A liposomal RNA vaccine inducing neoantigen-specific CD4
            <sup>+</sup>
            T cells augments the antitumor activity of local radiotherapy in mice

Salomon, Nadja; Vascotto, Fulvia; Selmi, Abderraouf; Vormehr, Mathias; Quinkhardt, Juliane; Bukur, Thomas; Schrörs, Barbara; Löewer, Martin; Diken, Mustafa; Türeci, Özlem; Şahin, Uğur; Kreiter, Sebastian

doi:10.1080/2162402x.2020.1771925

Cited by 36 publications

(34 citation statements)

References 59 publications

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“…Moreover, the induction of IFN-γ by the CD8 + epitope AH1-A5, although lower in magnitude compared with neoantigen-specific T cells, suggested that CD4 + T cell activation by the vaccine was required to promote antigenic spread (Figure 8B). This interpretation is consistent with recent data testing the effects of vaccination with CD4 + T cell neoepitopes in combination with focal tumor radiotherapy in the CT26 tumor model (30). To evaluate the cytotoxic activity of neoantigen-specific T cells, splenocytes were harvested from 4T1-bearing mice vaccinated with DHX58 and CAND1 or with Neo-vax.…”

Section: Resultssupporting

confidence: 89%

Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control

Lhuillier¹,

Rudqvist²,

Yamazaki³

et al. 2021

Journal of Clinical Investigation

146

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Section: Resultssupporting

confidence: 89%

Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control

Lhuillier¹,

Rudqvist²,

Yamazaki³

et al. 2021

Journal of Clinical Investigation

146

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“…Combination of local radiotherapy with an RNA-LPX vaccine that encodes CD4 + T cell-recognized neoantigens resulted in a poly-antigenic, potent CD8 + T cell response and memory that rejected CT26 tumor re-challenge, had higher number of polyfunctional IFN-γ + CD4 + T H 1 cells specific for the immunodominant CD4 neoantigen ME1, elevated numbers of activated gp70-specific CD8 + T cells, and lower PD-1/LAG-3 expression. Follow-up immunotherapy with anti-CTLA4 antibody resulted in complete remission of gp70-negative CT26 tumors in all mice in this study ( 178 ). In an inducible lung adenocarcinoma mouse model, vaccination using the G12D KRAS mutations as neoantigens and a novel synthetic long peptide-containing cationic lipoplex-based delivery platform stimulated both CD4 + and CD8 + T cell response and suppressed tumor growth, while combination with checkpoint inhibitor furthered such suppression ( 179 ).…”

Section: Oncodriver-specific and Neoantigen-driven Cd4 + mentioning

confidence: 64%

Differentiation and Regulation of TH Cells: A Balancing Act for Cancer Immunotherapy

et al. 2021

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Current success of immunotherapy in cancer has drawn attention to the subsets of TH cells in the tumor which are critical for activation of anti-tumor response either directly by themselves or by stimulating cytotoxic T cell activity. However, presence of immunosuppressive pro-tumorigenic TH subsets in the tumor milieu further contributes to the complexity of regulation of TH cell-mediated immune response. In this review, we present an overview of the multifaceted positive and negative effects of TH cells, with an emphasis on regulation of different TH cell subtypes by various immune cells, and how a delicate balance of contradictory signals can influence overall success of cancer immunotherapy. We focus on the regulatory network that encompasses dendritic cell-induced activation of CD4+ TH1 cells and subsequent priming of CD8+ cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic TH2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory TH9 and Tfh cells, immunosuppressive Treg cells, and the duality of TH17 function contribute to tip the balance of anti- vs pro-tumorigenic TH responses in the tumor. We highlight the developing knowledge of CD4+ TH1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4+ TH1 immunity, and how opposing action of TH cell subtypes can be explored further to amplify immunotherapy success in patients. Understanding the nuances of CD4+ TH cells regulation and the molecular framework undergirding the balancing act between anti- vs pro-tumorigenic TH subtypes is critical for rational designing of immunotherapies that can bypass therapeutic escape to maximize the potential of immunotherapy.

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“…Intravenously administered negatively charged to near-neutral RNA-LPX vaccines have been shown in mice to target APCs resident in lymphoid organs, including the spleen, lymph nodes and bone marrow, while inducing strong local (cell-specific activation) and systemic (proinflammatory cytokine abundance in the circulation) type I IFN-dominated immune modulation [ 40 ]. In several mouse tumor models, RNA-LPX vaccines induce strong effector and memory T-cell responses directed against the encoded TSAs or TAAs, and mediate tumor growth control or rejection, and improve survival [ 40 , 107 – 109 ]. In a phase I clinical trial (NCT02410733), 119 melanoma patients were vaccinated with an RNA-LPX vaccine encoding the four melanoma TAAs MAGE-A3, transmembrane phosphatase with tensin homology (TPTE), NY-ESO-1 and tyrosinase [ 40 , 41 ].…”

Section: Mrna-based Cancer Vaccinesmentioning

confidence: 99%

mRNA therapeutics in cancer immunotherapy

et al. 2021

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Synthetic mRNA provides a template for the synthesis of any given protein, protein fragment or peptide and lends itself to a broad range of pharmaceutical applications, including different modalities of cancer immunotherapy. With the ease of rapid, large scale Good Manufacturing Practice-grade mRNA production, mRNA is ideally poised not only for off-the shelf cancer vaccines but also for personalized neoantigen vaccination. The ability to stimulate pattern recognition receptors and thus an anti-viral type of innate immune response equips mRNA-based vaccines with inherent adjuvanticity. Nucleoside modification and elimination of double-stranded RNA can reduce the immunomodulatory activity of mRNA and increase and prolong protein production. In combination with nanoparticle-based formulations that increase transfection efficiency and facilitate lymphatic system targeting, nucleoside-modified mRNA enables efficient delivery of cytokines, costimulatory receptors, or therapeutic antibodies. Steady but transient production of the encoded bioactive molecule from the mRNA template can improve the pharmacokinetic, pharmacodynamic and safety properties as compared to the respective recombinant proteins. This may be harnessed for applications that benefit from a higher level of expression control, such as chimeric antigen receptor (CAR)-modified adoptive T-cell therapies. This review highlights the advancements in the field of mRNA-based cancer therapeutics, providing insights into key preclinical developments and the evolving clinical landscape.

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A liposomal RNA vaccine inducing neoantigen-specific CD4 ⁺ T cells augments the antitumor activity of local radiotherapy in mice

Abstract: Kreiter (2020) A liposomal RNA vaccine inducing neoantigen-specific CD4 + T cells augments the antitumor activity of local radiotherapy in mice,

Cited by 36 publications

References 59 publications

Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control

Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control

Differentiation and Regulation of TH Cells: A Balancing Act for Cancer Immunotherapy

mRNA therapeutics in cancer immunotherapy

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