RESUMEN
ABSTRACT: Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.
Asunto(s)
Anticuerpos Biespecíficos , Antineoplásicos , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Inmunidad Humoral , Inmunoglobulinas Intravenosas/uso terapéutico , Anticuerpos Biespecíficos/uso terapéutico , Antígeno de Maduración de Linfocitos B/uso terapéutico , Antineoplásicos/uso terapéutico , Suplementos DietéticosRESUMEN
PURPOSE: Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action. EXPERIMENTAL DESIGN: We evaluated the anti-MM activity of the fully human BCMA×CD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated. RESULTS: We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957-mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naïve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect. CONCLUSIONS: JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.
Asunto(s)
Anticuerpos Biespecíficos/farmacología , Anticuerpos Monoclonales/farmacología , Antígeno de Maduración de Linfocitos B/inmunología , Complejo CD3/inmunología , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Biespecíficos/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos , Antineoplásicos/farmacología , Médula Ósea/patología , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Inmunoterapia/métodos , Mieloma Múltiple/inmunología , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Células Tumorales CultivadasAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Hipersensibilidad/terapia , Inmunoterapia/métodos , Mieloma Múltiple/terapia , Células Plasmáticas/inmunología , ADP-Ribosil Ciclasa 1/inmunología , Animales , Antígenos Dermatofagoides/inmunología , Betula/inmunología , Aprobación de Drogas , Humanos , Hipersensibilidad/inmunología , Inmunoglobulina E/sangre , Mieloma Múltiple/inmunología , Países Bajos , Células Plasmáticas/efectos de los fármacos , Polen/inmunología , Pyroglyphidae/inmunologíaRESUMEN
CD38 is a multifunctional cell surface protein that has receptor as well as enzyme functions. The protein is generally expressed at low levels on various hematological and solid tissues, while plasma cells express particularly high levels of CD38. The protein is also expressed in a subset of hematological tumors, and shows especially broad and high expression levels in plasma cell tumors such as multiple myeloma (MM). Together, this triggered the development of various therapeutic CD38 antibodies, including daratumumab, isatuximab, and MOR202. Daratumumab binds a unique CD38 epitope and showed strong anti-tumor activity in preclinical models. The antibody engages diverse mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, programmed cell death, modulation of enzymatic activity, and immunomodulatory activity. CD38-targeting antibodies have a favorable toxicity profile in patients, and early clinical data show a marked activity in MM, while studies in other hematological malignancies are ongoing. Daratumumab has single agent activity and a limited toxicity profile, allowing favorable combination therapies with existing as well as emerging therapies, which are currently evaluated in the clinic. Finally, CD38 antibodies may have a role in the treatment of diseases beyond hematological malignancies, including solid tumors and antibody-mediated autoimmune diseases.
Asunto(s)
ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , ADP-Ribosil Ciclasa 1/genética , ADP-Ribosil Ciclasa 1/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Clínicos como Asunto , Citotoxicidad Inmunológica , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/metabolismo , Humanos , Inmunomodulación/efectos de los fármacos , Unión Proteica , Recurrencia , Resultado del TratamientoRESUMEN
PURPOSE: Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination with lenalidomide or bortezomib for the treatment of lenalidomide- and bortezomib-refractory patients. EXPERIMENTAL DESIGN: In ex vivo assays, mainly evaluating antibody-dependent cell-mediated cytotoxicity, and in an in vivo xenograft mouse model, we evaluated daratumumab alone or in combination with lenalidomide or bortezomib as a potential therapy for lenalidomide- and bortezomib-refractory multiple myeloma patients. RESULTS: Daratumumab induced significant lysis of lenalidomide/bortezomib-resistant multiple myeloma cell lines and of primary multiple myeloma cells in the bone marrow mononuclear cells derived from lenalidomide- and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumab-mediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide effectively reduced the tumorigenic growth of primary multiple myeloma cells from a lenalidomide- and bortezomib-refractory patient. CONCLUSIONS: Our results provide the first preclinical evidence for the benefit of daratumumab plus lenalidomide combination for lenalidomide- and bortezomib-refractory patients.