anti‐CD38 Dotaz Zobrazit nápovědu
Diffuse large B-cell lymphoma (DLBCL) is the most common and one of the most aggressive subtypes of non-Hodgkin's lymphomas. Front-line therapy consists of chemotherapy in combination with anti-CD20 monoclonal antibody rituximab. Relapses after rituximab-based regimen have poor prognosis and call for new treatment options. Immunohistochemistry analysis of relapsed DLBCL often reveal CD20-negative lymphoma, which limits repeated use of rituximab in combination with salvage chemotherapy. CD38 is a surface antigen that binds to CD38, CD31/PECAM-1 and hyaluronic acid. CD38 is an important mediator of signal transmission from the microenvironment into the cell. Anti-CD38 monoclonal antibody daratumumab has been approved for the treatment of multiple myeloma. Expression of CD38 on the surface of DLBCL is highly variable (compared to strong expression on myeloma cells), but can be easily assessed by flow cytometry or immunohistochemistry. A patient-derived xenograft (PDX) model of CD20-negative, CD38-positive DLBCL derived from a patient with rituximab-refractory DLBCL was used for in vivo experiments. We demonstrated that daratumumab suppressed growth of subcutaneous PDX tumours significantly more effectively than rituximab. Analysis of tumours obtained from mice treated with daratumumab revealed down-regulation of surface CD38, suggesting endocytosis of CD38-daratumumab complexes. The results suggest a potential clinical use of daratumumab in combination with salvage chemotherapy in patients with relapses of CD20-negative DLBCL. In addition, daratumumab might potentially serve as a suitable antibody moiety for derivation of antibodydrug conjugates for the targeted delivery of toxic payloads to the lymphoma cells.
- MeSH
- antigeny CD38 antagonisté a inhibitory MeSH
- antitumorózní látky * terapeutické užití MeSH
- difúzní velkobuněčný B-lymfom * farmakoterapie MeSH
- lidé MeSH
- membránové glykoproteiny antagonisté a inhibitory MeSH
- monoklonální protilátky terapeutické užití MeSH
- myši MeSH
- nádorové mikroprostředí MeSH
- protokoly antitumorózní kombinované chemoterapie MeSH
- rituximab terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Induction therapy followed by CD34+ cell mobilisation and autologous transplantation represents standard of care for multiple myeloma (MM). However, the anti-CD38 monoclonal antibodies daratumumab and isatuximab have been associated with mobilisation impairment, yet the mechanism remains unclear. In this study, we investigated the effect of three different regimens (dara-VCd, isa-KRd and VTd) on CD34+ cells using flow cytometry and transcriptomics. Decreased CD34+ cell peak concentration and yields, longer collection and delayed engraftment were reproduced after dara-VCd/isa-KRd versus VTd induction in 34 patients in total. Using flow cytometry, we detected major changes in the proportion of apheresis product and bone marrow CD34+ subsets in patients treated with regimens containing anti-CD38 therapy; however, without any decrease in CD38high B-lymphoid progenitors in both materials. RNA-seq of mobilised CD34+ cells from 21 patients showed that adhesion genes are overexpressed in CD34+ cells after dara-VCd/isa-KRd and JCAD, NRP2, MDK, ITGA3 and CLEC3B were identified as potential target genes. Finally, direct in vitro effect of isatuximab in upregulating JCAD and CLEC3B was confirmed by quantitative PCR. These findings suggest that upregulated adhesion-related interactions, rather than killing of CD34+ cells by effector mechanisms, could be leading causes of decreased mobilisation efficacy in MM patients treated with anti-CD38 therapy.
CD38 is a transmembrane glycoprotein that functions both as a receptor and an ectoenzyme, playing key roles in the regulation of calcium signaling and migration of immune cells to tumor microenvironments. High expression on multiple myeloma (MM) cells and limited expression on normal cells makes CD38 an ideal target for the treatment of MM patients. Two monoclonal antibodies directed at CD38, isatuximab and daratumumab, are available for use in patients with relapsed and/or refractory MM (RRMM); daratumumab is also approved in newly diagnosed MM and light-chain amyloidosis. Clinical experience has shown that anti-CD38 antibody therapy is transforming treatment of MM owing to its anti-myeloma efficacy and manageable safety profile. Isatuximab and daratumumab possess similarities and differences in their mechanisms of action, likely imparted by their binding to distinct, non-overlapping epitopes on the CD38 molecule. In this review, we present the mechanistic properties of these two antibodies and outline available evidence on their abilities to induce adaptive immune responses and modulate the bone marrow niche in MM. Further, we discuss differences in regulatory labeling between these two agents and analyze recent key clinical trial results, including evidence in patients with underlying renal impairment and other poor prognostic factors. Finally, we describe the limited existing evidence for the use of isatuximab or daratumumab after disease progression on prior anti-CD38 mono- or combination therapy, highlighting the need for additional clinical evaluations to define optimal anti-CD38 antibody therapy selection and sequencing in RRMM.
B-cell non-Hodgkin lymphomas (B-NHL) represent the most common type of hematologic malignancies in the Western hemisphere. The therapy of all B-NHL is based on the combination of different genotoxic cytostatics and anti-CD20 monoclonal antibody (mAb) rituximab. Unfortunately, many patients relapse after the mentioned front-line treatment approaches. The therapy of patients with relapsed/refractory (R/R) B-NHL represents an unmet medical need. We designed, developed and tested novel actively targeted hybrid mAb-polymer-drug conjugate (APDC) containing anti-CD20, anti-CD38 or anti-CD19 mAbs. Biocompatible copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) with cytostatic agent doxorubicin attached via stimuli-sensitive hydrazone bond were employed for the mAb grafting. Anti-lymphoma efficacy of the APDC nanotherapeutics was evaluated in vivo on a panel of three patient-derived lymphoma xenografts derived from two patients with R/R B-NHL and one patient with so far untreated B-NHL. In both PDX models derived from patients with R/R B-NHL, the targeting with anti-CD38 antibody daratumumab demonstrated highly improved anti-lymphoma efficacy compared to the targeting with anti-CD20 rituximab, two experimental anti-CD19 antibodies and non-targeted controls. The results represent a proof-of-concept of a new algorithm of personalized anti-tumor therapy based on highly innovative APDC biomaterials.
- MeSH
- antitumorózní látky * terapeutické užití MeSH
- léčivé přípravky * MeSH
- lidé MeSH
- monoklonální protilátky terapeutické užití MeSH
- nehodgkinský lymfom * farmakoterapie MeSH
- polymery terapeutické užití MeSH
- rituximab MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: The increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options. PATIENTS AND METHODS: We analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs. RESULTS: Sixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications. CONCLUSION: Selinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients.
Cellular immunotherapy is becoming a new pillar in cancer treatment after recent striking results in different clinical trials with chimeric antigen receptor T cells. However, this innovative therapy is not exempt from challenges such as off-tumor toxicity, tumor recurrence in heterogeneous tumors, and affordability. To surpass these limitations, we exploit the unique anti-tumor characteristics of natural killer (NK) cells. In this study, we aimed to obtain a clinically relevant number of allogeneic NK cells derived from peripheral blood (median of 14,050 million cells from a single donor) to target a broad spectrum of solid and liquid tumor types. To boost their anti-tumor activity, we combined allogeneic NK cells with the approved anti-cluster of differentiation 38 (CD-38) monoclonal antibody Daratumumab to obtain a synergistic therapeutic effect against incurable multiple myeloma. The combination therapy was refined with CD16 polymorphism donor selection and uncomplicated novel in vitro pretreatment to avoid undesired fratricide, increasing the in vitro therapeutic effect against the CD-38 positive multiple myeloma cell line by more than 20%. Time-lapse imaging of mice with established human multiple myeloma xenografts revealed that combination therapy of selected and pretreated NK cells with Daratumumab presented tumor volumes 43-fold smaller than control ones. Combination therapy with an allogeneic source of fully functional NK cells could be beneficial in future clinical settings to circumvent monoclonal antibodies' low therapeutic efficiency due to NK cell dysfunctionality in MM patients.
- MeSH
- buněčná a tkáňová terapie metody MeSH
- buňky NK imunologie MeSH
- imunoterapie metody MeSH
- lidé MeSH
- mnohočetný myelom farmakoterapie MeSH
- monoklonální protilátky farmakologie MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protinádorové látky imunologicky aktivní farmakologie MeSH
- studie případů a kontrol MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antigeny CD38 účinky léků MeSH
- cílená molekulární terapie metody MeSH
- cytostatické látky aplikace a dávkování terapeutické užití MeSH
- hematologické nádory farmakoterapie MeSH
- imunologické faktory fyziologie imunologie MeSH
- inhibitory angiogeneze MeSH
- lidé MeSH
- mnohočetný myelom * diagnóza ekonomika etiologie farmakoterapie patologie MeSH
- společnosti lékařské MeSH
- thalidomid analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- vztahy mezi lékařem a pacientem MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- rozhovory MeSH
HIV-specific and non-specific immune responses are crucial in the immunopathogenesis of HIV infection. Therefore, the objective of our study was to analyse the frequency and functional status of HIV-specific CD8+ T cells and the expression of non-specific activation markers on CD8+ T cells in HIV+ patients, and to assess the effects of combined antiretroviral treatment (cART). We examined 28 HIV+ patients, including 13 patients not receiving therapy and 15 patients on cART therapy using ELISpot assay and flow cytometry with intracellular and MHC tetramer staining. MHC tetramers detected HIV-specific CD8+ T cells in 6 HIV+ patients on cART and in 7 untreated individuals; the ELISpot method detected these cells in 5 untreated HIV+ individuals only. Reduced intracellular IFN-γ and IL-2 production by HIV-specific CD8+ T cells was detected in both treated and untreated HIV+ patients, and multifunctional CD8+ T cells simultaneously producing these cytokines were not found in any patient. In contrary to these findings, the percentage of CD8+ T cells expressing CD38 and HLA-DR was significantly higher in untreated patients as compared to HIV+ patients on cART. Together, these results suggest that the alterations of HIV-specific immunity are not influenced by the therapy of HIV infection; whereas, the non-specific chronic immune activation is down-regulated by cART.
- MeSH
- antigeny CD38 biosyntéza MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- dospělí MeSH
- ELISPOT MeSH
- HIV infekce farmakoterapie imunologie MeSH
- HIV imunologie MeSH
- HLA-DR antigeny biosyntéza MeSH
- interferon gama biosyntéza MeSH
- interleukin-2 biosyntéza MeSH
- látky proti HIV aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové glykoproteiny biosyntéza MeSH
- průtoková cytometrie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Antigen CD38 je uniformně a vysoce exprimován na plazmatických buňkách a stal se tak ideálním cílem pro léčbu mnohočetného myelomu (MM) pomocí anti-CD38 cílených monoklonálních protilátek (mAbs). Nejdále ve vývoji je daratumumab, nicméně podobně slibných výsledků dosahuje i isatuximab, který cílí na zcela jiný epitop molekuly CD38. Anti-CD38 mAbs mají pleiotropní mechanizmus účinku, který je popisován i u jiných mAbs, nicméně zásadním, novým a specifickým mechanizmem je tzv. imunomodulační efekt díky depleci CD38+ imunosupresivních buněčných populací. Monoterapie anti-CD38 mAbs vede k odpovědím u asi 30 % silně předléčených MM pacientů. Jelikož je toxicita těchto látek minimální a mají odlišný mechanizmus účinku, jsou ideálním partnerem do kombinační léčby s běžně užívanými antimyelomovými léky. Daratumumab je schválen jako součást již 3 režimů u relabovaných pacientů s MM a jeho kombinace s lenalidomidem a dexametazonem je v současné době považována za nejlepší možnou léčbu relapsu nemoci, při níž bylo dosaženo bezprecedentního prodloužení mediánu doby bez progrese (Progression Free Survival - PFS), celkové léčebné odpovědi, i kvality odpovědí. Anti-CD38 mAbs se postupně posouvají i do léčby první linie. Stejně tak jsou s úspěchem zkoušeny u dalších plazmocelulárních dyskrazií (AL-amyloidóza), dalších hematologických malignit (akutní lymfoblastická leukemie - ALL, akutní myeloidní leukemie - AML, chronická lymfocytární leukemie - CLL), a dokonce u solidních nádorů či autoimunitních onemocnění. Léčba pomocí anti-CD38 mAbs znamená podobnou revoluci pro pacienty s MM, jako zavedení anti-CD20 mAbs u nemocných s CLL či non-hodgkinskými lymfomy a zcela jistě je velkou nadějí do budoucna směřující k možnosti vyléčení alespoň části nemocných s MM.
CD38 antigen is highly and uniformly expressed on plasma cells and thus represents an ideal target for the treatment of multiple myeloma (MM) with anti-CD38 monoclonal antibodies (mAbs). Daratumumab is the most advanced anti-CD38 mAb in the clinical development with approval in several indications, nevertheless isatuximab that targets completely different epitope of CD38 molecule is also very promising drug. Anti-CD38 possess pleiotropic mechanism of action that have been described also in other mAbs, but quite specific, novel and very important seems to be the immunomodulatory effect provided by depletion of several CD38+ immunosuppressive immune cell populations. CD38-targeted mAbs induce partial response or better in approximately 30 % of heavily pre-treated myeloma patients as monotherapy. Based on their favourable toxicity profile and distinct mechanism of action, anti-CD38 mAbs represents very attractive partner to back-bone anti-myeloma drugs. Indeed, daratumumab is already approved as a part of three distinct combination regimens in relapsed setting. The combination of daratumumab with lenalidomide and dexamethasone is considered to be the best treatment option in relapsed myeloma with unprecedented prolongation of median PFS, including high rate of good quality responses. CD38 targeted therapy is rapidly moving toward the first line treatment. Anti-CD38 mAbs have been also successfully tested in other plasma cell dyscrasias (such as AL amyloidosis), and they are examined in other hematological malignancies (such as CLL, ALL, AML, etc.) and even in solid oncology as well as in autoimmune disorders. Implementation of CD38 targeted mAbs have been significant milestone in the treatment of MM, similar to that of CD20 targeted mAbs in CLL or non-Hodgkin lymphomas. We believe that this drug may eventually help to reach the cure at least in a subset of MM patients in the near future.
- Klíčová slova
- daratumumab, isatuximab,
- MeSH
- akutní myeloidní leukemie farmakoterapie MeSH
- antigeny CD38 * aplikace a dávkování farmakologie terapeutické užití MeSH
- cílená molekulární terapie MeSH
- imunologické faktory MeSH
- imunomodulace MeSH
- klinické zkoušky jako téma MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- mnohočetný myelom * farmakoterapie MeSH
- monoklonální protilátky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
B cells play an important role in the immune responses which affect the outcomes of kidney allografts. Dynamic changes of B-cell compartments in clinical kidney transplantation are still poorly understood. B-cell subsets were prospectively monitored using flow cytometry for 1 year in 98 kidney transplant recipients. Data were correlated with immunosuppression and clinical outcomes. An increase in the total population of B lymphocytes was observed during the first week after transplantation. The level of IgM(high) CD38(high) CD24(high) transitional B cells reduced significantly up until the third month, with partial repopulation in the first year. Lower numbers of transitional B cells in the third month were associated with higher risk of graft rejection. IgM(+) IgD(+) CD27(-) naive B cells did not change within follow-up. IgM(+) CD27(+) nonswitched memory B cells and IgM(-) CD27(+) switched memory B cells increased on post-operative day 7. IgM(-) CD38(high) CD27(high) plasmablasts showed similar kinetics during the first post-transplant year, similar to transitional B cells. In conclusion, sensitized kidney transplant recipients as well as those with either acute or chronic rejection within the first post-transplant year exhibited lower levels of transitional B cells. Therefore, these data further support the hypothesis that transitional B cells have a protective role in kidney transplantation.
- MeSH
- alografty MeSH
- antigen CD24 metabolismus MeSH
- antigeny CD27 metabolismus MeSH
- antigeny CD38 metabolismus MeSH
- časové faktory MeSH
- dítě MeSH
- dospělí MeSH
- imunologická paměť imunologie MeSH
- imunosupresivní léčba MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- plazmatické buňky imunologie MeSH
- podskupiny B-lymfocytů imunologie MeSH
- předškolní dítě MeSH
- prekurzorové B-lymfoidní buňky imunologie MeSH
- příjemce transplantátu MeSH
- prospektivní studie MeSH
- rejekce štěpu imunologie MeSH
- senioři MeSH
- senzitivita a specificita MeSH
- transplantace ledvin * MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
