Long Peptide Vaccination Can Lead to Lethality through CD4+ T Cell-Mediated Cytokine Storm

Kitamura, Hiroshi; Sedlik, Christine; Jacquet, Alexandra; Zaragoza, Bruno; Dusséaux, Mathilde; Prémel, Virginie; Sastre-Garau, Xavier; Lantz, Olivier

doi:10.4049/jimmunol.1000933

Cited by 20 publications

(12 citation statements)

References 54 publications

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“…3D). In vitro-and in vivo Ag-induced tumors were not rejected, in agreement with our previous reports, showing that Marilyn cells cannot reject MCA-DBY tumors in the absence of strong priming (25,29).…”

Section: H4b1 a Novel Transplanted Tumor Model With Conditional Exprsupporting

confidence: 92%

Modeling the Specific CD4+ T Cell Response against a Tumor Neoantigen

Flament

Ramírez

Prémel

et al. 2015

The Journal of Immunology

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The antitumor activity of CD4+ T cells is increasingly acknowledged in both humans and mice. The involved mechanisms have been mostly studied using transplanted tumor mouse systems. In these models, many tumor cells die at the time of implantation leading to the release of Ag in an inflammatory context contrasting with the slow and nondestructive growth of early-stage human tumors. In this study, we show that the presentation of a MHC class II–restricted model Ag (male, DBY) released by dying tumor cells may last more than 4 wk. The duration of Ag presentation varies according to the way the cells are killed before implantation. To avoid this artifactual early priming of the host precluding the study of the interactions between the immune system and tumors at the steady state, we generated a cell line expressing the DBY Ag in an inducible manner. Ag expression can be efficiently induced in vivo several days after tumor implantation. We show that the Ag reaches the lymph node and activates naive CD4+ T cells to proliferate and recirculate. We did not observe de novo induction of tumor-specific regulatory T cells. However, we observed Th1/Th17 effector cells in the tumor draining lymph node and tumors. Thus, when a neoantigen appears in established tumors, the immune system is not ignorant and naive CD4+ T cells are not tolerized. This opens up the possibility of therapeutic vaccines improving the immune response toward tumor-specific neoantigens.

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Section: H4b1 a Novel Transplanted Tumor Model With Conditional Exprsupporting

confidence: 92%

Modeling the Specific CD4+ T Cell Response against a Tumor Neoantigen

Flament

Ramírez

Prémel

et al. 2015

The Journal of Immunology

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“…The symptoms displayed by mice receiving high-dose soluble TLRLs resemble shock-like symptoms caused by cytokine storms after strong immune activation. 28 One of the key cytokines induced by poly I:C and R848 is IFN-␣, which is a potent DC activator but is also thought to be responsible for many of the adverse effects observed in human subjects treated with these TLRLs. 10,11,29,30 Indeed, in analyzing serum cytokine levels, we observed significantly increased IFN-␣ and IFN-␤ levels in mice treated with the high-dose soluble TLRLs compared with those in mice receiving low-dose targeted TLRLs.…”

Section: Targeted Delivery Of Tlrls Enhances Adjuvanticity and Reducementioning

confidence: 99%

Targeted delivery of TLR ligands to human and mouse dendritic cells strongly enhances adjuvanticity

Tacken

Zeelenberg

Cruz

et al. 2011

Blood

160

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Effective vaccines consist of 2 components: immunodominant antigens and effective adjuvants. Whereas it has been demonstrated that targeted delivery of antigens to dendritic cells (DCs) improves vaccine efficacy, we report here that co-targeting of TLR ligands (TLRLs) to DCs strongly enhances adjuvanticity and immunity. We encapsulated ligands for intracellular TLRs within biodegradable nanoparticles coated with Abs recognizing DC-specific receptors. Targeted delivery of TLRLs to human DCs enhanced the maturation and production of immune stimulatory cytokines and the Ag-specific activation of naive CD8 ؉ T cells. In vivo studies demonstrated that nanoparticles carrying Ag induced cytotoxic T-lymphocyte responses at 100-fold lower adjuvant dose when TLRLs were co-encapsulated instead of administered in soluble form. Moreover, the efficacy of these targeted TLRLs reduced the serum cytokine storm and related toxicity that is associated with administration of soluble TLRLs. We conclude that the targeted delivery of adjuvants may improve the efficacy and safety of DC-based vaccines. (Blood. 2011;118(26):6836-6844) IntroductionMost vaccines currently on the market are based on the induction of long-lived Ab responses. A major challenge is the generation of vaccines that, next to Abs, also induce Ag-specific killing of pathogen-infected cells or tumor cells by cytotoxic T lymphocytes (CTLs). This might open new opportunities for the treatment of cancer or persistent viral infections, for which induction of strong cellular immunity seems to be essential. 1 Dendritic cells (DCs) are professional APCs that play a key role in regulating adaptive immunity, and both preclinical and clinical studies have exploited DCs in an attempt to induce antiviral or antitumor CTL responses. Most of these studies explored ex vivo Ag loading of autologous monocyte-derived DCs that were readministered to the patient, a laborious and costly procedure. The discovery of pattern recognition receptors, such as C-type lectin receptors (CLRs) that mediate Ag uptake, allow for a more direct strategy by targeting Ags to DCs in vivo. Some of these CLRs are restricted to APCs, such as macrophages or DCs. Therefore, targeted delivery exploiting CLRs has already been demonstrated to enhance Ag presentation and results in immunity when DC maturation stimuli such as TLR ligands (TLRLs) are co-administered. 2 TLRs constitute a family of pattern recognition receptors that recognize pathogen-associated molecular patterns and trigger immune cell activation. Consequently, natural TLRLs and their mimetics are increasingly being applied in immunotherapeutic strategies. 3 TLRLs are potent inducers of innate immune responses and have been evaluated as monotherapies to treat infection and cancer. 4,5 In addition, TLRLs have been applied as adjuvants to stimulate adaptive immune responses. 3 We hypothesized that targeted delivery of both Ag and TLRLs directly to DCs may greatly enhance immune responses. This approach would guarantee that the APCs that take up Ag are...

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“…Adoptive transfer of tumor-specific CD4 or CD8 T cells can be effective in eradicating tumors in experimental models and in patients (1)(2)(3)(4)(5). However, more recently, adoptive transfer of TCR transgenic CD4 or CD8 T cells in combination with vaccination in experimental mouse models has shown severe side effects associated with expansion to very high numbers of tumor-specific T cells (6)(7)(8). It could thus be safer to vaccinate to expand endogenous T cells, which are unlikely to proliferate to such dangerously high levels.…”

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confidence: 99%

IgG-Mediated Anaphylaxis to a Synthetic Long Peptide Vaccine Containing a B Cell Epitope Can Be Avoided by Slow-Release Formulation

Quakkelaar

Fransen

Maren

et al. 2014

The Journal of Immunology

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Synthetic long peptides (SLP) are a promising vaccine modality to induce therapeutic T cell responses in patients with chronic infections and tumors. We studied different vaccine formulations in mice using SLP derived from carcinoembryonic Ag. We discovered that one of the SLP contains a linear Ab epitope in combination with a CD4 epitope. Repeated vaccination with this carcinoembryonic Ag SLP in mice shows improved T cell responses and simultaneously induced high titers of peptide-specific Abs. These Abs resulted in unexpected anaphylaxis after a third or subsequent vaccinations with the SLP when formulated in saline. Administration of low SLP doses in the slow-release vehicle IFA prevented the anaphylaxis after repeated vaccination. This study underscores both the immunogenicity of SLP vaccination, for inducing T cell as well as B cell responses, and the necessity of safe administration routes.

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Long Peptide Vaccination Can Lead to Lethality through CD4+ T Cell-Mediated Cytokine Storm

Cited by 20 publications

References 54 publications

Modeling the Specific CD4+ T Cell Response against a Tumor Neoantigen

Modeling the Specific CD4+ T Cell Response against a Tumor Neoantigen

Targeted delivery of TLR ligands to human and mouse dendritic cells strongly enhances adjuvanticity

IgG-Mediated Anaphylaxis to a Synthetic Long Peptide Vaccine Containing a B Cell Epitope Can Be Avoided by Slow-Release Formulation

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