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M Massaia

Publications and source records attributed to M Massaia.

At least 19 recordsLinked to original sources
PubMed2005

Effector gammadelta T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma.

The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood Vgamma9/Vdelta2 (gammadelta) T cells of normal donors and multiple myeloma (MM) patients. gammadelta T cells were stimulated with Zol and low doses of interleukin-2 (IL-2), and then analyzed for proliferation, cytokine production, and generation of effector activity against myeloma cell lines and primary myeloma cells. Proliferation of gammadelta T cells was observed in 100% of normal donors and 50% of MM patients. gammadelta T cells produced IFN-gamma, surface mobilized the CD107a and CD107b antigens, and exerted direct cell-to-cell antimyeloma activity irrespective of the ability to proliferate to Zol and IL-2. The memory phenotype was predominant in the MM gammadelta T cells that proliferated in response to Zol (responders), whereas effector cells were predominant in those that did not (nonresponders). Zol induced antimyeloma activity through the monocyte-dependent activation of gammadelta T cells and by enhancing the immunosensitivity of myeloma cells to gammadelta T cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.

Antineoplastic Agents↗
PubMed2004

Long-term follow-up of idiotype vaccination in human myeloma as a maintenance therapy after high-dose chemotherapy.

The aim of this work was to evaluate the long-term immunological and clinical impact of idiotype (Id) vaccination in multiple myeloma (MM) patients in first remission after high-dose chemotherapy. A total of 15 patients received a series of subcutaneous (s.c.) injections of autologous Id, conjugated to keyhole limpet hemocyanin (KLH) and in association with low doses of GM-CSF. The median duration of follow-up was 110 months from diagnosis. The vaccine induced immune responses that lasted almost 2 years after the end of treatment. Antibody responses included anti-KLH IgM and IgG (90% of patients), anti-KLH IgE (30%), anti-GM-CSF IgG (20%), anti-Id IgG (20%), and anti-Id IgE (30%). Id-specific delayed type hypersensitivity skin tests were positive in 85% of tested patients. Following vaccination, a progressive recovery of T-cell receptor (TCR) diversity was observed and the loss of oligoclonality was significantly correlated with the remission duration. Although Id/KLH conjugates did not eliminate the residual tumor burden, the median progression-free survival, and overall survival were 40 and 82 months, respectively. A retrospective case-matched analysis showed similar results in patients treated with IFN-alpha alone or in association with steroids. This vaccine formulation can overcome Id-specific immune tolerance by inducing clinical responses that are worthy of further investigation.

Adjuvants, Immunologic↗
PubMed2004

Multiple myeloma: comparison of two dose-intensive melphalan regimens (100 vs 200 mg/m(2)).

Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m(2), MEL200) vs standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m(2), MEL100) is also superior to the standard dose, but has not been clinically compared with MEL200. A total of 90 patients at diagnosis were treated with two MEL100 courses. Their clinical outcome was compared with that of a control group of 90 pair mates matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage. These patients were treated at diagnosis with two MEL200 courses. Patient characteristics were similar in both groups except that the median age of the MEL100 group was significantly higher (P<0.0001). Complete remission was 35% after MEL100 and 48% after MEL200 (P=0.08). Median event-free survival (EFS) was 32 months in the MEL100 group and 42 months in the MEL200 group (P<0.005), but overall survival (OS) was not different. Transplant-related mortality was not significantly different. Haematological and extra-haematological toxicity was significantly reduced after MEL100. Despite the significant age difference, tandem MEL100 was less toxic than tandem MEL200, and MEL100 was inferior to MEL200 in terms of EFS but not in terms of OS. The intensified nonmyeloablative MEL100 regimen is an effective first-line treatment.

Adult↗
PubMed2001

Severe and long-lasting disruption of T-cell receptor diversity in human myeloma after high-dose chemotherapy and autologous peripheral blood progenitor cell infusion.

Vaccine-based strategies are currently under investigation as a means of inducing tumour-specific immune responses and improving the clinical outcome of multiple myeloma (MM) patients in remission after high-dose chemotherapy and peripheral blood progenitor cell (PBPC) infusion. The immune competence of these patients was investigated by determining the overall diversity of the T-cell receptor (TCR) repertoire in the peripheral blood (PB) and bone marrow (BM). The average time after transplantation was 13 months. The clonality and reciprocal usage of BV gene segments (TCRBV repertoire) was estimated at the cDNA level and membrane protein expression. The TCRBV repertoire of MM was severely disrupted compared with age-matched normal donors. On average, one-third of the total repertoire in both the PB and the BM consisted of T cells expressing oligoclonal TCRbeta transcripts. Flow cytometry showed an increased frequency of abnormally expanded BV subfamilies at both sites. BV expansions were predominantly CD8+ and had the phenotype of antigen-experienced memory T cells as well as T cells with the naive phenotype. Oligoclonality was not restricted to phenotypically expanded BV subfamilies, but also involved normally represented BV subfamilies. The TCR repertoire of MM in remission was then compared with monoclonal gammopathy of undetermined significance (MGUS) and MM patients at diagnosis. The degree of TCR diversity was similar in age-matched normal donors and MGUS, but progressively decreased from MGUS to MM at diagnosis and then to MM in remission. These data indicate that: (1) there is a long-lasting and severe disruption of TCR diversity after high-dose chemotherapy and PBPC infusion, and (2) the extent of TCR disruption may affect the clinical outcome of vaccine-based strategies delivered at the stage of minimal residual disease.

Bone Marrow Cells↗
PubMed2001

[PSA/volume ratio in prostatic disease in the elderly].

Prostate Specific Antigen (PSA) is the most important marker of prostate diseases actually available. The aim of this study was to evaluate the relations between aging, PSA and prostatic volume's increase, and whether these relations justify the adoption of different normality ranges of PSA in the elderly. We considered 285 patients aged over 60 years (mean age 69.01 years), with Benign Prostatic Hyperplasia (BPH) and absence of malignant prostatic disease, prostatic phlogosis and absuntion of drugs that can influence the PSA's levels in the serum. Patients underwent PSA, digital rectal exploration and transrectal ultrasonography, with determination of the three prostatic diameters, of the prostatic volume by the ellipsoid formula and of the maximum adenoma diameter; PSA was determined in all patients and PSA free in those with total PSA > 4 ng/ml; the PSA density was calculated. We found that age does not correlate with PSA and is poorly correlated with prostatic volume (p < 0.05); on the contrary, PSA values are strongly related with prostatic volume and maximum diameter of adenoma (p < 0.01). Mean free PSA value was 16.3 +/- 5.99%, and most of patients had values in the so-called grey zone of discrimination between benignity and malignity. We conclude that in elderly patients with volume. These results suggest the possibility to consider as indicative of benignity also total PSA values between 4 and 10 ng/ml, when they are associated with a significative prostatic volume's increase and with free PSA greater than 10%.

Aged↗
PubMed2000

Increased expression of non-functional killer inhibitory receptor CD94 in CD8+ cells of myeloma patients.

Different MHC class I-specific killer inhibitory receptors (KIRs) are expressed in vivo by a minor fraction of activated memory CD8+ cells. It has been postulated that KIRs may 'fine-tune' specific responses by altering their threshold of activation by the TCR-CD3 complex. We have previously shown that, in multiple myeloma (MM) patients, a large fraction of peripheral blood CD8+ cells display the phenotype of chronically activated memory T cells (CD38+, HLA-DR+, CD25-, CD45R0+, CD28-). We investigated the expression of KIRs on MM T cells and determined their possible influence on cytolytic responses elicited via the CD3-TCR complex. The expression of CD94, a molecule that is part of a heterodimeric KIR recognizing the non-classical MHC surface HLA-E molecule, was almost threefold higher in MM T cells than in age-matched normal control subjects (P < 0.0001). CD94 expression was preferentially confined to CD8+ cells but not restricted to activated (HLA-DR+) and/or memory (CD45R0+) T cells. Unlike normal T cells, in which CD94 is assembled with glycoproteins of the NKG2 family to form functional receptors with activating or inhibitory properties, most CD94+ MM T cells were devoid of both the NKG2-A and NKG2-C glycoproteins detected in the inhibitory or activating form respectively. CD94 blockade did not significantly affect either T-cell proliferation or cytotoxic T-lymphocyte generation induced by the myeloma-derived cell lines NCI and RPMI 8226. Similarly, the cytolytic activity induced by direct anti-CD3-mediated targeting of MM T cells to FCR+ P815 target cells was unaffected by the addition of anti-CD94 and/or anti-NKG2-A/C monoclonal antibodies (mAbs). These data indicate that the large majority of MM CD8+ cells do not express a functional CD94 receptor. Thus, their ability to 'fine-tune' an appropriate immune response against tumour cells can be impaired.

Antibodies, Monoclonal↗
PubMed2000

Antitumor vaccination: where we stand.

BACKGROUND AND OBJECTIVES: Vaccination is an effective medical procedure of preventive medicine based on the induction of a long-lasting immunologic memory characterized by mechanisms endowed with high destructive potential and specificity. In the last few years, identification of tumor-associated antigens (TAA) has prompted the development of different strategies for antitumor vaccination, aimed at inducing specific recognition of TAA in order to elicit a persistent immune memory that may eliminate residual tumor cells and protect recipients from relapses. In this review characterization of TAA, different potential means of vaccination in experimental models and preliminary data from clinical trials in humans have been examined by the Working Group on Hematopoietic Cells. EVIDENCE AND INFORMATION SOURCES: The method employed for preparing this review was that of informal consensus development. Members of the Working Group met four times and discussed the single points, previously assigned by the chairman, in order to achieve an agreement on different opinions and approve the final manuscript. Some of the authors of the present review have been working in the field of antitumor immunotherapy and have contributed original papers to peer-reviewed journals. In addition, the material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF THE ART: The cellular basis of antitumor immune memory consists in the generation and extended persistence of expanded populations of T- and B-lymphocytes that specifically recognize and react against TAA. The efficacy of the memory can be modulated by compounds, called "adjuvants", such as certain bacterial products and mineral oils, cytokines, chemokines, by monoclonal antibodies triggering co-stimulatory receptors. Strategies that have been shown in preclinical models to be efficient in protecting from tumor engraftment, or in preventing a tumor rechallenge, include vaccination by means of soluble proteins or peptides, recombinant viruses or bacteria as TAA genes vectors, DNA injection, tumor cells genetically modified to express co-stimulatory molecules and/or cytokines. The use of professional antigen-presenting cells, namely dendritic cells, either pulsed with TAA or transduced with tumor-specific genes, provides a useful alternative for inducing antitumor cytotoxic activity. Some of these approaches have been tested in phase I/II clinical trials in hematologic malignancies, such as lymphoproliferative diseases or chronic myeloid leukemia, and in solid tumors, such as melanoma, colon cancer, prostate cancer and renal cell carcinoma. Different types of vaccines, use of adjuvants, timing of vaccination as well as selection of patients eligible for this procedure are discussed in this review. PERSPECTIVES: Experimental models demonstrate the possibility of curing cancer through the active induction of a specific immune response to TAA. However, while pre-clinical research has identified several possible targets and strategies for tumor vaccination the clinical scenario is far more complex for a number of possible reasons. Since experimental data suggest that vaccination is more likely to be effective on small tumor burden, such as a minimal residual disease after conventional treatments, or tumors at an early stage of disease, better selection of patients will allow more reliable clinical results to be obtained. Moreover, a poor correlation is frequently observed between the ability of TAA to induce a T-cell response in vitro and clinical responses. Controversial findings may also be due to the techniques used for monitoring the immune status. Therefore, the development of reliable assays for efficient monitoring of the state of immunization of cancer patients against TAA is an important goal that will markedly improve the progress of antitumor vaccines. (ABSTRACT TRUNCATED)

Adjuvants, Immunologic↗
PubMed1999

Idiotype vaccination in human myeloma: generation of tumor-specific immune responses after high-dose chemotherapy.

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-specific delayed-type hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH specificity was confirmed in 1 patient by investigating the reactivity to synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy chain. None of the patients generated soluble immune responses to Id, whereas the generation of soluble and cellular immune responses to KLH was observed in 100% and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient failed to finish owing to progression of disease. Freedom from disease progression (FFDP), measured from the date of first Id/KLH injection to the date of first treatment after vaccination or last follow-up, ranged from 9 to 36 months. These data indicate that the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation. It remains to be determined whether generation of Id-specific immune responses can reduce the relapse rate of patients with minimal residual disease.

Adjuvants, Immunologic↗
PubMed1999

CD38 stimulation lowers the activation threshold and enhances the alloreactivity of cord blood T cells by activating the phosphatidylinositol 3-kinase pathway and inducing CD73 expression.

We have recently described in cord blood T cells (CBTC) a novel pathway linking CD38 and CD73, two signal transducers with ecto-enzyme activity. The aim of this study was 2-fold: first, to characterize the mechanisms by which CD38 regulates CD73 expression; and second, to determine whether surface-induced CD73 modulates CBTC responses. A marked increase in CD73 expression was observed in CD38+ cells after incubation with the appropriate CD38 mAbs. The induction of CD73 was blocked by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3-K). CD38 stimulation induced tyrosine phosphorylation of the p85 regulatory subunit of PI3-K and its association with other tyrosine-phosphorylated proteins. Surface-induced CD73 was as efficient in delivering activatory signals as the CD73 constitutively expressed on adult T cells. Highly CBTC, totally unresponsive to mitogenic concentrations of plastic-immobilized CD3 mAb, proliferated vigorously when exposed to the combination of plastic-immobilized CD3 and CD73 mAbs. The reactivity to allogeneic irradiated PBMC was also significantly enhanced by CD38 stimulation and was dependent on CD73 expression. Thus, CD38 stimulation lowers the activation threshold of CBTC by the CD3/TCR complex and enhances their reactivity to allogeneic cells via activation of the PI3-kinase pathway and CD73 expression.

5'-Nucleotidase↗
PubMed1999

Idiotypic vaccination as therapy for multiple myeloma.

Although advances in the treatment of multiple myeloma have been made using high-dose chemotherapy with subsequent autologous stem-cell transplantation, recurrence of the underlying disease almost invariably occurs. One proposed strategy to increase survival is tumor-specific activation of the immune system via idiotypic protein vaccination. Current issues to be resolved in the development of this approach include optimal vaccine formulation, appropriate assays to monitor treatment results, and timing of vaccine administration. Several clinical trials of idiotypic vaccines are currently being conducted in the United States and Europe. Initial results support the use of these vaccines as adjunct therapy in patients with multiple myeloma after high-dose chemotherapy and transplantation.

Cancer Vaccines↗
PubMed1997

Transfer of the interleukin-2 gene into human cancer cells induces specific antitumor recognition and restores the expression of CD3/T-cell receptor associated signal transduction molecules.

Normal peripheral blood mononuclear cells (PBMC) were co-cultured with a human lung cancer cell line (LC89) transduced with the interleukin-2 (IL-2), IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha) genes to evaluate the capacity of the engineered cells to: allow survival of CD3+ and CD56+ cells, generate cytotoxic effectors with HLA class I restricted and unrestricted antitumor activity, and interfere in the molecular organization of the CD3/T-cell receptor associated signal transduction machinery. When PBMC were cultured up to 3 weeks with IL-2 releasing LC89 cells (LC89/IL-2), the number of viable CD3+ and CD56+ lymphocytes was much greater than in cultures with parental cells or with LC89 cells transduced with the other cytokine genes. After 1 week of coculture, a variable degree of restricted and unrestricted killing directed against different targets was observed. When the cultures were prolonged up to 3 weeks, LC89/IL-2 cells induced a marked increase in specific cytotoxic activity, which was coupled to a further enhancement of unrestricted lytic function. In the presence of LC89/IL-7 cells the degree of specific lysis remained unchanged, whereas unrestricted effectors were markedly decreased. No cytotoxic activity could be induced by LC89/GM-CSF and LC89/TNF-alpha cells in the few lymphocytes surviving after 3 weeks of culture. Coculture of parental LC89 cells with PBMC was consistently associated with a downmodulation in the expression of the CD3 zeta chain, as well as of the tyrosine kinases p56ick and ZAP-70. On the contrary, LC89/IL-2 cells, and not LC89 cells transduced with the IL-7, GM-CSF, or TNF-alpha gene, were capable of reverting the immunosuppressive effect exerted by the tumor cells. This protective effect could be maintained in cultures prolonged up to 4 weeks. When the same cultures were set up in Transwell, ie, with a membrane separation between cancer cells and PBMC, the expression of the CD3 zeta chain and of the p56ick and ZAP-70 tyrosine kinases remained unchanged under all culture conditions, indicating that the downmodulation of T-cell signal transduction molecules requires a direct cell to cell contact. These results show that transfer of the IL-2 gene into the DNA of human cancer cells promotes both restricted and unrestricted antitumor activity, and is capable of restoring and maintaining the expression of molecules involved in the process of T-cell mediated tumor cell recognition, thus underlining the potential role of the IL-2 gene in the design of vaccination protocols with cytokine gene transduced cancer cells.

Adenocarcinoma↗
PubMed1997

Idiotypic vaccination in B-cell malignancies.

Immunoglobulins contain unique portions, collectively termed idiotypes, that can be recognized by the immune system. Idiotypes expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and targets for vaccine immunotherapy. Haptens and adjuvants, including cytokines, have been used in several animal models to increase idiotype immunogenicity and establish protective anti-idiotype immunity. These results have been extended by the use of DNA technology, and this has led to the development of a new generation of immunogens, namely fusion proteins and naked-DNA vaccines. The central role of antigen-presenting cells as initiators of anti-idiotype immune responses has also been recognized. Guided by the experimental data, idiotypic vaccination has come into medical use in patients with lymphoma and multiple myeloma.

Antigen-Presenting Cells↗
PubMed1997

Distribution of T-cell signalling molecules in human myeloma.

It is controversial whether altered levels of TCR/CD3-associated signalling molecules play a role in the T-cell dysfunction of cancer patients. In multiple myeloma (MM), peripheral blood T (PBT) lymphocytes are functionally impaired by prolonged exposure to tumour cells, and so we investigated the organization of the TCR/CD3-associated signal transduction machinery. The aim of this study was two-fold: first, to investigate the levels of CD3zeta, p56(lck), p59(fyn), ZAP-70, protein kinase C-alpha (PKC-alpha) and phospholipase C-gamma (PLC-gamma) in MM PBT cells; second, to determine whether levels of expression were correlated with clinical or prognostic factors. Forty-four MM patients were studied and 25 age-matched normal donors served as controls. On average, PKC-alpha was the only significantly decreased (P<0.001) signalling molecule, whereas levels of CD3zeta, p56(lck), p59(fyn), PLC-gamma and ZAP-70 were not statistically different. However, there was wide variation between individual patients, and levels for each single protein also varied. A 75% or greater decrease in protein expression was observed, ranging from 8% (p59(fyn)) to 68% (PCK-alpha) of MM patients. When patients were grouped according to the cut-off values of prognostic factors such as the serum levels of C reactive protein (CRP), beta2-microglobulin (beta2M), neopterin (NPT) and the labelling index (LI%) of bone marrow (BM) plasma cells, the only difference observed was the lower PKC-alpha expression in patients with high serum NPT values. None of the T-cell signalling molecule levels was affected by the duration of tumour exposure, calculated on the number of years and/or months that had elapsed since diagnosis, or by disease status. In conclusion, there was a significant decrease of PCK-alpha in MM T cells; however, neither this decrease nor the heterogenous levels of the other T-cell signalling molecules were clearly correlated with prognosis, duration of tumour exposure, and disease status.

Cell Communication↗