Placebo-Controlled Phase III Trial of Patient-Specific Immunotherapy With Mitumprotimut-T and Granulocyte-Macrophage Colony-Stimulating Factor After Rituximab in Patients With Follicular Lymphoma

Freedman, Arnold S.; Neelapu, Sattva S.; Nichols, Craig R.; Robertson, Michael J.; Djulbegoviĉ, Benjamin; Winter, Jane N.; Bender, John F.; Gold, Daniel P.; Ghalie, Richard; Stewart, Morgan E.; Esquibel, Vanessa; Hamlin, Paul A.

doi:10.1200/jco.2008.19.8903

Cited by 136 publications

(88 citation statements)

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“…This technology has the advantage of a reduced time to obtain the Id-formulation, and it does not need a surgical biopsy, as adequate tumor cells can be obtained by core needle biopsy, bone marrow aspiration or sampling of involved peripheral blood. The phase III clinical trial employing this vaccine formulation corroborated the capability of this technique to obtain Id protein in more than 99% of cases in which tumor cells express surface Ig [48].Nevertheless, this double-blind, randomized phase III study, as well as the clinical trial sponsored by Favrille Inc, found no statistically significant differences in PFS between the Id-KLH plus GM-CSF vaccine and a control vaccine containing KLH plus GM-CSF, although the vaccine was generally safe [51] 4 . An interesting correlation between clinical and immune response was highlighted in the Genitope study, showing an increased progression-free survival in patients developing an anti-Id immune response, compared to patients who did not mounted such a response (40 versus 16 months).…”

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confidence: 91%

“…Nevertheless, this double-blind, randomized phase III study, as well as the clinical trial sponsored by Favrille Inc, found no statistically significant differences in PFS between the Id-KLH plus GM-CSF vaccine and a control vaccine containing KLH plus GM-CSF, although the vaccine was generally safe [51] 4 . An interesting correlation between clinical and immune response was highlighted in the Genitope study, showing an increased progression-free survival in patients developing an anti-Id immune response, compared to patients who did not mounted such a response (40 versus 16 months).…”

Section: Successes and Failures Of Current Idiotypic Vaccination For mentioning

confidence: 99%

“…The persistence of significant numbers of malignant cells may make the immune environment unfavorable for the development of an adequate immune response to the vaccine [15]. In addition, the pre-vaccine therapy was different in the 3 trials, with the Favrille trial being the only one employing rituximab instead of chemotherapy as debulking agent [51]. Moreover, while Genitope and Favrille trials used recombinant Id and exclusively with the IgG isotype, Biovest vaccination was performed with hybridoma products, which could express either IgG or IgM isotypes [37].…”

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confidence: 99%

“…B. Time to progression of intent-to-treat population in Favrille study [51]. C. Disease-free survival for randomly assigned patients who received at least one dose of Id vaccine (n=76) or control (n=41) in the NCI/Biovest study [14].…”

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confidence: 99%

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1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

Muraro¹,

Martorelli²,

Bomben³

et al. 2012

European Journal of Cancer

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B-cell Non-Hodgkin Lymphomas (B-NHL) are a heterogeneous group of cancers, broadly diffused worldwide and often relapsing after standard treatment and rituximab. Therapeutic vaccines targeting B-NHL idiotype (Id) represent a promising approach to maintain the complete response induced by standard treatments. However, customized idiotypic vaccination still remains a non-approved, experimental therapeutic option, mostly due to the personalized use and penalized by the lack of reliable clinical or biological markers of patient eligibility and responsiveness. Nevertheless, the molecular characterization of different lymphoid tumor histotypes revealed a set of stereotyped immunoglobulins among distinct B-cell lymphoma types. On this ground, we focused our attention on the IGHV1-69 protein, frequently expressed in HCV-associated lymphomas, chronic lymphocytic leukaemia, and auto-immunity related lymphoproliferations, and we characterized the ex vivo immunogenicity of this protein.Seventy IGHV1-69 sequences obtained from patients affected by different B-NHLs or pre-malignant lymphoproliferations were compared to design an optimized sequence characterized by the highest degree of similarity among studied cancers, and thus CDR3 hypervariable region free. Within this "immunogenically" optimized sequence, we identified 13 potential HLA class-I cytotoxic T lymphocyte (CTL) epitopes and synthesized the corresponding pentamers (Pent). We assessed by flow cytometry the presence and extent of epitope-specific T-cell responses in peripheral blood of patients with IGHV1-69 + B-cell lymphoproliferative disorders and healthy donors, and validated these data in IFN-γ ELISPOT (Enzyme-linked immunosorbent spot) assays. Finally, we boosted in vitro IGHV1-69-specific responses by stimulating peripheral blood lymphocytes (PBL) from donors and patients with different protocols for the generation of epitope-specific CTL cultures.Interestingly, the IGHV1-69 Pent + population observed in patients' samples was generally larger than in donors, supporting the existence of spontaneous memory T-cell responses against IGHV1-69, at least for some HLA-restrictions. Surprisingly, in patients' samples, IGHV1-69-recognizing T cells displayed higher IFN-γ release in ELISPOT assays compared to viral-specific T cells. Moreover, we obtained peptide-specific CTL lines, which showed a weak but specific lysis against peptide-pulsed targets, especially when derived from patients' PBLs. In addition, we were able to generate IGHV1-69-epitope specific CTL clones from healthy donors CD8 + T cells, employing synthetic artificial APC, developed to elicit and expand low-avidity tumor-directed human CTL lines. Finally, IGHV1-69-induced CTL lines showed specific lysis also towards an IGHV1-69 naturally expressing cell line, suggesting that IGHV1-69 memory T-cell responses could be boosted for therapeutic purposes.These results show that IGHV1-69 constitutes a potential target for the development of a subset-specific Id vaccine. Furthermore, multimer (tetramers...

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confidence: 91%

Section: Successes and Failures Of Current Idiotypic Vaccination For mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

Muraro¹,

Martorelli²,

Bomben³

et al. 2012

European Journal of Cancer

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“…Furthermore, studies of Id vaccination had suggested a correlation between induced anti-Id antibody responses and progression-free survival and overall survival of patients (2)(3)(4). Despite these encouraging results, phase III trials have not established a clinical benefit from Id vaccination, except for a possible subset of patients who have prolonged remissions after initial chemotherapy (5)(6)(7). One possible problem may have been the chemical conjugation of Id to the carrier protein, keyhole limpet hemocyanin (KLH).…”

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confidence: 99%

A vaccine directed to B cells and produced by cell-free protein synthesis generates potent antilymphoma immunity

Jia

Patel³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Clinical studies of idiotype (Id) vaccination in patients with lymphoma have established a correlation between the induced anti-Id antibody responses and favorable clinical outcomes. To streamline the production of an Id vaccine, we engineered a small diabody (Db) molecule containing both a B-cell-targeting moiety (anti-CD19) and a lymphoma Id. This molecule (αCD19-Id) was designed to penetrate lymph nodes and bind to noncognate B cells to form an antigen presentation array. Indeed, the αCD19-Id molecule accumulated on B cells in vivo after s.c. administration. These noncognate B cells, decorated with the diabody, could then stimulate the more rare Id-specific B cells. Peptide epitopes present in the diabody linker augmented the response by activating CD4 + helper T cells. Consequently, the αCD19-Id molecule induced a robust Id-specific antibody response and protected animals from tumor challenge. Such diabodies are produced in a cell-free protein expression system within hours of amplification of the specific Ig genes from the B-cell tumor. This customized product can now be available to vaccinate patients before they receive other, potentially immunosuppressive, therapies.immunotherapy | tumor-specific antigen | bispecific antibody fragments I diotype (Id), the unique Ig molecule of each lymphoma tumor, is a good target for the immune system. Passively administered monoclonal antibodies (mAbs) against this target are effective in therapy (1). Furthermore, studies of Id vaccination had suggested a correlation between induced anti-Id antibody responses and progression-free survival and overall survival of patients (2-4). Despite these encouraging results, phase III trials have not established a clinical benefit from Id vaccination, except for a possible subset of patients who have prolonged remissions after initial chemotherapy (5-7). One possible problem may have been the chemical conjugation of Id to the carrier protein, keyhole limpet hemocyanin (KLH). Antigenic determinants on the Id could have been damaged in this process (8). Recombinant vaccines that do not require chemical conjugation may lead to improved immunogenicity and clinical outcomes.Recent studies on antigen (Ag) acquisition by B cells have provided new insights for vaccine design. The majority of B cells reside in follicles within secondary lymphoid organs. Foreign Ags in the form of immune complexes are transported into lymph node follicles by subcapsular sinus macrophages (9-11), and into spleen follicles by marginal zone B cells (12). In the follicles, nonspecific B cells retain immune complexes on their cell surfaces. Some complexes are transferred to follicular dendritic cells (9-11), whereas others may directly cross-link the Ag-specific receptors (BCRs) on cognate B cells (10, 11). These roles played by noncognate B cells in the generation of specific antibody responses were previously not appreciated. In addition to forming immune complexes that facilitate entering the follicles and presenting on the cell surface, foreign Ags may also b...

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Adverse effects of biologics: a network meta-analysis and Cochrane overview

Singh

Wells

Christensen

et al. 2011

Cochrane Database of Systematic Reviews

486

197

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To compare the potential adverse e ects of tumor necrosis factor inhibitor (adalimumab, certolizumab, etanercept, golimumab, infliximab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS). Methods Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open-label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre-specified adverse outcomes (serious adverse events (SAEs), withdrawals due to adverse events (AEs), total AEs, serious infections; specific AEs, namely, tuberculosis (TB) reactivation, lymphoma and congestive heart failure) were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network metaanalysis, we performed both Bayesian mixed-treatment comparison models and arm-based generalized linear mixed models. Main results We included 160 RCTs with 48,676 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for TB reactivation, lymphoma, and congestive heart failure. Using standard dose, compared with control, biologics as a group were associated with a statistically significant higher rate of total AEs (odds ratio (OR) 1.28, 95% credible interval (CI) 1.09 to 1.50; number needed to treat to harm (NNTH) = 22, 95% confidence interval (CI) 14 to 60), withdrawals due to AEs (

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Placebo-Controlled Phase III Trial of Patient-Specific Immunotherapy With Mitumprotimut-T and Granulocyte-Macrophage Colony-Stimulating Factor After Rituximab in Patients With Follicular Lymphoma

Abstract: TTP was shorter with mitumprotimut-T/GM-CSF compared with placebo/GM-CSF. This difference was possibly due to the imbalance in FLIPI scores.

Cited by 136 publications

References 19 publications

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

A vaccine directed to B cells and produced by cell-free protein synthesis generates potent antilymphoma immunity

Adverse effects of biologics: a network meta-analysis and Cochrane overview

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