Immunization with a HER-2/neu helper peptide vaccine generates HER-2/neu CD8 T-cell immunity in cancer patients

Knutson, Keith L.; Schiffman, Kathy; Disis, Mary L.

doi:10.1172/jci11752

Cited by 394 publications

(273 citation statements)

References 42 publications

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“…These data demonstrate that both CD8 + and CD4 + T cells are necessary for the therapeutic effect of adjuvant αhCD27 but that CD4 + T cells contribute to this effect only during the priming phase of the vaccine response. Consistent with our own data and previous reports showing that class II epitopes are integral for robust class I-restricted vaccine responses, 11 these results suggest that CD4 + T cell help is critical for the adjuvant effect of αhCD27.…”

Section: Resultssupporting

confidence: 93%

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

Riccione

Fecci

et al. 2018

OncoImmunology

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Despite their promise, tumor-specific peptide vaccines have limited efficacy. CD27 is a costimulatory molecule expressed on CD4+ and CD8+ T cells that is important in immune activation. Here we determine if a novel CD27 agonist antibody (αhCD27) can enhance the antitumor T cell response and efficacy of peptide vaccines. We evaluated the effects of αhCD27 on the immunogenicity and antitumor efficacy of whole protein, class I-restricted, and class II-restricted peptide vaccines using a transgenic mouse expressing human CD27. We found that αhCD27 preferentially enhances the CD8+ T cell response in the setting of vaccines comprised of linked class I and II ovalbumin epitopes (SIINFEKL and TEWTSSNVMEERKIKV, respectively) compared to a peptide vaccine comprised solely of SIINFEKL, resulting in the antitumor efficacy of adjuvant αhCD27 against intracranial B16.OVA tumors when combined with vaccines containing linked class I/II ovalbumin epitopes. Indeed, we demonstrate that this efficacy is both CD8- and CD4-dependent and αhCD27 activity on ovalbumin-specific CD4+ T cells is necessary for its adjuvant effect. Importantly for clinical translation, a linked universal CD4+ helper epitope (tetanus P30) was sufficient to instill the efficacy of SIINFEKL peptide combined with αhCD27, eliminating the need for a tumor-specific class II-restricted peptide. This approach unveiled the efficacy of a class I-restricted peptide vaccine derived from the tumor-associated Trp2 antigen in mice bearing intracranial B16 tumors. CD27 agonist antibodies combined with peptide vaccines containing linked tumor-specific CD8+ epitopes and tumor-specific or universal CD4+ epitopes enhance the efficacy of active cancer immunotherapy.

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Section: Resultssupporting

confidence: 93%

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

Riccione

Fecci

et al. 2018

OncoImmunology

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“…The vaccine described here utilized GM-CSF as an adjuvant to mobilize skin dendritic cells, Langerhans' cells, in vivo (16). Injection of GM-CSF as a vaccine adjuvant was shown to be associated with the generation of a Th1 immune response stimulating interferon gamma secretion and the development of a predominant cellular rather than humoral immune response (17). The use of GM-CSF as a vaccine adjuvant has been studied recently in multiple vaccine models due to the low incidence of side effects related to the adjuvant in human clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Humoral Epitope-Spreading Following Immunization with a HER-2/neu Peptide Based Vaccine in Cancer Patients

et al. 2004

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HER-2/neu is a tumor antigen in patients with breast and ovarian cancer. Multiple varieties of vaccine strategies are being developed to immunize patients against HER-2/neu. Studies in animal models have demonstrated both T cell and antibody immunity are needed to mediate an antitumor response. Thirty-five patients, immunized with HER-2/neu peptide based vaccines, were evaluated for the generation of HER-2/neu-specific antibody immunity. Sixty percent of patients developed HER-2/neu IgG specific antibody responses to at least one peptide included in their vaccine. Twenty-nine percent of patients developed IgG immunity to the native HER-2/neu protein after peptide immunization. Humoral intramolecular epitope-spreading within the HER-2/neu protein occurred in 49% of immunized patients. Intermolecular epitope-spreading to p53 was evident in 20% of vaccinated patients. Of those patients who developed new immunity to p53, 71% had demonstrated antibody epitope-spreading within HER-2/neu.

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“…16,17 Furthermore, naturally occurring, linked CTL and T h epitopes with improved immunogenicity are present in humans, such as human papillomavirus (HPV), 18,19 NY-ESO-1 (a cancer testis antigen), 20 and HER-2/neu. 21,22 One of the major mechanisms for the enhanced vaccine potency of long peptides is most likely that, unlike 8-mer to 10-mer CTL epitopes, these are not able to bind directly to MHC class I molecules, so their presentation to CTL precursors must follow processing by DCs. 2,23 Thus, long-peptide vaccines obviate binding to MHC class Iexpressing, nonspecialized APCs, which often results in transient CTL responses or tolerance.…”

Section: Therapeutic Vaccines Combined With Chemotherapymentioning

confidence: 99%

“…Two clinical studies 21,22 tested whether HER-2/neuspecific CD8 T-cell immunity could be elicited using HER-2/neu-derived MHC class II helper peptides that encompassed HLA-A2-binding motifs. Nineteen HLA-A2 patients who had HER-2/neu-overexpressing cancers received a vaccine preparation consisting of putative HER-2/neu helper peptides p369 to p384, p688 to 703, and p971 to p984.…”

Section: Clinical Trials Using Polyepitope Long-peptide Vaccinesmentioning

confidence: 99%

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A new era in anticancer peptide vaccines

Perez

Hofe

Kallinteris

et al. 2010

Cancer

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The use of synthetic peptides as vaccines aimed at the induction of therapeutic CD8-positive T-cell responses against tumor cells initially experienced great enthusiasm, mostly because of advances in vaccine technology, including design, synthesis, and delivery. However, despite impressive results in animal models, the application of such vaccines in humans has met with only limited success. The therapeutic activity of vaccine-stimulated, tumor-specific, CD8-positive T cells can be hampered through the physical burden of the tumor, tolerance mechanisms, and local factors within the tumor microenvironment. Recently, accumulating evidence has suggested that combining a peptide-based therapeutic vaccination with conventional chemotherapy can uncover the full potential of the antitumor immune response, increasing the success of immunotherapy. In addition, therapeutic vaccination in the preventive setting has been extremely effective in eliciting antitumor responses in preclinical tumor models and has demonstrated good promise clinically in patients with minimal residual disease. The rationale behind preventive vaccination is that patients with minimal tumor burden still have a fully competent immune system capable of developing robust antitumor responses. Finally, therapeutic CD8-positive T-cell peptide vaccines have been improved by coimmunization with T-helper epitopes expressed on long peptides.

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Immunization with a HER-2/neu helper peptide vaccine generates HER-2/neu CD8 T-cell immunity in cancer patients

Cited by 394 publications

References 42 publications

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

Humoral Epitope-Spreading Following Immunization with a HER-2/neu Peptide Based Vaccine in Cancer Patients

A new era in anticancer peptide vaccines

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