Upfront immunization with autologous recombinant idiotype Fab fragment without prior cytoreduction in indolent B-cell lymphoma

Navarrete, Marcelo A.; Heining-Mikesch, Kristina; Schüler, Frank; Bertinetti-Lapatki, Cristina; Ihorst, Gabriele; Keppler‐Hafkemeyer, Andrea; Dölken, Gottfried; Veelken, Hendrik

doi:10.1182/blood-2010-06-292342

Cited by 30 publications

(32 citation statements)

References 48 publications

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“…The rat variable regions of anti-CD19 might have been expected to be the source of CD4 + T-cell epitopes. However, instead, our data indicate that the nonnatural Gly 4 Ser linker provided such epitopes (Fig. 6B and Fig.…”

Section: Discussioncontrasting

confidence: 59%

“…αCD19-Id is a heterodimer of noncovalently associated polypeptides containing the variable regions of 38C13 and anti-CD19, separated by Gly 4 Ser linkers ( Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

“…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)(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).…”

mentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 59%

“…αCD19-Id is a heterodimer of noncovalently associated polypeptides containing the variable regions of 38C13 and anti-CD19, separated by Gly 4 Ser linkers ( Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…4 In conclusion, we provide further support for the exishaematologica 2015; 100:e145 LETTERS TO THE EDITOR …”

Section: 4mentioning

confidence: 93%

“…Lymphoma samples were obtained with written informed consent from the Freiburg University idiotype vaccination program [2][3][4] and the hematology biobank of Leiden University Medical Center with approval of the ethics committee of Freiburg University. HLA alleles were identified by serotyping and high-resolution genotyping (Olerup SSP kit, Qiagen, Hilden, Germany).…”

Section: Evidence For Idiotype-directed Immunosurveillance Is Restricmentioning

confidence: 99%

Evidence for idiotype-directed immunosurveillance is restricted to follicular lymphoma and attributable to somatic hypermutation

et al. 2015

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Selective targeting of Toll-like receptors and OX40 inhibit regulatory T-cell function in follicular lymphoma

et al. 2014

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Immunotherapeutic strategies are promising approaches for the treatment of follicular lymphoma (FL). However, their efficacy may be limited by immunosuppressive elements in the immune system and tumor microenvironment. Therefore, strategies to reverse the effects of the immunosuppressive elements are needed. We observed that regulatory T cells (Tregs) were increased in the peripheral blood at diagnosis and persisted in high numbers after induction of clinical remission with a cyclophosphamide and doxorubicin-containing chemotherapy regimen in FL patients. High levels of peripheral blood Tregs prior to therapy were associated with decreased progression-free survival in FL patients treated with either chemotherapy or combination immunotherapy that targeted CD20 and PD-1 with monoclonal antibodies rituximab and pidilizumab, respectively. Intratumoral and peripheral blood Tregs potently suppressed autologous antitumor effector T cells in FL. However, the effects of FL Tregs could be reversed by triggering Toll-like receptors (TLR) with TLR ligands Pam3CSK4 (TLR 1/2), flagellin (TLR 5), and CpG-B (TLR 9), and/or OX40. The TLR ligands synergized with each other as well as OX40 signaling to inhibit Tregs. Furthermore, they restored the function of FL tumor-specific effector T cells. Our results suggest that a state of tolerance exists in FL patients at diagnosis and after induction of clinical remission, and agents that activate TLRs 1/2, 5, and 9, and OX40 may serve as adjuvants to enhance the efficacy of antitumor immunotherapeutic strategies and preventive vaccines against infectious diseases in these patients.

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Upfront immunization with autologous recombinant idiotype Fab fragment without prior cytoreduction in indolent B-cell lymphoma

Cited by 30 publications

References 48 publications

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

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

Evidence for idiotype-directed immunosurveillance is restricted to follicular lymphoma and attributable to somatic hypermutation

Selective targeting of Toll-like receptors and OX40 inhibit regulatory T-cell function in follicular lymphoma

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