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. Key words: acute myeloid leukemia - CD38 - daratumumab - isatuximab - multiple myeloma.

• Klíčová slova
• acute myeloid leukemia - CD38 - daratumumab - isatuximab - multiple myeloma,
• MeSH
• antigeny CD38 * účinky léků   fyziologie   MeSH
• imunoterapie MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   imunologie   MeSH
• monoklonální protilátky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD38 * MeSH
• monoklonální protilátky MeSH

BACKGROUND: HIV infection causes chronic activation of cytotoxic CD8+ T-lymphocytes, which is partly responsible for the hallmark of the disease--progressive loss of CD4+ T-lymphocytes. The aim of this study was to evaluate an influence of HIV infection and long-term antiretroviral therapy (HAART) on expression of the activation molecules CD38 on CD8+ T-lymphocytes. METHODS: A group of 16 HIV-positive patients treated with HAART was followed for 12 months. Also, we examined 10 persons with a newly diagnosed HIV infection that were not treated with HAART. Expression of CD38 molecules on CD8+ T-lymphocytes was determined with five-parameter cytometric analysis using monoclonal antibodies as well as their mean fluorescence intensity (MFI). RESULTS: The percentage of CD8+/CD38+ T-lymphocytes in HIV-positive patients treated with HAART significantly decreased during the follow-up period from 46.1 I 3.7 to 35.2 I 3.8 (p = 0,01). Furthermore, the percentage of these cells correlated negatively with the number of CD4+T-lymphocytes at the beginning and the end of the study (r = -0,679, p < 0.01; r = -0,51, p = 0,05, respectively). There was no correlation between these parameters in persons with newly diagnosed HIV infection. However, the percentage of CD8+/CD38+ T-lymphocytes in these patients was significantly higher than in persons treated with HAART (68.5 I 5.3 vs. 35.2 I 3.8, p < 0,01). CONCLUSIONS: Our findings support the importance of expression of CD38 antigen on CD8+ T-lymphocytes as a biological and clinical marker of HIV infection and indicate its usefulness for monitoring of the efficacy of HAART therapy.

• MeSH
• ADP-ribosylcyklasa analýza   MeSH
• antigeny CD38 MeSH
• biologické markery analýza   MeSH
• CD antigeny analýza   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• dospělí MeSH
• HIV infekce diagnóza   farmakoterapie   MeSH
• HIV séropozitivita imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• vysoce aktivní antiretrovirová terapie 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
• Názvy látek
• ADP-ribosylcyklasa MeSH
• antigeny CD38 MeSH
• biologické markery MeSH
• CD antigeny MeSH
• CD38 protein, human MeSH Prohlížeč
• membránové glykoproteiny MeSH

We present a case report of a patient relapsing after anti-CD38 treatment (daratumumab). The phenotype of the disease changed during this treatment, and the myeloma clone became CD38 negative and daratumumab refractory. We expected clonal shift, however, based on immunophenotyping, cytogenetics and arrayCGH; the clone was identical as before daratumumab-based treatment with the exception of CD38 negativity. We suggest that the downregulation or loss of CD38 might be an epigenetic "escape mechanism" of malignant plasma cells from antibody-based treatment. The aim of our study was to point out the pitfalls of immunophenotyping and cytogenetics in both assessing the minimal residual disease and clone detection after monoclonal antibody-based therapy.

• Klíčová slova
• CD38-negativity, cytogenetics, immunophenotyping, multiple myeloma,
• MeSH
• antigeny CD38 antagonisté a inhibitory   metabolismus   MeSH
• biologické markery MeSH
• cílená molekulární terapie MeSH
• cytogenetické vyšetření MeSH
• imunofenotypizace MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom diagnóza   farmakoterapie   genetika   metabolismus   MeSH
• monoklonální protilátky MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• recidiva MeSH
• srovnávací genomová hybridizace MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• antigeny CD38 MeSH
• biologické markery MeSH
• daratumumab MeSH Prohlížeč
• monoklonální protilátky MeSH

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
• Názvy látek
• antigeny CD38 MeSH
• antitumorózní látky * MeSH
• CD38 protein, human MeSH Prohlížeč
• daratumumab MeSH Prohlížeč
• membránové glykoproteiny MeSH
• monoklonální protilátky MeSH
• rituximab MeSH

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.

• Klíčová slova
• CD38, Monoclonal antibody, Myeloma, Therapy,
• MeSH
• antigeny CD38 MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• mnohočetný myelom * terapie   MeSH
• nádorové mikroprostředí MeSH
• protinádorové látky imunologicky aktivní * terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antigeny CD38 MeSH
• protinádorové látky imunologicky aktivní * MeSH

In 72 patients with blood malignancies (leukemias), the expression and distribution of the "B-lineage" antigen CD38, was analyzed, individually and in combination with CD19, CD10, HLA-DR, CD13, CD14, CD33, CDw65, CD2 and CD7. The expression of CD38 on the surface of leukemic cells was totally different from its expression on normal hematopoietic cells. Its positivity in myeloid malignancies was as follows: In patients with acute myeloid leukemia in 21/28 cases-75% (probability of expression 0.68 +/- 0.2, p < 0.05) and in patients with chronic myeloid leukemia in 4/6 cases-66%. In lymphoproliferative malignancies the CD38 antigen was expressed as follows: In patients with acute non-T lymphoblastic leukemia in 12/16 cases-75% (probability of expression 0.7 +/- 0.2, p < 0.05) and in patients with chronic B lymphocytic leukemia in 6/8 cases-75%. CD38 was also found positive in patients with acute mixed lineage leukemia.

• MeSH
• ADP-ribosylcyklasa MeSH
• antigeny CD38 MeSH
• CD antigeny biosyntéza   MeSH
• diferenciační antigeny biosyntéza   MeSH
• fluorescenční protilátková technika MeSH
• HLA-DR antigeny biosyntéza   MeSH
• imunofenotypizace MeSH
• imunoglobulin G biosyntéza   MeSH
• imunoglobulin M biosyntéza   MeSH
• leukemie imunologie   MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• myeloidní leukemie imunologie   MeSH
• průtoková cytometrie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ADP-ribosylcyklasa MeSH
• antigeny CD38 MeSH
• CD antigeny MeSH
• CD38 protein, human MeSH Prohlížeč
• diferenciační antigeny MeSH
• HLA-DR antigeny MeSH
• imunoglobulin G MeSH
• imunoglobulin M MeSH
• membránové glykoproteiny MeSH

BACKGROUND: This study was aimed at following the changes in the expression of CD38 ADP-ribosyl cyclase ectoenzyme on peripheral blood immune cells of patients undergoing cardiac surgical operations. PATIENTS AND METHODS: The expression of CD38 on lymphoid and myeloid cells was determined by immunofluorescence and flow cytometry in forty cardiac surgical patients assigned to surgery either using ("on-pump", n=20) or without the use ("off-pump", n=20) of cardiopulmonary bypass. RESULTS: There was a very rapid upregulation of CD38 expression in "on-pump" patients, becoming significant at declamping of aorta (p<0.01) for myeloid cells and at the weaning from CPB (p<0.001) for lymphocytes. The increased expression of CD38 on lymphocytes in "off-pump" patients was prolonged for the entire observation period. However, significant differences in the expression of CD38 between "on-pump" and "off-pump" patients were not found either in lymphoid or myeloid cells. CONCLUSION: CD38 expression in immune cells of cardiac surgical patients is upregulated early during surgery, providing additional activation stimuli to the cell substrate of the inflammatory response induced by cardiac surgery.

• MeSH
• ADP-ribosylcyklasa metabolismus   MeSH
• antigeny CD38 metabolismus   MeSH
• kardiopulmonální bypass * MeSH
• koronární bypass bez mimotělního oběhu MeSH
• koronární bypass * MeSH
• lidé MeSH
• lymfocyty imunologie   MeSH
• myeloidní buňky imunologie   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• ADP-ribosylcyklasa MeSH
• antigeny CD38 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.

• Klíčová slova
• CD34+ cells, daratumumab, isatuximab, mobilisation, multiple myeloma,
• MeSH
• antigeny CD34 analýza   MeSH
• antigeny CD38 MeSH
• kostní dřeň chemie   MeSH
• lidé MeSH
• mnohočetný myelom * terapie   MeSH
• mobilizace hematopoetických kmenových buněk MeSH
• průtoková cytometrie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD34 MeSH
• antigeny CD38 MeSH

The aim of this study was to assess whether the density of CD38 antigen expression on CD8+ T cells can be used as a marker of activation of the immune system in Human immunodeficiency virus 1 (HIV-1)-positive patients treated with highly active antiretroviral therapy (HAART). T cell subsets, expression of CD38 antigen on CD8+T cells, HIV-1 viral load and stage of the disease were analyzed at baseline and after 12 months of HAART in 24 HIV-1-infected patients. Our data showed that the use of HAART is effective in reducing plasma viral load and in achieving a stable CD4+ count and percentage of CD8+/CD38+ cells. The percentages of CD8/CD38+ cells in HIV-1-infected patients at baseline and after 12 months of HAART were significantly higher than those of controls. Analysis of the density of CD38 expression revealed that it was due to CD8+/CD38+ subsets with low and medium density of antigen expression. Absolute number of CD4+ T cells correlated negatively with the percentage of CD8+/CD38+ cells at baseline of the study. Persistent up-regulation of the CD38 expression on CD8+ T cells and its correlation with the decreased CD4+ count despite the reduction of plasma viral load may reflect residual replication of HIV-1 in reservoirs. Thus, this immunological parameter can serve as a biological marker of HIV-1 infection and might have utility in clinical management of HIV-1-infected persons.

• MeSH
• ADP-ribosylcyklasa biosyntéza   MeSH
• aktivace lymfocytů * MeSH
• antigeny CD38 MeSH
• biologické markery analýza   MeSH
• CD antigeny biosyntéza   MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   metabolismus   MeSH
• dospělí MeSH
• HIV infekce farmakoterapie   imunologie   virologie   MeSH
• HIV-1 MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• virová nálož MeSH
• vysoce aktivní antiretrovirová terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ADP-ribosylcyklasa MeSH
• antigeny CD38 MeSH
• biologické markery MeSH
• CD antigeny MeSH
• CD38 protein, human MeSH Prohlížeč
• membránové glykoproteiny MeSH

• MeSH
• akutní myeloidní leukemie * farmakoterapie   MeSH
• antigeny CD28 MeSH
• antigeny CD3 imunologie   MeSH
• antigeny CD38 * antagonisté a inhibitory   metabolismus   MeSH
• humanizované monoklonální protilátky * terapeutické užití   MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• protilátky bispecifické terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• T-lymfocyty imunologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD28 MeSH
• antigeny CD3 MeSH
• antigeny CD38 * MeSH
• CD38 protein, human MeSH Prohlížeč
• humanizované monoklonální protilátky * MeSH
• isatuximab MeSH Prohlížeč
• membránové glykoproteiny MeSH
• protilátky bispecifické MeSH