Phase II Trial of Idiotype Vaccination in Previously Treated Patients With Indolent Non-Hodgkin’s Lymphoma Resulting in Durable Clinical Responses

Redfern, Charles H.; Guthrie, Troy H.; Bessudo, Alberto; Densmore, John; Holman, Peter; Janakiraman, Nalini; Leonard, John P.; Levy, Ronald; Just, R.; Smith, Mitchell R.; Rosenfelt, Fred; Wiernik, Peter H.; Carter, William D.; Gold, Daniel P.; Melink, Teresa J.; Gutheil, John; Bender, John F.

doi:10.1200/jco.2005.04.4289

Cited by 85 publications

(61 citation statements)

References 15 publications

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“…An immune response to unique Ags that was found to be associated to a clinical benefit has been described in patients with renal cancer cells vaccinated with GM-CSF gene-transduced tumor cells (43) and patients with melanoma as indirectly shown from the analysis of clonal T cell response in patients immunized with a (48,49). T cell reactions against multiple unique epitopes were documented and found to be associated with molecular remission in a significant fraction of patients (48).…”

Section: Immunogenicity Of Unique Agsmentioning

confidence: 99%

“…How to design clinical trials that preferentially boost the immune response targeting truly tumor-specific unique Ags? While this is relatively easy and already possible for tumors of hematological origin as B cell lymphomas whose altered Ig Id can be sequenced and used as patient-specific unique tumor Ag (48,49), it represents a quite difficult task for solid human tumors. Obviously, the ultimate strategy for targeting such types of Ags will imply sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor.…”

Section: Implications For Immunotherapymentioning

confidence: 99%

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Unique Human Tumor Antigens: Immunobiology and Use in Clinical Trials

Parmiani

Filippo

Novellino

et al. 2007

The Journal of Immunology

146

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The individual, unique tumor Ags, which characterize each single tumor, were described 50 years ago in rodents but their molecular characterization was limited to few of them and obtained during the last 20 years. Here we summarize the evidence for the existence and the biological role of such Ags in human tumors, although such evidence was provided only during the last 10 years and by a limited number of studies, a fact leading to a misrepresentation of unique Ags in human tumor immunology. This was also due to the increasing knowledge on the shared, self-human tumor Ags, which have been extensively used as cancer vaccines. In this review, we highlight the biological and clinical importance of unique Ags and suggest how they could be used in clinical studies aimed at assessing their immunogenic and clinical potential both in active and adoptive immunotherapy of human tumors.

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Section: Immunogenicity Of Unique Agsmentioning

confidence: 99%

Section: Implications For Immunotherapymentioning

confidence: 99%

Unique Human Tumor Antigens: Immunobiology and Use in Clinical Trials

Parmiani

Filippo

Novellino

et al. 2007

The Journal of Immunology

146

View full text Add to dashboard Cite

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“…In a phase II study performed in a second chemotherapy-induced complete response, the Id-KLH plus GM-CSF formulation induced a specific immune response in the majority of patients (80%) with FL, and a highly significant increase in disease-free survival [49]. Moreover, in a phase II trial in patients with measurable disease, Id-vaccination alone was able to induce tumor regression and durable clinical response [50] (Figure 5). Id proteins were generated through hybridoma techniques as in the Bendandi et al [47] clinical trial, or by recombinant production, through PCR amplification of the tumor-specific variable region Ig sequences and cloning into expression vectors carrying the desired isotype backbone [48].…”

Section: Successes and Failures Of Current Idiotypic Vaccination For mentioning

confidence: 99%

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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“…As mentioned above, both these studies are also flawed by a number of both conceptual and design-related pitfalls that may ultimately endanger their chances of success, irrespective of the actual value of the Id vaccines they are based on (Bendandi, 2006). Indeed, at least in the case of Favrille's Id vaccine, recently published data from a phase-II clinical trial, in which previously treated patients were treated at relapse with Id vaccine alone, are particularly promising (Redfern et al, 2006). Finally, scientists from the University of Freiburg have recently reported on the clinical application of a recombinant Id vaccine consisting of the sole tumorspecific Ig's Fab produced in Escherichia coli (Bertinetti et al, 2006a, b).…”

Section: Recombinant Id Vaccines For Flmentioning

confidence: 99%

Anti-idiotype antibodies in cancer treatment

et al. 2007

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As a cancer immunotherapy tool, idiotypes (Ids) have been used in different ways over the last three decades, depending on the actual human tumor cell target. It all started with passive, monoclonal, anti-Id antibody treatment of B-cell lymphoma, a setting in which results were tantalizing, but logistics unsustainable. It then moved toward the development of anti-Id vaccines for the treatment of the same tumors, a setting in which we have recently provided the first formal proof of principle of clinical benefit associated with the use of a human cancer vaccine. Meanwhile, it also expanded in the direction of exploiting the antigenic mimicry of some Ids with Idunrelated, tumor-associated antigens for the immunotherapy of a number of solid tumors, a setting in which clinical results are still far from being consolidated. All in all, over the years Id-based immunotherapy has paved the way for a number of seminal therapeutic improvements for cancer patients, including the development of most if not all Id-unrelated monoclonal antibodies that have recently revolutionized the field.

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Phase II Trial of Idiotype Vaccination in Previously Treated Patients With Indolent Non-Hodgkin’s Lymphoma Resulting in Durable Clinical Responses

Abstract: This trial demonstrates that Id/KLH alone can induce tumor regression and durable objective responses. Further study of Id/KLH is recommended in other settings where efficacy may be further enhanced as in first-line therapy or after cytoreductive therapy.

Cited by 85 publications

References 15 publications

Unique Human Tumor Antigens: Immunobiology and Use in Clinical Trials

Unique Human Tumor Antigens: Immunobiology and Use in Clinical Trials

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

Anti-idiotype antibodies in cancer treatment

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