A New Strategy Toward B Cell-Based Cancer Vaccines by Active Immunization With Mimotopes of Immune Checkpoint Inhibitors

Tobias, Joshua; Battin, Claire; Linhares, Annika De Sousa; Lebens, Michael; Baier, Karin; Ambroz, Katharina; Drinić, Mirjana; Högler, Sandra; Inić-Kanada, Aleksandra; Garner-Spitzer, Erika; Preusser, Matthias; Kenner, Lukas; Kundi, Michael; Zielinski, Christoph; Schmitz, Peter; Wiedermann, Ursula

doi:10.3389/fimmu.2020.00895

Cited by 25 publications

(46 citation statements)

References 41 publications

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“…As described for trastuzumab, selective pressure on HER2 might also be exerted by vaccine-induced HER2specific Abs, giving HER2-negative cancer cell clones a survival advantage which eventually leads to tumor progression (45). This indicates that efforts to overcome treatment limitations due to loss of HER2-expression may have to extend to immunizations with cancer vaccines (46), possibly in the form of combining the IMU-131 vaccine with check point inhibitors as we recently demonstrated in a pre-clinical setting (17).…”

Section: Discussionmentioning

confidence: 96%

Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer—Results from Phase Ib Trial IMU.ACS.001

Wiedermann

Garner-Spitzer

Chao

et al. 2021

Clinical Cancer Research

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Section: Discussionmentioning

confidence: 96%

Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer—Results from Phase Ib Trial IMU.ACS.001

Wiedermann

Garner-Spitzer

Chao

et al. 2021

Clinical Cancer Research

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“…The significant antitumor effect observed in our study was associated with a marginal induction of PD-1-specific antibodies. 39 This suggests that vaccination with PD1derived mimotopes/peptides might potentially be associated with a reduced degree of irAEs, in comparison to the ICIs which are administered at doses to ensure their immediate bioavailability and potency in targeting the respective immune checkpoints. 36 The development of molecules or peptides targeting PD-L1, which can be used as blocking compounds or in vaccination approaches, is a viable alternative strategy to block the PD-1 pathway.…”

Section: Biological Backgroundmentioning

confidence: 99%

“…We have recently shown, for the first time, the concept of vaccination with mimotopes (B-cell epitope) of anti-PD-1 mAbs. 39 Active immunization with a mimotope, as…”

Section: Current Ongoing Clinical Trialsmentioning

confidence: 99%

“…The application of peptide libraries, displayed on the surface of bacteria or bacteriophages, is an alternative strategy to identify and select the epitopes of ICIs or other therapeutic mAbs. 37 , 38 , 39 Based on this strategy, the use of mimotopes, i.e. peptides mimicking or representing immunodominant epitopes on the target protein or the binding epitopes of the therapeutic mAb, has become a promising strategy both for infectious diseases 40 , 41 , 42 , 43 and for cancer therapy.…”

Section: Biological Backgroundmentioning

confidence: 99%

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Emerging targets for anticancer vaccination: PD-1

et al. 2021

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Among the mechanisms by which tumor cells escape the immune surveillance, one is the interaction between programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1). Inhibition of the PD-1/ PD-L1 pathway with monoclonal antibodies as immune checkpoint inhibitors targeting PD-1 or its ligand, PD-L1, represents a milestone in cancer therapy. The application of these antibodies, however, suffers from drawbacks including failure to show a response or benefit in a majority of patients following monotherapy or combination therapy, their frequent administration, and cost intensiveness. Small peptides capable of interfering with PD-1/PD-L1 interaction represent interesting alternatives to antibody-based immune checkpoint inhibitors. Moreover, peptides representing PD-1 or PD-L1 sequences can be used in active immunization approaches to induce antibodies that enhance antitumor immunity by effectively preventing PD-1-mediated inhibition in the host. Importantly, such peptides can readily be combined with peptides derived from cancer antigens to effectively induce an antitumor immune response. In this review, we have summarized the recent developments in the use of small molecules and peptides either to directly block PD-1/PD-L1 interaction, or in vaccination approaches to induce antibody responses stimulating anticancer immunity by blocking PD-1-mediated T-cell inhibition.

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“…With advances in peptide technology, short/stapled peptides can also be used without going to the DNA level for recombinant expression and over the commonly used whole cells or antigens 12,13 . Recent developments in cyclic peptides and peptide vaccines allow for immunization against specific conformational structures as epitopes instead of whole antigens through mimotopes 14 as B cell peptides 15 . Such more selective methods can support the development of therapeutics to reduce side effects due to off-target effects, although some level of lower specificity could be of value for vaccines and to an extent, diagnostics to target variants.…”

Section: Introductionmentioning

confidence: 99%

Sagacious Epitope Selection for Vaccines, and Both Antibody-Based Therapeutics and Diagnostics: Tips From Virology and Oncology<strong> </strong>

Gan¹,

Phua²,

Yeo³

2021

Preprint

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The target of an antibody plays a significant role in the success of antibody-based therapeutics and diagnostics, and to an extent, that of vaccine development. This importance is focussed on the target binding site – epitope, that sagacious epitope selection in a form of design thinking beyond traditional antigen selection using whole cell or whole protein immunisation can positively improve success. Intrinsic factors that can affect the functioning of resulting antibodies can be more easily selected for with purified recombinant protein production and peptide synthesis to display limited/selected epitopes. Many of these factors stem from the location of the epitope that can affect the accessibility of the antibody to the epitope at a cellular or molecular level, direct inhibition of target antigen activity, conservation of function despite escape mutations, and even non-competitive inhibition sites. Through the incorporation of novel computational methods for predicting antigen changes to model-informed drug design development, superior vaccines and antibody-based therapeutics or diagnostics can now be more easily designed, mitigating failures. With detailed examples, this review highlights the new opportunities, factors and methods of predicting antigenic changes for consideration in sagacious epitope selection.

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A New Strategy Toward B Cell-Based Cancer Vaccines by Active Immunization With Mimotopes of Immune Checkpoint Inhibitors

Cited by 25 publications

References 41 publications

Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer—Results from Phase Ib Trial IMU.ACS.001

Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer—Results from Phase Ib Trial IMU.ACS.001

Emerging targets for anticancer vaccination: PD-1

Sagacious Epitope Selection for Vaccines, and Both Antibody-Based Therapeutics and Diagnostics: Tips From Virology and Oncology<strong> </strong>

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