scholarly journals Mutations in the Fas Antigen in Patients With Multiple Myeloma

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4266-4270 ◽  
Author(s):  
Terry H. Landowski ◽  
Ning Qu ◽  
Ibrahim Buyuksal ◽  
Jeffrey S. Painter ◽  
William S. Dalton
Keyword(s):  
Multiple Myeloma ◽  
Fas Ligand ◽  
Genetic Defect ◽  
Point Mutations ◽  
Neoplastic Disease ◽  
Loss Of Function ◽  
Fas Antigen ◽  
Immune Effector ◽  
Effector Cells ◽  
A Site

Abstract Programmed cell death, or apoptosis, is well documented as a physiological means of eliminating activated lymphocytes and maintaining immune homeostasis. Apoptosis has also been implicated in the targeting of tumor cells by cytotoxic T lymphocytes and natural killer cells. One of the two primary mechanisms used in cell-mediated cytotoxicity is the Fas/FasLigand system. Activated or transformed cells expressing the Fas antigen on their surface are susceptible to killing by immune effector cells that express the Fas ligand. Many neoplastic cells, including those derived from patients with multiple myeloma, express Fas antigen on their surface, but do not undergo apoptosis in response to antigen crosslinking. One possibility for the lack of Fas-mediated apoptosis includes mutations in the Fas antigen. Loss of function mutations in the Fas antigen have been associated with congenital autoimmune disease in humans, and have been defined as the genetic defect the in lpr mice. Mutations in the Fas antigen have not been previously described in cancer patients. In this study, we show that mutations occur in the Fas antigen which may cause loss of function and contribute to the pathogenesis of the neoplastic disease, multiple myeloma. Using reverse transcriptase-polymerase chain reaction (RT-PCR), single-stranded conformation polymorphism (SSCP) analysis, and DNA sequencing, we examined the cDNA structure of the Fas antigen in 54 bone marrow (BM) specimens obtained from myeloma patients. Six patient specimens (11%) did not express detectable levels of Fas antigen mRNA. Of the 48 BM specimens which did express Fas antigen, 5 (10%) displayed point mutations. All of the mutations identified were located in the cytoplasmic region of the Fas antigen known to be involved in transduction of an apoptotic signal. Two separate individuals demonstrated an identical mutation at a site previously shown to be mutated in the congenital autoimmune syndrome, ALPS. One patient exhibited a point mutation at a site only two amino acids removed from the documented lesion of the lprcg mouse. Although the functional status of these point mutations remains to be determined, we propose that Fas antigen mutations may contribute to the pathogenesis and progression of myeloma in some patients.

scholarly journals Mutations in the Fas Antigen in Patients With Multiple Myeloma

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4266-4270 ◽  
Author(s):  
Terry H. Landowski ◽  
Ning Qu ◽  
Ibrahim Buyuksal ◽  
Jeffrey S. Painter ◽  
William S. Dalton
Keyword(s):  
Multiple Myeloma ◽  
Fas Ligand ◽  
Genetic Defect ◽  
Point Mutations ◽  
Neoplastic Disease ◽  
Loss Of Function ◽  
Fas Antigen ◽  
Immune Effector ◽  
Effector Cells ◽  
A Site

Programmed cell death, or apoptosis, is well documented as a physiological means of eliminating activated lymphocytes and maintaining immune homeostasis. Apoptosis has also been implicated in the targeting of tumor cells by cytotoxic T lymphocytes and natural killer cells. One of the two primary mechanisms used in cell-mediated cytotoxicity is the Fas/FasLigand system. Activated or transformed cells expressing the Fas antigen on their surface are susceptible to killing by immune effector cells that express the Fas ligand. Many neoplastic cells, including those derived from patients with multiple myeloma, express Fas antigen on their surface, but do not undergo apoptosis in response to antigen crosslinking. One possibility for the lack of Fas-mediated apoptosis includes mutations in the Fas antigen. Loss of function mutations in the Fas antigen have been associated with congenital autoimmune disease in humans, and have been defined as the genetic defect the in lpr mice. Mutations in the Fas antigen have not been previously described in cancer patients. In this study, we show that mutations occur in the Fas antigen which may cause loss of function and contribute to the pathogenesis of the neoplastic disease, multiple myeloma. Using reverse transcriptase-polymerase chain reaction (RT-PCR), single-stranded conformation polymorphism (SSCP) analysis, and DNA sequencing, we examined the cDNA structure of the Fas antigen in 54 bone marrow (BM) specimens obtained from myeloma patients. Six patient specimens (11%) did not express detectable levels of Fas antigen mRNA. Of the 48 BM specimens which did express Fas antigen, 5 (10%) displayed point mutations. All of the mutations identified were located in the cytoplasmic region of the Fas antigen known to be involved in transduction of an apoptotic signal. Two separate individuals demonstrated an identical mutation at a site previously shown to be mutated in the congenital autoimmune syndrome, ALPS. One patient exhibited a point mutation at a site only two amino acids removed from the documented lesion of the lprcg mouse. Although the functional status of these point mutations remains to be determined, we propose that Fas antigen mutations may contribute to the pathogenesis and progression of myeloma in some patients.

scholarly journals Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1353
Author(s):  
Andrea Díaz-Tejedor ◽  
Mauro Lorenzo-Mohamed ◽  
Noemí Puig ◽  
Ramón García-Sanz ◽  
María-Victoria Mateos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Cytotoxic Effects ◽  
Disease Evolution ◽  
Immune Effector ◽  
Effector Cells ◽  
Surface Molecules ◽  
Immune Effector Cells

Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterations in the expression of surface molecules are also responsible for immunosuppression. In this scenario, immunotherapy, as is the case of immunotherapeutic monoclonal antibodies (mAbs), aims to boost the immune system against tumor cells. In fact, mAbs exert part of their cytotoxic effects through different cellular and soluble immune components and, therefore, patients’ immunosuppressive status could reduce their efficacy. Here, we will expose the alterations observed in symptomatic MM, as compared to its precursor stages and healthy subjects, in the main immune populations, especially the inhibition of effector cells and the activation of immunosuppressive populations. Additionally, we will revise the mechanisms responsible for all these alterations, including the interplay between MM cells and immune cells and the interactions among immune cells themselves. We will also summarize the main mechanisms of action of the four mAbs approved so far for the treatment of MM. Finally, we will discuss the potential immune-stimulating effects of non-immunotherapeutic drugs, which could enhance the efficacy of immunotherapeutic treatments.

scholarly journals Immunotherapy Using Dendritic Cells against Multiple Myeloma: How to Improve?

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Thanh-Nhan Nguyen-Pham ◽  
Yoon-Kyung Lee ◽  
Hyeoung-Joon Kim ◽  
Je-Jung Lee
Keyword(s):  
Multiple Myeloma ◽  
Dendritic Cells ◽  
Myeloma Cell ◽  
Cellular Immunotherapy ◽  
Immune Effector ◽  
Effector Cells ◽  
Good Target ◽  
Target Disease ◽  
Antigen Presenting ◽  
Dying Cells

Multiple myeloma (MM) is a good target disease in which one can apply cellular immunotherapy, which is based on the graft-versus-myeloma effect. This role of immune effector cells provides the framework for the development of immune-based therapeutic options that use antigen-presenting cells (APCs) with increased potency, such as dendritic cells (DCs), in MM. Current isolated idiotype (Id), myeloma cell lysates, myeloma dying cells, DC-myeloma hybrids, or DC transfected with tumor-derived RNA has been used for immunotherapy with DCs. Immunological inhibitory cytokines, such as TGF-β, IL-10, IL-6 and VEGF, which are produced from myeloma cells, can modulate antitumor host immune response, including the abrogation of DC function, by constitutive activation of STAT3. Therefore, even the immune responses have been observed in clinical trials, the clinical response was rarely improved following DC vaccinations in MM patients. We are going to discuss how to improve the efficacy of DC vaccination in MM.

scholarly journals IL-31, itch and hematological malignancies

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Eleonora Di Salvo ◽  
Alessandro Allegra ◽  
Marco Casciaro ◽  
Sebastiano Gangemi
Keyword(s):  
Disease Stage ◽  
Neoplastic Disease ◽  
Immune Effector ◽  
Effector Cells ◽  
Th2 Cytokine ◽  
Oncologic Patients ◽  
Immune Effector Cells ◽  
Oncologic Diseases

AbstractPruritus is one of the most common symptoms experienced by neoplastic patients. The pathogenesis of neoplastic itch is complex and multifactorial and could be due to an unbalanced production of humoral mediators by altered immune effector cells. IL-31 is a pro-inflammatory cytokine produced by CD4 + T helper cells. The aim of this review was to evaluate the role of this Th2 cytokine and its receptor IL-31RA, in the onset of neoplastic pruritus. We analysed scientific literature looking for the most relevant original articles linking IL-31to itch in oncologic diseases. Interleukin-31 seems to be a main itch mediator in several hematologic disease such as Cutaneous T cells lymphomas. In these patients IL-31 was positively linked to itch level, and IL-31 matched with disease stage. IL-31 seems to play an important role in the signalling pathway involved in pruritus, but it is also suggested to play a proinflammatory and immunomodulatory role which could play a part in the progression of the neoplastic disease. Further studies will be fundamental in facing pruritus in oncologic patients, since this problem compromise their quality of life worsening an already critic picture.

scholarly journals A Novel Class of Bifunctional Immunotherapeutic That Exploit a Universal Antibody Binding Terminus (uABT) to Recruit Endogenous Antibodies to Cells Expressing CD38 Demonstrates Anti-Multiple Myeloma Activity in Vitro and Ex Vivo against Patient Tumor Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4411-4411
Author(s):  
Ann Marie Rossi ◽  
Anna Bunin ◽  
Lawrence Iben ◽  
Matthew Welsch ◽  
Tanya Berbasova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Ex Vivo ◽  
Employment Equity ◽  
Myeloma Cells ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Human Igg1 ◽  
Equity Ownership

Background: Antibody recruiting molecules (ARM) are novel, immunotherapeutic bifunctional molecules composed of two active termini connected by a linker. One of the termini binds to a target molecule on a cancer cell. The other terminus, called universal antibody binding terminus (uABT), recruit all endogenous IgG antibodies independent of their antigen binding specificity. As a result, the target cell is "opsonized" by antibodies which then bring the immune effector cells to eliminate the target through various antibody-dependent destruction mechanisms. Kleo Pharmaceuticals has developed a series of CD38-ARM mlecules which target human CD38 highly expressed by multiple myeloma cells. CD38-ARM compounds are able to mediate ADCC without depleting CD38 expressing immune effector cells like existing therapeutic antibodies such as Daratumumab. Methods: Cyclized peptides containing natural and non-natural amino-acid that selectively bind to human CD38 were identified using Peptidream Flexizyme-based, cell free Peptide Discovery Translation System. These peptides were linked to uABT antibody binder via a linker to generate the final CD38-ARM molecules Binding of CD38-ARM was tested by ternary complex formation between CD38 expressing cells, CD38-ARM and labelled human IgG1. To confirm the activity of CD38-ARM, surrogate CD16a binding and signaling assays were performed using the NFAT Promega system. Antibody dependent cellular cytotoxicity (ADCC) assays using purified NK cells from multiple donors with polymorphism variants (V/V, F/F, and V/F) of CD16a were performed to confirm activity. Live cell imaging was utilized to assess the dynamics of NK-RAJI cell interactions mediated by CD38-ARM +/- IgG. We evaluated the ability of compounds to mediate complement dependent cytotoxicity (CDC). We tested the effect of CD38-ARM on human immune cell populations within PBMC and whole bone marrow (WBM) by flow cytometry. Lastly, ex vivo samples from WBM of MM patients at diagnosis or relapse were used to evaluate CD38-ARM anti-tumor activity as well as off-target effects, without the addition of external source of IgG, through multiparametric flow-cytometry (CD45, CD19, CD38, CD138, CD56, CD27, CD8, CD117). Results: The CD38-ARM were shown to have the ability to bind to CD38 with a 7nM affinity and to human IgG1 and IgG2 with affinity of 15nM and 11nM by SPR. Activity of KP compounds was observed in all assays except for CDC. In ternary assay, KP-6 had an apparent EC50 of 16nM while KP-7's EC50 was 6nM. Both KP-6 and 7 had comparable EC50s in the single digit nanamolar range in the NFAT activation assay induced by CD16a binding was confirmed using human IgG to induce, while Daratumumab had an apparent EC50 of 0.04nM. In the ADCC assay, both KP-6 & KP-7 had EC50s of 7 & 6nM respectively, while Daratumumab had an EC50 of 0.1nM. In addition, no NK cell depletion was observed when PBMC were treated with KP compounds, whereas a profound reduction in both percentages and absolute numbers in this cell subset was observed with Daratumumab treatment. Increasing dose of CD38-ARM (range 0.1uM- 25uM) were tested in ex vivo WBM samples from MM patients together with a negative control and Daratumumab. At concentrations of 10uM and 25uM, CD38-ARM induced a significant reduction of MM cells achieving results comparable to those of Daratumumab activity (p >0.05 in both cases), while sparing all other CD38+ normal cells such as NK, T lymphocytes, monocytes and granulocytes, which are always reduced in the presence of Daratumumab. Conclusions: CD38-ARMs are able to kill MM cells by ADCC without depleting CD38 expressing immune cells contrary to existing antibodies such as Daratumumab. CD38-ARMs do not activate complement, which might be involved in the infusion reaction seen with Daratumumab. Most importantly, CD38-ARMs kill multiple myeloma cells ex vivo in patient bone marrow samples as well as plasma cell leukemia in patient blood. Combined with the in vivo efficacy data presented elsewhere, this data establishes the therapeutic potential of CD38-ARM. They also represent the first demonstration of the ARM platform ability to generate therapeutic agents tailored to a specific indication, by varying target binding moiety of the molecule. Disclosures Rossi: Kleo pharmaceuticals: Employment, Equity Ownership. Bunin:Kleo pharmaceuticals: Employment, Equity Ownership. Iben:Kleo Pharmaceuticals: Employment, Equity Ownership. Welsch:Kleo pharmaceuticals: Employment, Equity Ownership. Berbasova:Kleo Pharmaceuticals: Employment, Equity Ownership. Riillo:Kleo Pharmaceuticals: Research Funding. Ohuchi:Peptidream Inc.: Employment. Alvarez:Kleo pharmaceuticals: Employment, Equity Ownership. Kawakami:Peptidream Inc.: Employment. Nagasawa:Peptidream Inc.: Employment. Spiegel:Kleo pharmaceuticals: Equity Ownership. Rastelli:Kleo pharmaceuticals: Employment, Equity Ownership.

Role of Fas–FasL in inflammatory diseases

2001 ◽  
Vol 3 (31) ◽  
pp. 1-18 ◽  
Author(s):  
Joe O'Connell
Keyword(s):  
Fas Ligand ◽  
Inflammatory Diseases ◽  
Inflammatory Cells ◽  
Cell Types ◽  
Inflammatory Reactions ◽  
Immune Effector ◽  
Effector Cells ◽  
Therapeutic Goals ◽  
Cytokines And Chemokines ◽  
Apoptosis And Inflammation

Fas ligand (FasL) induces programmed cell death, or ‘apoptosis’, in cells expressing its cognate receptor, Fas (CD95/APO-1). There is evidence that FasL precludes inflammatory reactions from sites of ‘immune privilege’ by triggering Fas-mediated apoptosis of infiltrating pro-inflammatory cells. The ability of FasL to impair immune responses is being pursued as a possible means of protecting tissue transplants from immunological rejection, and therapeutic promise has been reported in some experiments. However, FasL is becoming an enigmatic molecule, exhibiting pro-inflammatory activity independently of its ability to mediate immune downregulation. FasL can recruit and activate neutrophils and macrophages in some experimental situations. Triggering of Fas in some cell types has been shown to upregulate expression of certain pro-inflammatory cytokines and chemokines, providing an unexpected link between apoptosis and inflammation. FasL appears to contribute to the destruction of Fas-sensitive end-organ cells during inflammation. This appears to occur in two ways: (1) direct killing by cytotoxic immune effector cells expressing FasL; or (2) autocrine cell suicide of end-organ cells that upregulate their own FasL in the inflammatory context. Depending on the condition, or the site of inflammation, either or both mechanisms may occur. Prevention of Fas-mediated end-organ apoptosis and enhancement of Fas-mediated apoptosis of inflammatory cells are emerging as potential anti-inflammatory therapeutic goals.

scholarly journals Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma

2020 ◽  
Vol 9 (7) ◽  
pp. 2166 ◽  
Author(s):  
Xiang Zhou ◽  
Hermann Einsele ◽  
Sophia Danhof
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Proteasome Inhibitors ◽  
Treatment Strategies ◽  
Autologous Stem Cell Transplant ◽  
Resistance Mechanisms ◽  
Bispecific Antibodies ◽  
Cell Transplant ◽  
Immune Effector ◽  
Effector Cells

Despite the introduction of novel agents such as proteasome inhibitors, immunomodulatory drugs, and autologous stem cell transplant, multiple myeloma (MM) largely remains an incurable disease. In recent years, monoclonal antibody-based treatment strategies have been developed to target specific surface antigens on MM cells. Treatment with bispecific antibodies (bsAbs) is an immunotherapeutic strategy that leads to an enhanced interaction between MM cells and immune effector cells, e.g., T-cells and natural killer cells. With the immune synapse built by bsAbs, the elimination of MM cells can be facilitated. To date, bsAbs have demonstrated encouraging results in preclinical studies, and clinical trials evaluating bsAbs in patients with MM are ongoing. Early clinical data show the promising efficacy of bsAbs in relapsed/refractory MM. Together with chimeric antigen receptor-modified (CAR)-T-cells, bsAbs represent a new dimension of precision medicine. In this review, we provide an overview of rationale, current clinical development, resistance mechanisms, and future directions of bsAbs in MM.

scholarly journals Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy

Oncogene ◽  
2021 ◽  
Author(s):  
Audrey Lequeux ◽  
Muhammad Zaeem Noman ◽  
Malina Xiao ◽  
Kris Van Moer ◽  
Meriem Hasmim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Transcriptional Activity ◽  
Immune Cell ◽  
Tumor Resistance ◽  
Combination Strategy ◽  
Immune Effector ◽  
Effector Cells ◽  
Melanoma Patients ◽  
The Impact

AbstractHypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.

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