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John M Timmerman

Publications and source records attributed to John M Timmerman.

13 recordsLinked to original sources
PubMed2005

Current status of therapeutic vaccines for non-Hodgkin's lymphoma.

PURPOSE OF REVIEW: Therapeutic vaccines targeting B cell lymphoma idiotype have reached an advanced stage of clinical development, with three multicenter randomized clinical trials ongoing. This review describes the rationale and development of this immunotherapeutic approach, the design of current phase III trials, and other active vaccination approaches likely to move forward into clinical testing for lymphomas. RECENT FINDINGS: Several groups have achieved promising results in phase II trials of patient-specific idiotype vaccines, with very few side effects noted. Anti-idiotype antibodies, in addition to cytotoxic T cells, are now believed to be important effectors of antitumor immunity after idiotype vaccination. The manufacturing of autologous tumor idiotype proteins is being rapidly refined by the use of molecular technologies. Two trials involving more than 1000 patients are now under way, which use idiotype vaccination after induction chemotherapy; one trial completed accrual in early 2004. A third trial opened in 2004, using rituximab followed by idiotype vaccine with maintenance booster vaccines continuing throughout the period of normal B cell recovery. In accordance with the United States Food and Drug Administration, progression-free survival serves as the accepted primary efficacy endpoint in these studies. SUMMARY: Lymphoma idiotype vaccination represents a promising immunotherapeutic approach targeting a patient-specific tumor antigen. The results of pivotal phase III trials for three first-generation idiotype vaccines will become available in the next several years. Advanced manufacturing techniques should permit application of this tailor-made treatment to large numbers of non-Hodgkin's lymphoma patients.

Cancer Vaccines↗
PubMed2005

Recombinant, tumour-derived idiotype vaccination for indolent B cell non-Hodgkin's lymphomas: a focus on FavId.

FavId (Favrille, Inc., San Diego, CA, USA) is a personalized therapeutic vaccine product for B cell non-Hodgkin's lymphoma, custom-manufactured from individual patient's tumour cells. This investigational agent consists of recombinant tumour-specific immunoglobulin (idiotype [Id]) chemically conjugated to the highly immunogenic carrier protein keyhole limpet haemocyanin (Id-KLH). The vaccine product is administered by subcutaneous co-injection with the cytokine adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) with the goal of stimulating tumour-specific T cell and humoral immunity. Therapeutic Id vaccines have shown promising results in early phase clinical trials in follicular lymphoma, and several Phase III trials are ongoing. FavId's advantages over other Id vaccine formulations include its rapid and efficient manufacturing technology utilising recombinant baculovirus, with a production time of only 8-12 weeks. In Phase II studies, FavId Id-KLH plus GM-CSF vaccines have been found to be safe, immunogenic and clinically active in follicular lymphoma. At present, FavId is being tested in a randomised, placebo-controlled Phase III trial in follicular lymphoma, aimed at improving the time to disease progression when administered following cytoreduction with rituximab. If found to be efficacious in this pivotal trial, FavId would represent a tumour-selective immunotherapy for lymphoma with little toxicity and a novel mechanism of action.

Animals↗
PubMed2003

Antitumor immunity after vaccination with B lymphoma cells overexpressing a triad of costimulatory molecules.

BACKGROUND: The costimulatory molecules B7-1, intercellular adhesion molecule-1 (ICAM-1), and leukocyte function-associated antigen-3 (LFA-3) play pivotal roles in the activation of T cells. We investigated whether in vivo vaccination with lymphoma cells infected with a recombinant, nonreplicating fowlpox (FP) virus encoding this triad of costimulatory molecules (TRICOM) could stimulate lymphoma-specific immunity. METHODS: TRICOM-infected A20 B lymphoma cells were analyzed for expression of B7-1, ICAM-1, and LFA-3. Mice (10 per group) were vaccinated with irradiated A20 cells infected with either the TRICOM vector or the wild-type FP virus (WT-FP), challenged with live A20 tumor cells, and followed for survival. Mice with established A20 tumors were also treated with irradiated TRICOM-infected A20 cells. Survival curves were compared with the log-rank statistic. The mechanism of the antitumor effect was studied by in vivo depletion of CD4(+) and CD8(+) T cells and in vitro cytotoxicity assays. All statistical tests were two-sided. RESULTS: A20 tumor cells infected with TRICOM expressed high levels of B7-1, ICAM-1, and LFA-3. Mice vaccinated with irradiated TRICOM-infected A20 cells had prolonged survival relative to mice vaccinated with WT-FP-infected cells (80% versus 20% survival at 110 days; P<.001). In mice with established tumors, tumor growth was slower in those treated with TRICOM-infected tumor cells than in those treated with WT-FP-infected cells, and this treatment provided a survival advantage (P<.001). Depletion of CD4(+) or CD8(+) T cells reduced the antitumor immunity provided by the tumor cell-TRICOM vaccine, and lymphocytes from vaccinated mice displayed in vitro cytotoxic activity toward A20 cells. CONCLUSIONS: Increasing expression of costimulatory molecules on B lymphoma cells by infection with a recombinant FP virus encoding B7-1, ICAM-1, and LFA-3 stimulates antitumor immune responses in vivo and may provide a novel strategy for treating patients with B-cell malignancies.

Animals↗
PubMed2003

Immunotherapy for lymphomas.

A growing list of immunotherapeutic strategies is now being employed to combat lymphoid malignancies. These efforts are warranted given that B-cell lymphomas, particularly those of the common follicular subtype, are among the most "immune-responsive" of all human cancers. Although systemic cytokine therapies for B-cell malignancies have been largely disappointing to date, monoclonal antibody therapies, principally the anti-CD20 antibody rituximab, have already made enormous impact on the treatment algorithm for many B-cell lymphomas. Therapeutic vaccines targeting the tumor-specific immunoglobulin idiotype have demonstrated promising results against lymphomas in phase I/II studies and are currently being evaluated in phase III randomized trials. Additional vaccine therapies being developed include those based on dendritic cells, recombinant idiotype proteins, DNA, heat shock proteins, and gene-modified tumor cells. It is hoped that immunotherapeutic agents, used in tandem or in combination, may someday allow effective treatment of lymphoid malignancies and delay or even replace the need for conventional cytotoxic therapies.

Antibodies, Monoclonal↗
PubMed2003

Determinant spreading and tumor responses after peptide-based cancer immunotherapy.

Modern immunological assays are very sensitive for detection of antigen-specific T cells. These assays are used to detect increased levels of T cells after peptide-based immunotherapy for cancer in an attempt to describe surrogate endpoints correlated with anti-tumor activity. Recent reports demonstrate that determinant spreading develops in a high frequency of subjects with tumor regression responses after this type of immunotherapy and could be valuable for trial monitoring and the design of more effective vaccines.

Cancer Vaccines↗
PubMed2002

Immunogenicity of a plasmid DNA vaccine encoding chimeric idiotype in patients with B-cell lymphoma.

B-cell lymphomas express tumor-specific immunoglobulin, the variable regions of which [idiotype (Id)] can serve as a target for active immunotherapy. Promising results have been obtained in clinical studies of Id vaccination using Id proteins.However, Id protein is laborious and time-consuming to produce. DNA vaccination is an attractive alternative for delivering Id vaccines, because Id DNA can be rapidly isolated by PCR techniques. DNA coding for lymphoma Id can provide protective immunity in murine models. In the present study, we performed a Phase I/II clinical trial to study the safety and immunogenicity of naked DNA Id vaccines in 12 patients with follicular B-cell lymphoma. The DNA encoded a chimeric immunoglobulin molecule containing variable heavy and light chain immunoglobulin sequences derived from each patient's tumor, linked to the IgG2a and kappa mouse immunoglobulin (MsIg) heavy- and light-chain constant regions chains, respectively. Patients in remission after chemotherapy received three monthly i.m. injections of the DNA in three dose escalation cohorts of four patients each (200, 600, and 1800 micro g). After vaccination, 7 of 12 patients mounted either humoral (n = 4) or T-cell-proliferative (n = 4) responses to the MsIg component of the vaccine. In one patient, a T-cell response specific to autologous Id was also measured. Anti-Id antibodies were not detectable in any patient. A second series of vaccinations was then administered using a needle-free injection device (Biojector) to deliver 1800 micro g both i.m. and intradermally (i.d.); 9 of 12 patients had humoral (n = 6) and/or T-cell (n = 4) responses to MsIg. Six of 12 patients exhibited humoral and/or T-cell anti-Id responses; yet, these were cross-reactive with Id proteins from other patient's tumors. Subsequently, a third series of vaccinations was carried out using 500 micro g of human granulocyte-macrophage colony-stimulating factor DNA mixed with 1800 micro g of Id DNA. The proportion of patients responding to MsIg remained essentially unchanged (8 of 12), although humoral or T-cell responses were boosted in some cases. Throughout the study, no significant side effects or toxicities were observed. Despite the modest level of antitumor immune responses in this study, DNA vaccine technology retains potential advantages in developing anti-Id immunotherapies. Additional studies are warranted to optimize vaccine dose, routes of administration, vector designs, and prime-boost strategies. These results will help guide the design of such future DNA vaccine trials.

Adult↗
PubMed2002

Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients.

Tumor-specific clonal immunoglobulin expressed by B-cell lymphomas (idiotype [Id]) can serve as a target for active immunotherapy. We have previously described the vaccination of 4 patients with follicular lymphoma using dendritic cells (DCs) pulsed with tumor-derived Id protein and now report on 35 patients treated using this approach. Among 10 initial patients with measurable lymphoma, 8 mounted T-cell proliferative anti-Id responses, and 4 had clinical responses--2 complete responses (CRs) (progression-free [PF] for 44 and 57 months after vaccination), 1 partial response (PR) (PF for 12 months), and 1 molecular response (PF for 75+ months). Subsequently, 25 additional patients were vaccinated after first chemotherapy, and 15 of 23 (65%) who completed the vaccination schedule mounted T-cell or humoral anti-Id responses. Induction of high-titer immunoglobulin G anti-Id antibodies required coupling of Id to the immunogenic carrier protein keyhole limpet hemocyanin (Id-KLH). These antibodies could bind to and induce tyrosine phosphorylation in autologous tumor cells. Among 18 patients with residual tumor at the time of vaccination, 4 (22%) had tumor regression, and 16 of 23 patients (70%) remain without tumor progression at a median of 43 months after chemotherapy. Six patients with disease progression after primary DC vaccination received booster injections of Id-KLH protein, and tumor regression was observed in 3 of them (2 CRs and 1 PR). We conclude that Id-pulsed DC vaccination can induce T-cell and humoral anti-Id immune responses and durable tumor regression. Subsequent boosting with Id-KLH can lead to tumor regression despite apparent resistance to the primary DC vaccine.

Adult↗
PubMed2002

Vaccine therapies for non-Hodgkin's lymphoma.

Various clinical observations suggest that non-Hodgkin's lymphomas (NHLs), particularly those of low histologic grade, can be controlled by immunologic mechanisms. Although many effective therapies exist for the initial treatment of low grade lymphomas, none are curative and most have significant toxic side effects. Several promising lymphoma tumor antigen vaccines are being studied at medical centers throughout North America. I favor the scientific evaluation of a therapeutic strategy for follicular NHL that places immune-based therapies forward in the treatment algorithm to the initial therapeutic decision point. Active immunotherapies (therapeutic tumor vaccines) are instituted in tandem with initial cytoreductive chemotherapy, and followed by passive monoclonal antibody therapies. The tumor-specific idiotype vaccines are favored because of their demonstrated potential for clinical activity in numerous human studies and their lack of significant toxic side effects. Rituximab and other monoclonal antibodies directed at normal B-cell antigens are known to abrogate the host's ability to mount primary humoral immune responses, including antitumor antibodies evoked by tumor vaccines. Therefore, one should consider deferring the use of these agents until after an attempt at generating a host humoral antitumor response using investigational tumor vaccines. Chemotherapy regimens containing highly immunosuppressive agents (ie, fludarabine) or organ dose-limiting toxicities (ie, doxorubicin) may be best reserved for later in the disease course for those failing the more conservative approaches and for cases with adverse prognostic features. This strategy may give patients the greatest chance at prolonged remission or cure while minimizing acute and chronic toxicities, although its impact on overall survival has not been proven. Low grade NHLs remain the proving ground for this treatment philosophy. Hopefully, in the future, similar strategies may be applicable to NHLs of other grades and histologies.

Antibodies, Monoclonal↗
PubMed2002

BLyS and BLyS receptor expression in non-Hodgkin's lymphoma.

OBJECTIVE: B Lymphocyte Stimulator (BLyS) protein and its receptor are new members of the tumor necrosis factor family, with specific effects exclusively on B cells. We have studied the tumor cell expression of the BLyS-Receptor (BLyS-R) and the serum BLyS protein levels in patients with different types of non-Hodgkin's lymphomas (NHL). METHODS: BLyS-R expression was assessed by flow cytometry on B cells from 43 NHL patients and 10 normal donors. BLyS protein serum levels were analyzed by ELISA. RESULTS: All B cells, tumor and normal, expressed BLyS-R. The mean fluorescence intensity (MFI +/- SD) of BLyS-R on normal B cells was 25.2 +/- 2.3 arbitrary units, while follicular NHL and chronic lymphocytic leukemia (CLL) exhibited significantly lower expression of the BLyS-R (17.7 +/- 3.1; 15.5 +/- 3.9, respectively, p < 0.0001 for both); other lymphoma subtypes expressed levels comparable to normal B cells (diffuse large cell, 24.8 +/- 4.3; mantle cell, 20 +/- 4.7; marginal zone, 20.7 +/- 3.7). BLyS protein serum levels were analyzed in 15 normal donors and 17 patients with follicular NHL. Levels of BLyS protein were, on average, threefold higher in patients with follicular lymphoma compared to normal donors (mean +/- SD; 13.4 +/- 5.6 ng/mL vs 4.6 +/- 0.7 ng/mL; p < 0.0001). BLyS protein alone was unable to stimulate proliferation in cultures of follicular lymphoma B cells or normal B cells. CONCLUSION: The specificity of the expression of BLyS-R by B-cell lymphomas opens new opportunities for the treatment of these cancers by targeting this ligand-receptor pair.

B-Cell Activating Factor↗