CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination

Ahrends, Tomasz; Bąbała, Nikolina; Xiao, Yanling; Yagita, Hideo; Eenennaam, Hans van; Borst, Jannie

doi:10.1158/0008-5472.can-15-3130

Cited by 106 publications

(117 citation statements)

References 47 publications

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“…Recent studies have demonstrated that CD27 engagement can lead to Fas expression and T cell apoptosis, while other studies have seen an increased in the expression of the immune checkpoint PD-1. 42,43 In support of these observations, our supplemental Figure 4 demonstrates that administration of αhCD27 with vaccination increases the expression of PD-1 on CD8 + T cells. Importantly, a recent study showed that PD-1 blockade can augment the efficacy of αhCD27 administration in the absence of vaccination through increasing T cell cytotoxicity.…”

Section: Discussionsupporting

confidence: 63%

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: Discussionsupporting

confidence: 63%

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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“…CD27 signaling is controlled by its ligand, CD70, the expression of which is transient upon activation of dendritic cells (DCs), B cells, and T cells, and is tightly regulated (11)(12)(13). CD70-CD27 interaction provides a potent second signal for CD4 T cell-dependent and -independent CD8 T cell priming, effector differentiation, and memory development in virus clearance or tumor rejection (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Human CD27 or CD70 deficiency due to genetic mutations resulted in persistent symptomatic EBV infection and EBV-associated lymphoproliferative disorders, including lethal lymphoma (26)(27)(28)(29)(30).…”

mentioning

confidence: 99%

CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy

Wasiuk

Testa

Weidlick

et al. 2017

The Journal of Immunology

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CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varlilumab (clone 1F5), is ongoing in cancer patients. In this study, we set out to further understand CD27 as an immunomodulatory target and to address the mechanism of antitumor efficacy using different IgG isotypes of 1F5 in human CD27-transgenic mice. 1F5mIgG1, the only isotype engaging inhibitory FcγRIIB expressed in B cells, elicited the most potent and broad immune response, but terminal differentiation, exhaustion, and apoptosis in the activated effector T cells were inevitable. Accordingly, this isotype was the most effective in eradicating BCL1 lymphoma but had limited efficacy in s.c. tumors. Conversely, 1F5mIgG2a, which interacts with cells expressing activating FcγRs, led to moderate immune activation, as well as to prominent reduction in the number and suppressive activity of regulatory T cells. These combined mechanisms imparted potent antitumor activity to 1F5mIgG2a, particularly against the s.c. tumors. 1F5hIgG1, varlilumab, showed balanced agonistic activity that was prominent at lower doses and depleting activity that was greater at higher doses. 1F5hIgG1 had good antitumor activity in all tumor models tested. Thus, both agonist and depleting properties contribute to the antitumor efficacy of CD27-targeted immunotherapy, and modulation of these activities in patients may be achieved by varying the dose and regimen.

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“…This conclusion was also made in one recent study using the TC-1 tumor model and vaccination with conventional DNA encoding E7sh. 35 The authors achieved 100% survival by combining vaccination with CD27 agonism and programmed death receptor 1 (PD1) blockade. 35 At day 15 after tumor inoculation, the combined treatments resulted in approximately 20% of E7-specific T cells compared to 60% with replacing PD1 blockade with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).…”

Section: Discussionmentioning

confidence: 99%

“…35 The authors achieved 100% survival by combining vaccination with CD27 agonism and programmed death receptor 1 (PD1) blockade. 35 At day 15 after tumor inoculation, the combined treatments resulted in approximately 20% of E7-specific T cells compared to 60% with replacing PD1 blockade with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). However, CTLA-4 blockade with CD27 agonism and vaccination resulted in half of mice surviving by day 100.…”

Section: Discussionmentioning

confidence: 99%

Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens

Wall

Ljungberg

et al. 2018

OncoImmunology

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Cervical cancer develops as a result of infection with high-risk human papillomavirus (HPV) through persistent expression of early proteins E6 and E7. Our group pioneered a recombinant viral vector system based on Semliki Forest virus (SFV) for vaccination against cervical cancer. The most striking benefit of this alphavirus vector-based vaccine platform is its high potency. DNA vaccines on the other hand, have a major advantage with respect to ease of production. In this study, the benefits associated with both SFV-based vaccines and DNA vaccines were combined with the development of a DNA-launched RNA replicon (DREP) vaccine targeting cervical cancer. Using intradermal delivery followed by electroporation, we demonstrated that DREP encoding for E6,7 (DREP-E6,7) induced effective, therapeutic antitumor immunity. While immunizations with a conventional DNA vaccine did not prevent tumor outgrowth, immunization with a 200-fold lower equimolar dose of DREP (0.05 µg of DREP) resulted in approximately 85% of tumor-free mice. To overcome the safety concern of potential malignant transformation at the vaccination site, we evaluated the anti-tumor effect of a DREP vaccine encoding a shuffled version of E7 (DREP-E7sh). DREP-E7sh delayed tumor growth yet not to the same extent as DREP-E6,7. In addition, inclusion of a helper cassette and an ER targeting signal (sigHelp) did not significantly further enhance the suppression of tumor outgrowth in the long term, albeit exhibiting better tumor control early after immunization. Collectively, this study points towards the clinical evaluation of DREP encoding HPV antigens as a potent immunotherapy for patients with HPV16 (pre)-malignancies.

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CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination

Abstract: While showing promise, vaccination strategies to treat cancer require further optimization. Likely barriers to efficacy involve cancer-associated immunosuppression and peripheral tolerance, which limit the generation of effective vaccine-specific cytotoxic T lymphocytes (CTL

Cited by 106 publications

References 47 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

CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy

Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens

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