IntroductionBone marrow (BM) Vγ9Vδ2 T cells are intrinsically predisposed to sense the immune fit... more IntroductionBone marrow (BM) Vγ9Vδ2 T cells are intrinsically predisposed to sense the immune fitness of the tumor microenvironment (TME) in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).MethodsIn this work, we have used BM Vγ9Vδ2 T cells to interrogate the role of the immune checkpoint/immune checkpoint-ligand (ICP/ICP-L) network in the immune suppressive TME of MM patients.ResultsPD-1+ BM MM Vγ9Vδ2 T cells combine phenotypic, functional, and TCR-associated alterations consistent with chronic exhaustion and immune senescence. When challenged by zoledronic acid (ZA) as a surrogate assay to interrogate the reactivity to their natural ligands, BM MM Vγ9Vδ2 T cells further up-regulate PD-1 and TIM-3 and worsen TCR-associated alterations. BM MM Vγ9Vδ2 T cells up-regulate TIM-3 after stimulation with ZA in combination with αPD-1, whereas PD-1 is not up-regulated after ZA stimulation with αTIM-3, indicating a hierarchical regulation of inducible ICP e...
Understanding antibody-based SARS-CoV-2 immunity in hematologic malignancy (HM) patients followin... more Understanding antibody-based SARS-CoV-2 immunity in hematologic malignancy (HM) patients following infection is crucial to inform vaccination strategies for this highly vulnerable population. This cross-sectional study documents the anti-SARS-CoV-2 humoral response and serum neutralizing activity in 189 HM patients recovering from a PCR-confirmed infection. The overall seroconversion rate was 85.7%, with the lowest values in patients with lymphoid malignancies or undergoing chemotherapy. Therapy-naive patients in the “watch and wait” status were more likely to seroconvert and display increased anti-s IgG titers. Enhanced serum neutralizing activity was observed in the following SARS-CoV-2-infected HM patient groups: (i) males; (ii) severe COVID-19; and (iii) “watch and wait” or “complete/partial response”. The geometric mean (GeoMean) ID50 neutralization titers in patients analyzed before or after 6 months post-infection were 299.1 and 306.3, respectively, indicating that >50% of...
Background Immunoglobulin M multiple myeloma and Waldenström macroglobulinemia are two different ... more Background Immunoglobulin M multiple myeloma and Waldenström macroglobulinemia are two different hematological diseases with the common finding of an immunoglobulin M monoclonal gammopathy of unknown significance. However, clinical characteristics of the two entities can overlap. Case presentation In this report, we describe two cases of immunoglobulin M neoplasm with the same histological bone marrow presentation but with different clinical behavior, cytogenetics, and biological assessment. On the basis of comprehensive diagnostic workup, these patients were considered to have different diseases and treated accordingly with different approaches. Patient 1 (Caucasian man) presented with increased serum protein and immunoglobulin M (7665 mg/L) with an M-spike electrophoresis of 4600 mg/L. His bone marrow biopsy revealed a small-cell immunoglobulin M multiple myeloma. The result of testing for the MYD88 L265P mutation was negative, while fluorescence in situ hybridization analysis sho...
Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the im... more Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id...
Vγ9Vδ2 T cells are non-conventional T cells with a natural inclination to recognize and kill canc... more Vγ9Vδ2 T cells are non-conventional T cells with a natural inclination to recognize and kill cancer cells. Malignant B cells, including myeloma cells, are privileged targets of Vγ9Vδ2 T cells . However, this inclination is often lost due to multiple mechanisms mediated by tumor cells and local microenvironment. Multiple myeloma (MM) is a paradigm disease in which antitumor immunity is selectively impaired at the tumor site. By interrogating the immune reactivity of bone marrow (BM) Vγ9Vδ2 T cells to phosphoantigens, we have revealed a very early and long-lasting impairment of Vγ9Vδ2 T-cell immune functions which is already detectable in monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even in clinical remission after autologous stem cell transplantation. Multiple cell subsets [MM cells, myeloid-derived suppressor cells, regulatory T cells, and BM-derived stromal cells (BMSC)] are involved in Vγ9Vδ2 T-cell inhibition several immune suppressive mechanis...
Perceiving the need for rigorous recommendations to facilitate decisions concerning the managemen... more Perceiving the need for rigorous recommendations to facilitate decisions concerning the management of patients with multiple myeloma (MM), the Italian Society of Hematology (SIE) and the two affiliate societies (SIES and GITMO) commissioned a project to develop guidelines for the therapy of MM using evidence-based knowledge and consensus formation techniques. After a comprehensive systematic review of 1,450 papers, an Expert Panel formulated and graded sixty recommendations according to the supporting evidence. Evidence gaps were filled with twenty-two consensus-based statements. High grade recommendations (grade A) are reported below. Treatment should be immediately initiated in MM patients with related organ damage: those patients aged below 65 years who do not have severe co-morbidities should receive autologous stem cell transplantation, while patients not candidates for autologous stem cell transplantation should receive oral melphalan and prednisone. Interferon-a should not be...
Vγ9Vδ2 T cells play a major role as effector cells of innate immune responses against microbes, s... more Vγ9Vδ2 T cells play a major role as effector cells of innate immune responses against microbes, stressed cells, and tumor cells. They constitute <5% of PBLs but can be expanded by zoledronic acid (ZA)-treated monocytes or dendritic cells (DC). Much less is known about their ability to act as cellular adjuvants bridging innate and adaptive immunity, especially in patients with cancer. We have addressed this issue in multiple myeloma (MM), a prototypic disease with several immune dysfunctions that also affect γδ T cells and DC. ZA-treated MM DC were highly effective in activating autologous γδ T cells, even in patients refractory to stimulation with ZA-treated monocytes. ZA inhibited the mevalonate pathway of MM DC and induced the intracellular accumulation and release into the supernatant of isopentenyl pyrophosphate, a selective γδ T cell activator, in sufficient amounts to induce the proliferation of γδ T cells. Immune responses against the tumor-associated Ag survivin (SRV) by ...
Purpose: Polyclonal IgG, IgA, and IgM immunoglobulins are often decreased in sera of patients wit... more Purpose: Polyclonal IgG, IgA, and IgM immunoglobulins are often decreased in sera of patients with multiple myeloma (MM), whereas very few data are available on polyclonal IgE levels. We have determined IgE levels in a large series of MM patients at diagnosis and subjects with monoclonal gammopathy of undetermined significance (MGUS) and correlated IgE levels with survival and prognostic factors in MM.Experimental Design: IgE were determined with a commercially available ELISA kit in 201 MM patients at diagnosis, 144 subjects with MGUS, and 77 age-matched controls.Results: IgE levels progressively decreased from controls to MGUS and from MGUS to MM (P = 0.001). MM patients with IgE levels of >11.5 IU/mL (median) had a better survival than patients with IgE of <11.5 IU/mL (P = 0.048). The difference was even more significant when MM patients were divided according to clinical cutoff values. Patients with elevated IgE levels (>100 IU/mL) had from 2 to 3 years longer survival ...
SUMMARY The recombinant interleukin-2 (rIL-2) generation of lymphokine-activated killer (LAK) cel... more SUMMARY The recombinant interleukin-2 (rIL-2) generation of lymphokine-activated killer (LAK) cells wasinvestigated in peripheral blood T lymphocytes (PBT) of 16 patients with monoclonal gammopathyof undetermined significance (MGUS) and 32 patients with multiple myeloma (MM). LAK activitywas significantly decreased in MM. but not in MGUS patients, and was partially recovered in MM inthe remission phase. This finding was unexpected, because CD8+ CD11b+ cells, which contain LAKprecursors, are significantly increased in MM. LAK activity was investigated in purifiedCD8+ CD11b+ lymphocytes to discriminate between an intrinsic defect or a defective regulation byother T cell subsets. These cells were intrinsically unable to generate LAK activity fully followingrIL-2 stimulation. MM showed the more pronounced LAK deficiency, while MGUS patients showedintermediate values. Phenotyping revealed significantly increased proportions of Leu7+ and HLA-DR+ cells in MM patients. These data reveal ano...
High-dose (200 mg/m2, MEL200) and intermediate-dose melphalan (100 mg/m2, MEL100) showed signific... more High-dose (200 mg/m2, MEL200) and intermediate-dose melphalan (100 mg/m2, MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestin...
IntroductionBone marrow (BM) Vγ9Vδ2 T cells are intrinsically predisposed to sense the immune fit... more IntroductionBone marrow (BM) Vγ9Vδ2 T cells are intrinsically predisposed to sense the immune fitness of the tumor microenvironment (TME) in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).MethodsIn this work, we have used BM Vγ9Vδ2 T cells to interrogate the role of the immune checkpoint/immune checkpoint-ligand (ICP/ICP-L) network in the immune suppressive TME of MM patients.ResultsPD-1+ BM MM Vγ9Vδ2 T cells combine phenotypic, functional, and TCR-associated alterations consistent with chronic exhaustion and immune senescence. When challenged by zoledronic acid (ZA) as a surrogate assay to interrogate the reactivity to their natural ligands, BM MM Vγ9Vδ2 T cells further up-regulate PD-1 and TIM-3 and worsen TCR-associated alterations. BM MM Vγ9Vδ2 T cells up-regulate TIM-3 after stimulation with ZA in combination with αPD-1, whereas PD-1 is not up-regulated after ZA stimulation with αTIM-3, indicating a hierarchical regulation of inducible ICP e...
Understanding antibody-based SARS-CoV-2 immunity in hematologic malignancy (HM) patients followin... more Understanding antibody-based SARS-CoV-2 immunity in hematologic malignancy (HM) patients following infection is crucial to inform vaccination strategies for this highly vulnerable population. This cross-sectional study documents the anti-SARS-CoV-2 humoral response and serum neutralizing activity in 189 HM patients recovering from a PCR-confirmed infection. The overall seroconversion rate was 85.7%, with the lowest values in patients with lymphoid malignancies or undergoing chemotherapy. Therapy-naive patients in the “watch and wait” status were more likely to seroconvert and display increased anti-s IgG titers. Enhanced serum neutralizing activity was observed in the following SARS-CoV-2-infected HM patient groups: (i) males; (ii) severe COVID-19; and (iii) “watch and wait” or “complete/partial response”. The geometric mean (GeoMean) ID50 neutralization titers in patients analyzed before or after 6 months post-infection were 299.1 and 306.3, respectively, indicating that >50% of...
Background Immunoglobulin M multiple myeloma and Waldenström macroglobulinemia are two different ... more Background Immunoglobulin M multiple myeloma and Waldenström macroglobulinemia are two different hematological diseases with the common finding of an immunoglobulin M monoclonal gammopathy of unknown significance. However, clinical characteristics of the two entities can overlap. Case presentation In this report, we describe two cases of immunoglobulin M neoplasm with the same histological bone marrow presentation but with different clinical behavior, cytogenetics, and biological assessment. On the basis of comprehensive diagnostic workup, these patients were considered to have different diseases and treated accordingly with different approaches. Patient 1 (Caucasian man) presented with increased serum protein and immunoglobulin M (7665 mg/L) with an M-spike electrophoresis of 4600 mg/L. His bone marrow biopsy revealed a small-cell immunoglobulin M multiple myeloma. The result of testing for the MYD88 L265P mutation was negative, while fluorescence in situ hybridization analysis sho...
Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the im... more Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id...
Vγ9Vδ2 T cells are non-conventional T cells with a natural inclination to recognize and kill canc... more Vγ9Vδ2 T cells are non-conventional T cells with a natural inclination to recognize and kill cancer cells. Malignant B cells, including myeloma cells, are privileged targets of Vγ9Vδ2 T cells . However, this inclination is often lost due to multiple mechanisms mediated by tumor cells and local microenvironment. Multiple myeloma (MM) is a paradigm disease in which antitumor immunity is selectively impaired at the tumor site. By interrogating the immune reactivity of bone marrow (BM) Vγ9Vδ2 T cells to phosphoantigens, we have revealed a very early and long-lasting impairment of Vγ9Vδ2 T-cell immune functions which is already detectable in monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even in clinical remission after autologous stem cell transplantation. Multiple cell subsets [MM cells, myeloid-derived suppressor cells, regulatory T cells, and BM-derived stromal cells (BMSC)] are involved in Vγ9Vδ2 T-cell inhibition several immune suppressive mechanis...
Perceiving the need for rigorous recommendations to facilitate decisions concerning the managemen... more Perceiving the need for rigorous recommendations to facilitate decisions concerning the management of patients with multiple myeloma (MM), the Italian Society of Hematology (SIE) and the two affiliate societies (SIES and GITMO) commissioned a project to develop guidelines for the therapy of MM using evidence-based knowledge and consensus formation techniques. After a comprehensive systematic review of 1,450 papers, an Expert Panel formulated and graded sixty recommendations according to the supporting evidence. Evidence gaps were filled with twenty-two consensus-based statements. High grade recommendations (grade A) are reported below. Treatment should be immediately initiated in MM patients with related organ damage: those patients aged below 65 years who do not have severe co-morbidities should receive autologous stem cell transplantation, while patients not candidates for autologous stem cell transplantation should receive oral melphalan and prednisone. Interferon-a should not be...
Vγ9Vδ2 T cells play a major role as effector cells of innate immune responses against microbes, s... more Vγ9Vδ2 T cells play a major role as effector cells of innate immune responses against microbes, stressed cells, and tumor cells. They constitute <5% of PBLs but can be expanded by zoledronic acid (ZA)-treated monocytes or dendritic cells (DC). Much less is known about their ability to act as cellular adjuvants bridging innate and adaptive immunity, especially in patients with cancer. We have addressed this issue in multiple myeloma (MM), a prototypic disease with several immune dysfunctions that also affect γδ T cells and DC. ZA-treated MM DC were highly effective in activating autologous γδ T cells, even in patients refractory to stimulation with ZA-treated monocytes. ZA inhibited the mevalonate pathway of MM DC and induced the intracellular accumulation and release into the supernatant of isopentenyl pyrophosphate, a selective γδ T cell activator, in sufficient amounts to induce the proliferation of γδ T cells. Immune responses against the tumor-associated Ag survivin (SRV) by ...
Purpose: Polyclonal IgG, IgA, and IgM immunoglobulins are often decreased in sera of patients wit... more Purpose: Polyclonal IgG, IgA, and IgM immunoglobulins are often decreased in sera of patients with multiple myeloma (MM), whereas very few data are available on polyclonal IgE levels. We have determined IgE levels in a large series of MM patients at diagnosis and subjects with monoclonal gammopathy of undetermined significance (MGUS) and correlated IgE levels with survival and prognostic factors in MM.Experimental Design: IgE were determined with a commercially available ELISA kit in 201 MM patients at diagnosis, 144 subjects with MGUS, and 77 age-matched controls.Results: IgE levels progressively decreased from controls to MGUS and from MGUS to MM (P = 0.001). MM patients with IgE levels of >11.5 IU/mL (median) had a better survival than patients with IgE of <11.5 IU/mL (P = 0.048). The difference was even more significant when MM patients were divided according to clinical cutoff values. Patients with elevated IgE levels (>100 IU/mL) had from 2 to 3 years longer survival ...
SUMMARY The recombinant interleukin-2 (rIL-2) generation of lymphokine-activated killer (LAK) cel... more SUMMARY The recombinant interleukin-2 (rIL-2) generation of lymphokine-activated killer (LAK) cells wasinvestigated in peripheral blood T lymphocytes (PBT) of 16 patients with monoclonal gammopathyof undetermined significance (MGUS) and 32 patients with multiple myeloma (MM). LAK activitywas significantly decreased in MM. but not in MGUS patients, and was partially recovered in MM inthe remission phase. This finding was unexpected, because CD8+ CD11b+ cells, which contain LAKprecursors, are significantly increased in MM. LAK activity was investigated in purifiedCD8+ CD11b+ lymphocytes to discriminate between an intrinsic defect or a defective regulation byother T cell subsets. These cells were intrinsically unable to generate LAK activity fully followingrIL-2 stimulation. MM showed the more pronounced LAK deficiency, while MGUS patients showedintermediate values. Phenotyping revealed significantly increased proportions of Leu7+ and HLA-DR+ cells in MM patients. These data reveal ano...
High-dose (200 mg/m2, MEL200) and intermediate-dose melphalan (100 mg/m2, MEL100) showed signific... more High-dose (200 mg/m2, MEL200) and intermediate-dose melphalan (100 mg/m2, MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestin...
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