative approaches, whether these various BCMA‐directed modalities induce cross‐resistance to each other, and how the relative efficacy, toxicity, and logistical complexity of these competing therapies balance.…”

Section: Resultsmentioning

confidence: 99%

Chimeric antigen receptor T cell immunotherapy for multiple myeloma: A review of current data and potential clinical applications

2019

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Multiple myeloma (MM) is a malignant plasma cell disorder that remains incurable for most patients despite significant improvements achieved with modern therapy. Tumor evasion is a key process in the pathogenesis of MM and a compromised immune system is associated with more aggressive forms of the disease. In contrast, the emergence of myeloma‐specific immune responses after both autologous and allogeneic stem cell transplantation is associated with better prognosis. Adoptive T cell therapies may improve specific anti‐myeloma immunity resulting in long‐lasting remissions. CAR T cell therapies for MM are at an early stage of clinical development. To date, anti‐BCMA CAR T cells have shown the greatest results in early‐phase clinical trials. Toxicities have included cytokine release syndrome (CRS) and neurotoxicity. Current areas of research in CAR T cell therapies include the use of gene‐editing to enhance their effectiveness and safety, the integration of CAR T cells with other therapies (immunomodulatory drugs, checkpoint inhibitors) and CAR T cells to target multiple antigens.

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Section: Resultsmentioning

confidence: 99%

Chimeric antigen receptor T cell immunotherapy for multiple myeloma: A review of current data and potential clinical applications

2019

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“…In 2018, the results of a first in-human phase I study investigating GSK2857916, a BCMA-targeting mAb conjugated to the antimitotic agent monomethyl auristatin F (MMAF), in 73 RRMM patients were published. BCMA, a transmembrane receptor required for B cell maturation, was chosen as an optimal target, as it is expressed almost exclusively on MM cells and plasma cells [104][105][106]. In the dose-escalation phase of the study, 38 patients received escalating doses of IV GSK2857916 (0.03-4.6 mg/kg) every 3 weeks.…”

Section: Rationalementioning

confidence: 99%

“…The most common treatment-related toxicities were thrombocytopenia (63%; grades 3-4: 26%) and corneal events in terms of blurred vision and photophobia (51%; grades 3-4: 3%). Ocular toxicity was mainly limited to grades 1-2 and was reversible and easily manageable with dose reductions (51% of patients) [104,106]. Because GSK285791 showed high ORR in patients previously treated with anti-CD38 mAbs, a phase I/II clinical trial exploring its efficacy as monotherapy in patients with previous exposure to daratumumab/isatuximab has recently completed enrollment and results will soon be available (NCT03525678).…”

Section: Rationalementioning

confidence: 99%

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

Bonello

Mina

Boccadoro

2019

Cancers

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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.Cancers 2020, 12, 15 2 of 24 Cancers 2020, 12, 15 3 of 24 (Bregs, which promote tumor growth and immune escape), as well as a subset of regulatory T cells (Tregs) express CD38, and their levels are reduced after daratumumab exposure. Conversely, daratumumab results in significant expansion of CD8+ cytotoxic and CD4+ helper T cells, likely following the depletion of regulatory cells. Remarkably, expanded effector T cells also show increased killing capacity due to augmented levels of granzyme B, which activates caspases and triggers cell apoptosis [23][24][25]. In addition, among the activities promoted by CD38, there is a nicotinamide adenine dinucleotide (NAD)-ase activity, which results in reduced levels of NAD+ in T cells, responsible for the loss of their effector functions (exhausted T cells). In murine models, anti-CD38 mAbs administration induced higher levels of NAD+ in T effector cells, thus enhancing their antitumor activity [23]. The main mechanisms of action of anti-CD38 monoclonal antibodies are summarized in Figure 1.

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“…The safety, tolerability, and preliminary clinical activity of BCMA-ADC, a novel anti-BCMA antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (GSK2857916), were reported [22]. In RRMM patients (n = 35), including 20 (57%) heavily treated patients who had received ≥5 lines of therapy, the ORR was 60% (stringent CR 3%, CR 6%, VGPR 43%, and PR 9%) with a median PFS of 7.9 months.…”

Section: Immunochemotherapy and Adcsmentioning

confidence: 99%

Immunotherapy for Multiple Myeloma

Tamura

Ishibashi

Sunakawa

et al. 2019

Cancers

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Despite therapeutic advances over the past decades, multiple myeloma (MM) remains a largely incurable disease with poor prognosis in high-risk patients, and thus new treatment strategies are needed to achieve treatment breakthroughs. MM represents various forms of impaired immune surveillance characterized by not only disrupted antibody production but also immune dysfunction of T, natural killer cells, and dendritic cells, although immunotherapeutic interventions such as allogeneic stem-cell transplantation and dendritic cell-based tumor vaccines were reported to prolong survival in limited populations of MM patients. Recently, epoch-making immunotherapies, i.e., immunomodulatory drug-intensified monoclonal antibodies, such as daratumumab combined with lenalidomide and chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, have been developed, and was shown to improve prognosis even in advanced-stage MM patients. Clinical trials using other antibody-based treatments, such as antibody drug-conjugate and bispecific antigen-directed CD3 T-cell engager targeting, are ongoing. The manipulation of anergic T-cells by checkpoint inhibitors, including an anti-T-cell immunoglobulin and ITIM domains (TIGIT) antibody, also has the potential to prolong survival times. Those new treatments or their combination will improve prognosis and possibly point toward a cure for MM.

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Targeting B-cell maturation antigen with GSK2857916 antibody–drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial

Cited by 209 publications

References 31 publications

Chimeric antigen receptor T cell immunotherapy for multiple myeloma: A review of current data and potential clinical applications

Chimeric antigen receptor T cell immunotherapy for multiple myeloma: A review of current data and potential clinical applications

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

Immunotherapy for Multiple Myeloma

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