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J G Gribben

Publications and source records attributed to J G Gribben.

At least 19 recordsLinked to original sources
PubMed2005

The evolving role of alemtuzumab in management of patients with CLL.

New insights into prognostic markers and the pathophysiology of chronic lymphocytic leukemia (CLL) are beginning to change the concept of CLL treatment. Alemtuzumab has evolved as a potent and effective therapeutic option for patients with CLL. Specifically, alemtuzumab has demonstrated substantial efficacy in fludarabine-refractory patients and has shown impressive responses when administered subcutaneously in first-line therapy. A group of experts gathered to discuss new data related to the use of alemtuzumab in CLL and to assess its place in the rapidly changing approach to treating patients with this disease. The main goals of this program were to update the management guidelines that were previously developed for alemtuzumab-treated patients and to provide community oncologists with guidance on the most effective way to integrate alemtuzumab into a CLL treatment plan.

Alemtuzumab↗
PubMed2004

Prognostic impact of p27KIP1 expression in cyclin D1 positive lymphoproliferative disorders.

Nodal mantle cell lymphoma (MCL) is a well-defined entity, but non-nodal leukemic cyclin D1 positive lymphoproliferative disorders have been reported and their relationship with MCL remains controversial and their prognosis heterogeneous. We prospectively studied the expression of cyclin D1 in CD5 positive leukemic B lymphoproliferative disorders at diagnosis and identified 65 cases overexpressing cyclin D1. We did not distinguish any clinical or biological criteria allowing one to identify a non-MCL group. Multivariate analysis identified age, anemia and p27kip1 expression as independent prognostic factors of survival. By univariate analysis, p27kip1 high expression proved to be the strongest predictor of prolonged survival. The median survival of p27 low expressors was 30 months, while it was not reached for p27 high expressors. A high level of p27 expression was often found associated with the absence of nodal involvement and the presence of somatic mutations, but neither of them was restricted to the p27 high expression group. In conclusion, we hypothesize that MCL and these cyclin D1 positive leukemic lymphoproliferative disorders represent a continuous spectrum of diseases. Determination of p27 expression level appears as a routine applicable test allowing identification of a subset of patients who could be considered for different therapeutic approaches.

Adult↗
PubMed2004

CD40 activation: potential for specific immunotherapy in B-CLL.

Despite encouraging scientific and therapeutic advances, chronic lymphocytic leukemia (CLL) principally remains an incurable disease. Allogeneic transplantation represents the only curative approach, but is marked by high mortality. Novel and less toxic treatment modalities are needed. Immunotherapeutic approaches have clearly demonstrated potential effectiveness in CLL and other B-cell malignancies. To successfully direct immunity against CLL, highly immunogenic tumor cells or tumor-antigen-loaded antigen-presenting cells are necessary. The CD40-CD40L interaction has been shown to significantly increase antigen presentation in normal and malignant B-cells. Here we discuss biology and potential therapeutic applications of the CD40-system in CLL.

Antigen Presentation↗
PubMed2003

Ex vivo B cell depletion using the Eligix B Cell SC system and autologous peripheral blood stem cell transplantation in patients with follicular non-Hodgkin's lymphoma.

One limitation of ASCT is the potential reinfusion of tumor cells contaminating PBSC. The Eligix B cell SC system consists of high-density microparticles coated with anti-B cell antibodies. To determine if this system eliminates B cells and lymphoma cells from PBSC, immunocytochemistry and PCR of the bcl-2/IgH rearrangement were performed, and correlated with patient outcome after ASCT. Eligible patients (n=29) had relapsed or transformed follicular NHL with bone marrow involvement <20%, and all lymph nodes <5 cm. PBSCs were mobilized with cyclophosphamide/G-CSF (n=21), and patients were conditioned with cyclophosphamide, carmustine and etoposide. Using immunocytochemistry on PBSC, the median number of CD20+ cells pre-purge was 310/10(6) (range 0-16692) and post-purge was 0.75/10(6); the median log B cell depletion was 2.7 (range 1.4-3.9). B cell depletion correlated with PFS after ASCT (P=0.06). Of 17 available samples for PCR, only four had a detectable t(14;18) breakpoint. After purging, all four remained PCR+; two had a 1-3 log depletion of lymphoma cells. At median follow-up of 18 months, 10 patients, including five infused with PCR-negative PBSC, have had disease progression. The paucity of PCR-informative patients, possibly related to in vivo rituximab therapy, limited the utility of minimal residual disease as a surrogate marker of clinical outcome.

Adult↗
PubMed2002

Autologous hematopoietic transplantation for low-grade lymphomas.

BACKGROUND: Autologous stem cell transplantation (SCT) has become the treatment of choice for patients with relapsed chemo-sensitive intermediate grade lymphoma, but its role in the treatment of low-grade lymphomas and in selected patients in first remission remains controversial. METHODS: A large number of clinical trials have evaluated the role autologous SCT in both low grade and intermediate grade non-Hodgkin's lymphomas (NHL). These studies have attempted to evaluate the role of high dose therapy with stem cell support in comparison to more conventional chemotherapy approaches. Studies have also focused on methods to assess whether contaminating tumor cells are contained with the stem cell collection and whether this has impact on outcome. With an increased number of patients now long term survivors, additional studies are focusing on long term complications and in particular the emergence of secondary malignancies. RESULTS: Virtually all patients now receive peripheral blood stem cells rather than bone marrow as a source of stem cells. The role of purging of residual tumor cells remains controversial and no randomized trial has been published to date that could evaluate the clinical utility of cell manipulation to attempt to remove contaminating lymphoma cells. Secondary leukemia is emerging as a major source of long-term morbidity and mortality after autologous stem cell transplantation. CONCLUSION: Autologous SCT is associated with improved outcome in patients with relapsed intermediate grade lymphoma and most likely prolongs disease free survival in patients with low grade NHL. Morbidity and mortality of the procedure is low and major efforts are being made to attempt to decrease the major causes of failure, which remain disease relapse and occurrence of secondary malignancies.

Bone Marrow Transplantation↗
PubMed2001

Induction of cytotoxic T-cell responses against immunoglobulin V region-derived peptides modified at human leukocyte antigen-A2 binding residues.

Cytotoxic T-lymphocyte (CTL) responses can be generated against peptides derived from the immunoglobulin (Ig) V region in some but not all patients. The main reason for this appears to be the low peptide-binding affinity of Ig-derived peptides to major histocompatibility complex (MHC) class I molecules and their resulting low immunogenicity. This might be improved by conservative amino acid modifications at the MHC-binding residues of the peptides (heteroclitic peptides). In this study, it was found that in 18 Ig-derived peptides, that heteroclitic peptides from the Ig gene with improved binding to human leukocyte antigen (HLA)-A*0201 can be used to improve CTL responses. Amino acid substitution substantially increased predicted binding affinity, and there was a strong correlation between predicted and actual binding to HLA-A*0201. CTLs generated against the heteroclitic peptide had not only enhanced cytotoxicity against the heteroclitic peptide but also increased killing of antigen-presenting cells pulsed with the native peptide. Surprisingly, no difference was observed in the frequency of T cells detected by MHC class I peptide tetramers after stimulation with the heteroclitic peptide compared with the native peptide. CTLs generated against heteroclitic peptides could kill patients' tumor cells, showing that Ig-derived peptides can be presented by the tumor cell and that the failure to mount an immune response (among other reasons) likely results from the low immunogenicity of the native Ig-derived peptide. These results suggest that heteroclitic Ig-derived peptides can enhance immunogenicity, thereby eliciting immune responses, and that they might be useful tools for enhancing immunotherapy approaches to treating B-cell malignant diseases.

Amino Acid Sequence↗
PubMed2001

Phase I study of recombinant human CD40 ligand in cancer patients.

PURPOSE: To determine the toxicity, maximum-tolerated dose (MTD), and pharmacokinetics of recombinant human CD40 ligand (rhuCD40L) (Avrend; Immunex Corp, Seattle, WA), suggested in preclinical studies to mediate cytotoxicity against CD40-expressing tumors and immune stimulation. PATIENTS AND METHODS: Patients with advanced solid tumors or intermediate- or high-grade non-Hodgkin's lymphoma (NHL) received rhuCD40L subcutaneously daily for 5 days in a phase I dose-escalation study. Subsequent courses were given until disease progression. RESULTS: Thirty-two patients received rhuCD40L at three dose levels. A total of 65 courses were administered. The MTD was 0.1 mg/kg/d based on dose-related but transient elevations of serum liver transaminases. Grade 3 or 4 transaminase elevations occurred in 14%, 28%, and 57% of patients treated at 0.05, 0.10, and 0.15 mg/kg/d, respectively. Other toxicities were mild to moderate. At the MTD, the half-life of rhuCD40L was calculated at 24.8 +/- 22.8 hours. Two patients (6%) had a partial response on study (one patient with laryngeal carcinoma and one with NHL). For the patient with laryngeal cancer, a partial response was sustained for 12 months before the patient was taken off therapy and observed on no additional therapy. Three months later, the patient was found to have a complete response and remains biopsy-proven free of disease at 24 months. Twelve patients (38%) had stable disease after one course, which was sustained in four patients through four courses. CONCLUSION: The MTD of rhuCD40L when administered subcutaneously daily for 5 days was defined by transient serum elevations in hepatic transaminases. Encouraging antitumor activity, including a long-term complete remission, was observed. Phase II studies are warranted.

Adult↗
PubMed2001

Generation of cytotoxic T lymphocytes against native and altered peptides of human leukocyte antigen-A*0201 restricted epitopes from the human epithelial cell adhesion molecule.

A growing number of human tumor antigens have been described that can be recognized by CTLs in a MHC class I restricted fashion. The epithelial cell adhesion molecule (Ep-CAM) is expressed in a variety of human tumors and has attracted attention as a therapeutic target for monoclonal antibody serotherapy. We have identified immunogenic peptides derived from Ep-CAM, that bind to human leukocyte antigen-A*0201 and elicit strong peptide-specific human CTL responses, demonstrating that there is an effective T-cell repertoire against these Ep-CAM-derived peptides that can be recruited. Alterations to these peptides were made to increase their binding affinity to MHC class I molecules. The use of such "heteroclitic" peptides allowed generation of cytotoxic T cells that demonstrated increased killing of target cells pulsed not only with the heteroclitic but also with the native peptide. Most important, CTL cell lines that are generated against these peptides specifically lyse epithelial tumor cells expressing Ep-CAM but not normal hematopoietic or bronchial epithelial cells.

Antigens, Neoplasm↗
PubMed2001

A validated real-time quantitative PCR approach shows a correlation between tumor burden and successful ex vivo purging in follicular lymphoma patients.

OBJECTIVE: Purging procedures are increasingly used to provide stem cell collections devoid of contaminating tumor cells. In follicle center lymphoma (FCL), most approaches eradicate polymerase chain reaction (PCR);-detectable disease in only a fraction of harvests undergoing ex vivo manipulation. In this study we evaluated whether there is a relationship between tumor burden of stem cell harvests and successful clearance of PCR-detectable disease following ex vivo manipulation. MATERIALS AND METHODS: To address this issue, we developed a real-time PCR approach for quantitative measurement of tumor contamination using the bcl-2 rearrangement. Real-time PCR was used to evaluate the relationship between tumor burden of stem-cell harvests and purging effectiveness in PCR(+) samples derived from 10 FCL patients. Ex vivo purging was performed using the MaxSep cell separator (Baxter Immunotherapy, Deerfield, IL, USA). RESULTS: Our real-time PCR method proved effective, sensitive, accurate, and reproducible. Four collections were successfully cleared of minimal residual disease (MRD) whereas six remained PCR(+). Real-time PCR showed that the four collections successfully cleared of MRD had a prepurging tumor burden significantly lower than those remaining PCR(+) (p = 0.04). CONCLUSION: This study provides the first evidence that evaluation of tumor burden in stem-cell harvests by real-time PCR can predict the effectiveness of therapeutic intervention in non-Hodgkin's lymphoma. Based on these findings, we foresee a more widespread use of this technique to evaluate the impact of different therapeutic approaches in FCL.

Adolescent↗
PubMed2001

A pilot study of combined immunotherapy with autologous adoptive tumour-specific T-cell transfer, vaccination with CD40-activated malignant B cells and interleukin 2.

Most B-cell malignancies are incurable diseases and therefore warrant new therapeutic approaches. In a pilot study, we tested the feasibility and safety of combined immunotherapy consisting of adoptive transfer of autologous tumour-specific T cells, low-dose interleukin 2 (IL-2) and a cellular vaccine of CD40-activated plasma cell leukaemia (PCL) cells in a patient who failed tandem repeat stem cell transplantation and idiotype vaccination. Autologous tumour-specific T cells for adoptive T-cell transfer were propagated in vitro by repetitive stimulation with autologous ex vivo CD40-activated PCL cells. CD40-activated PCL cells for vaccination were similarly generated ex vivo by co-culture with CD40 ligand transfectants. Autologous T cells (5 x 108 and 2.5 x 109 for two separate treatment cycles) generated ex vivo and cytotoxic against autologous tumours were infused and well tolerated by the patient. Fever and myalgias were closely related to IL-2 injections and no other adverse effects were observed. A temporary decrease of PCL cells in peripheral blood was seen after the first cycle of adoptive T-cell therapy, tumour cell vaccination and low-dose IL-2. Tumour progression was associated with tumour cells that (1) expressed a complex karyotype, (2) demonstrated loss of MHC class II, and (3) did not induce autologous tumour-specific T-cell lines ex vivo. We demonstrated the safety and feasibility in combining autologous tumour-specific T-cell therapy with low-dose IL-2 and that clinical trials based on the use of CD40-activated autologous tumour cell vaccines are warranted in patients with CD40-activated autologous tumour cells, either as a vaccine or for ex vivo stimulation of autologous T cells.

Adoptive Transfer↗
PubMed2001

CD40 activation of carcinoma cells increases expression of adhesion and major histocompatibility molecules but fails to induce either CD80/CD86 expression or T cell alloreactivity.

A major obstacle for the development of cancer immunotherapy is the poor capacity of most tumor cells to present antigen. It has previously been shown that ligation of CD40 on the surface of malignant B cells results in the induction of efficient antigen presentation primarily because of upregulated expression of MHC, costimulatory, and adhesion molecules. Ongoing clinical trials are testing the impact of CD40 ligation as immunotherapy for B cell malignancies. Because CD40 is also widely expressed in carcinomas, we studied whether CD40 activation of these cells using soluble recombinant trimeric human CD40 ligand (srhCD40L) can also induce T cell responses. Here, we show that carcinoma cells upregulate expression of CD54 and MHC molecules following in vitro exposure to srhCD40L but do not upregulate CD80 or CD86. CD40-activated carcinoma cells failed to trigger mixed lymphocyte reactions, in sharp contrast to CD40-activated lymphoma cells for which CD40 activation, as expected, resulted in increased expression of MHC, adhesion, and costimulatory molecules, and generated brisk allogeneic lymphocyte reactions. Retroviral-mediated expression of CD80 in carcinoma cells, with or without CD40 activation, triggered mixed lymphocyte reactions, provided cells were treated with IFN-gamma. Thus, the cell surface phenotype induced on carcinoma cells following CD40 activation is not fully capable of inducing T cell proliferation; however, these results support ongoing efforts to exploit costimulation in clinical efforts aimed at increasing carcinoma immunogenicity.

Antigen Presentation↗
PubMed2000

Immunoglobulin heavy-chain consensus probes for real-time PCR quantification of residual disease in acute lymphoblastic leukemia.

Tumor-related immunoglobulin heavy-chain (IgH) rearrangements are markers for polymerase chain reaction (PCR) detection of minimal residual disease (MRD) in B-cell malignancies. Nested PCR with patient IgH allele-specific oligonucleotide primers can detect 1 tumor cell in 10(4) to 10(6) normal cells. In childhood acute lymphoblastic leukemia (ALL), persistence of PCR-detectable disease is associated with increased risk of relapse. The clinical significance of qualitative PCR data can be limited, however, because patients can harbor detectable MRD for prolonged periods without relapse. Recent studies indicate that a quantitative rise in tumor burden identifies patients who are at high risk for relapse. Therefore, an efficient and reliable PCR method for MRD quantification is needed for ALL patients. We have developed a real-time PCR method to quantify MRD with IgH V(H) gene family consensus fluorogenically labeled probes. With this method, a small number of probes can be used to quantify MRD in a large number of different patients. The assay was found to be both accurate and reproducible over a wide range and capable of detecting approximately 1 tumor cell in 5 x 10(4) normal cells. We demonstrate that this methodology can discriminate between patients with persistence of MRD who relapse and those who do not. This technique is generally applicable to B-cell malignancies and is currently being used to quantify MRD in a number of prospective clinical studies at our institution. (Blood. 2000;95:2651-2658)

Base Sequence↗
PubMed2000

Real-Time polymerase chain reaction of immunoglobulin rearrangements for quantitative evaluation of minimal residual disease in multiple myeloma.

The majority of patients with multiple myeloma (MM) have persistence of minimal residual disease (MRD), as determined by polymerase chain reaction (PCR) detection of clonal immunoglobulin H (IgH) gene rearrangements. As a result, PCR analysis has not provided clinically useful prognostic information in myeloma patients. Instead, quantitative PCR approaches are required to predict patient outcomes and assess response to novel treatment strategies. We adapted real-time PCR technology to quantify myeloma cells using the IgH rearrangement and then assessed the utility of this approach in 29 patients with myeloma who had undergone autologous stem cell transplantation. Because of the high cost of producing a specific reporting probe for each patient, H-chain V-region family-specific consensus probes were used in association with allele-specific oligonucleotides for PCR amplification. Because of the high frequency with which somatic hypermutation at the immunoglobulin locus occurs in MM, a number of mismatches occurred between the patient sequences and the consensus probe. However, construction of a limited number of probes allowed real-time PCR with a sensitivity of 10(-4) to 10(-5). To validate this method, we extensively evaluated assay accuracy and reproducibility. Results indicate that real-time PCR using consensus probes provides a feasible, accurate, and reproducible method for evaluating MRD in M M and possibly in other differentiated B-cell malignancies, and one that is less expensive than the use of patient-specific probes. This technique is being used to assess tumor depletion after immunologic purging and changes in tumor burden in patients undergoing stem cell transplantation and novel treatment approaches.

Gene Rearrangement, B-Lymphocyte, Heavy Chain↗
PubMed2000

Immunoglobulin framework-derived peptides function as cytotoxic T-cell epitopes commonly expressed in B-cell malignancies.

Although the idiotypic structures of immunoglobulin from malignant B cells were the first tumor-specific determinants recognized, and clinical vaccination trials have demonstrated induction of tumor-specific immunity, the function of immunoglobulin-specific CD8+ cytotoxic T lymphocytes in tumor rejection remains elusive. Here, we combined bioinformatics and a T cell-expansion system to identify human immunoglobulin-derived peptides capable of inducing cytotoxic T-lymphocyte responses. Immunogenic peptides were derived from framework regions of the variable regions of the immunoglobulin that were shared among patients. Human-leukocyte-antigen-matched and autologous cytotoxic T lymphocytes specific for these peptides killed primary malignant B cells, demonstrating that malignant B cells are capable of processing and presenting such peptides. Targeting shared peptides to induce T-cell responses might further improve current vaccination strategies in B-cell malignancies.

B-Lymphocytes↗
PubMed1999

Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma.

We report the results of high-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation (ABMT) in patients with relapsed indolent follicular lymphoma. Between March 1985 and May 1995, 153 patients underwent ABMT using a uniform ablative regimen with cyclophosphamide and total body irradiation and bone marrow (BM) purging. All patients received multiple chemotherapy regimens before ABMT. At BM harvest, only 30% of patients were in complete remission, and overt BM infiltration was present in 47%. The disease-free survival (DFS) and overall survival (OS) are estimated to be 42% and 66% at 8 years, respectively. Patients whose BM was negative by polymerase chain reaction (PCR) for bcl2/IgH rearrangement after purging experienced longer freedom from recurrence than those whose BM remained PCR positive (P <.0001). Continued PCR negativity in follow-up BM samples was also strongly predictive of continued complete remission (CR). The 12-year survival from diagnosis for these 153 patients is 69%. Considering that the median survival from diagnosis and first recurrence of patients with advanced follicular lymphoma are 8 and 5 years, respectively, our results provide evidence that myeloablative therapy and ABMT may prolong overall survival.

Adult↗
PubMed1999

Transplantation of anergic histoincompatible bone marrow allografts.

BACKGROUND: Successful allogeneic bone marrow transplantation relies on global immunosuppression or elimination of T cells. In contrast, the induction of anergy can inactivate specific sets of alloreactive T cells in the donor marrow. Previous work has shown that anergy can be induced by blocking the interaction of the B7 molecule on the surface of antigen-presenting cells with the CD28 molecule on the surface of T cells, thus preventing key signaling events essential for the activation of T cells. To investigate the feasibility of this approach with respect to transplantation of histoincompatible bone marrow, we undertook a clinical trial of ex vivo induction of anergy in T cells present in donor marrow to recipient alloantigens. METHODS: Outcomes in 12 transplant recipients were evaluated. The recipients' peripheral-blood lymphocytes were collected before myeloablation and served as alloantigen-presenting cells. To induce alloantigen-specific anergy, bone marrow from a donor mismatched with the recipient for one HLA haplotype was cocultured with irradiated cells from the recipient for 36 hours in the presence of CTLA-4-Ig, an agent that inhibits B7:CD28-mediated costimulation. After conventional myeloablation and immunoprophylaxis, the treated donor cells were transfused into the recipient. RESULTS: After the induction of anergy, the frequency of T cells capable of recognizing alloantigens of the recipient in donor marrow was sharply reduced (P<0.001), whereas the responsiveness to alloantigens from persons unrelated to the recipient or the donor was unaffected (P=0.51). In the 11 patients who could be evaluated, the haploidentical bone marrow cells engrafted. Of these 11 patients, 3 had acute graft-versus-host disease (GVHD) confined to the gastrointestinal tract. No deaths were attributable to GVHD. Five of the 12 patients were alive and in remission 4.5 to 29 months after transplantation. CONCLUSIONS: Donor bone marrow treated ex vivo to induce anergy to alloantigens from the recipient can reconstitute hematopoiesis in vivo with a relatively low risk of GVHD.

Abatacept↗