High vaccination efficiency of low-affinity epitopes in antitumor immunotherapy

Gross, David A.; Graff‐Dubois, Stéphanie; Opolon, Paule; Cornet, Sébastien; Alves, Pedro M. Sousa; Bennaceur‐Griscelli, Annelise; Faure, Olivier; Guillaume, Philippe; Firat, Hüseyin; Chouaı̈b, Salem; Lemonnier, François; Davoust, Jean; Miconnet, Isabelle; Vonderheide, Robert H.; Kosmatopoulos, Kostas

doi:10.1172/jci19418

Cited by 44 publications

(47 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In an earlier peptide immunization study, 48 self-antigens showed markedly lower immunogenicity in HHD mice despite forming stable MHC complexes. In contrast, 3/4 self-antigen peptides in our study generated significant CMI responses.…”

Section: Discussionmentioning

confidence: 91%

“…This increase in immunogenicity may be offset further by a potential decrease in CTL avidity 47 . Nonetheless, the use of analogs may be warranted in cases in which the analog is significantly more immunogenic than the native peptide 45 , 48 . For example, analogs of CEA.310 and TERT.540(10) (Table 1) and the analogs of CEA.411 and CEA.589 that we have previously described 49 are immunogenic while the native peptides are not.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

An efficient T-cell epitope discovery strategy using in silico prediction and the iTopia assay platform

et al. 2012

View full text Add to dashboard Cite

Functional T-cell epitope discovery is a key process for the development of novel immunotherapies, particularly for cancer immunology. In silico epitope prediction is a common strategy to try to achieve this objective. However, this approach suffers from a significant rate of false-negative results and epitope ranking lists that often are not validated by practical experience. A high-throughput platform for the identification and prioritization of potential T-cell epitopes is the iTopiaTM Epitope Discovery SystemTM, which allows measuring binding and stability of selected peptides to MHC Class I molecules. So far, the value of iTopia combined with in silico epitope prediction has not been investigated systematically. In this study, we have developed a novel in silico selection strategy based on three criteria: (1) predicted binding to one out of five common MHC Class I alleles; (2) uniqueness to the antigen of interest; and (3) increased likelihood of natural processing. We predicted in silico and characterized by iTopia 225 candidate T-cell epitopes and fixed-anchor analogs from three human tumor-associated antigens: CEA, HER2 and TERT. HLA-A2-restricted fragments were further screened for their ability to induce cell-mediated responses in HLA-A2 transgenic mice. The iTopia binding assay was only marginally informative while the stability assay proved to be a valuable experimental screening method complementary to in silico prediction. Thirteen novel T-cell epitopes and analogs were characterized and additional potential epitopes identified, providing the basis for novel anticancer immunotherapies. In conclusion, we show that combination of in silico prediction and an iTopia-based assay may be an accurate and efficient method for MHC Class I epitope discovery among tumor-associated antigens.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

An efficient T-cell epitope discovery strategy using in silico prediction and the iTopia assay platform

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Vaccinations consisted of aqueous solutions of hTERT peptides I540 (ILAKFLHWL) (42), 572Y (YLFFYRKSU) (43), 988Y (YLQVNSLQTV) (43), Sur1M2 (LMLGEFLKL) (44), and N495 (NLVPMVATV) from CMV pp65 (45) (each peptide >92% pure and Good Manufacturing Practice–grade; Merck Biosciences AG) emulsified in the adjuvant Montanide ISA 51 VG (Seppic) and delivered subcutaneously in the thighs. Sargramostim (clinical-grade granulocyte-macrophage colony-stimulating factor; Berlex Laboratories) was given subcutaneously at the two injection sites (70 μg per site) with each peptide vaccination.…”

Section: Methodsmentioning

confidence: 99%

CD25 Blockade Depletes and Selectively Reprograms Regulatory T Cells in Concert with Immunotherapy in Cancer Patients

et al. 2012

Self Cite

View full text Add to dashboard Cite

Regulatory T cells (Tregs) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25+ FoxP3+ Tregs in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration–approved CD25-blocking monoclonal antibody daclizumab with regard to human Treg survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25high CD45RAneg Tregs. Moreover, daclizumab-treated CD45RAneg Tregs lost suppressive function and regained the ability to produce interferon-γ, consistent with reprogramming. To understand the impact of daclizumab on Tregs in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in Tregs in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms Tregs in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated Tregs while avoiding autoimmunity.

show abstract

“…1A, the hTERT immunogen was developed with several modifications, including codon/RNA optimization and the addition of a highly efficient leader sequence, to enhance the expression and immunogenicity of phTERT. Two mutations (R589Y and D1005Y) were incorporated into the hTERT sequence to assist in breaking tolerance (41). The modified gene was subcloned into pGX0001 and named as phTERT for further study (Fig.…”

Section: Resultsmentioning

confidence: 99%

Highly Optimized DNA Vaccine Targeting Human Telomerase Reverse Transcriptase Stimulates Potent Antitumor Immunity

Yan

Pankhong

Shin

et al. 2013

Cancer Immunology Research

View full text Add to dashboard Cite

High levels of human Telomerase Reverse Transcriptase (hTERT) are detected in over 85% of human cancers. Immunological analysis supports hTERT is a widely applicable target recognized by T cells and can be potentially studied as a broad cancer immune therapeutic, or a unique line of defense against tumor recurrence. There remains an urgent need to develop more potent hTERT vaccines. Here, a synthetic highly optimized full-length hTERT DNA vaccine (phTERT) was designed and the induced immunity was examined in mice and non-human primates. When delivered by electroporation, phTERT elicited strong, broad hTERT-specific CD8 responses including induction of T-cells expressing CD107a, IFN-γ and TNF-α in mice. The ability of phTERT to overcome tolerance was evaluated in a NHP model, whose TERT is 96% homologous to that of hTERT. Immunized monkeys exhibited robust (average 1834 SFU/106 PBMCs), diverse (multiple immunodominant epitopes) IFN-γ responses and antigen-specific perforin release (average 332 SFU/106 PBMCs), suggesting phTERT breaks tolerance and induces potent cytotoxic responses in this human relevant model. Moreover, in an HPV16-associated tumor model, vaccination of phTERT slows tumor growth and improves survival rate in both prophylactic and therapeutic studies. Lastly, in vivo cytotoxicity assay confirmed that phTERT-induced CD8 T cells exhibited specific CTL activity, capable of eliminating hTERT-pulsed target cells. These findings support that this synthetic EP-delivered DNA phTERT may have a role as a broad therapeutic cancer vaccine candidate.

show abstract

High vaccination efficiency of low-affinity epitopes in antitumor immunotherapy

Cited by 44 publications

References 46 publications

An efficient T-cell epitope discovery strategy using in silico prediction and the iTopia assay platform

An efficient T-cell epitope discovery strategy using in silico prediction and the iTopia assay platform

CD25 Blockade Depletes and Selectively Reprograms Regulatory T Cells in Concert with Immunotherapy in Cancer Patients

Highly Optimized DNA Vaccine Targeting Human Telomerase Reverse Transcriptase Stimulates Potent Antitumor Immunity

Contact Info

Product

Resources

About