Tumor infiltrating lymphocytes as an endpoint in cancer vaccine trials

McCarthy, Patrick M.; Valdera, Franklin A.; Smolinsky, Todd R.; Adams, Alexandra; O’Shea, Anne E.; Thomas, Katryna K.; Decar, Spencer Van; Carpenter, Elizabeth L.; Tiwari, Ankur; Myers, Judith M.; Hale, Diane F.; Vreeland, Timothy J.; Peoples, George E.; Stojadinovic, Alexander; Clifton, Guy T.

doi:10.3389/fimmu.2023.1090533

Cited by 2 publications

(1 citation statement)

References 79 publications

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“…The impairment of naïve T cell priming caused by the activation of cancer cell-specific oncogenic pathways, which leads to ineffective intratumoral recruitment of dendritic cells (DCs), is associated with ICB resistance in melanoma and hepatocellular cancer models (10,11). In weakly immunogenic and/or immune desert tumors, therapeutic cancer vaccine by eliciting a specific T cell response that promotes intratumoral T-cell trafficking and because of its low toxicity would be a leading treatment to be combined with ICB (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Second generation of LNP based mRNA vaccine leads to a T cell–inflamed tumor microenvironment favorable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumor model

Fournier,

Mercey-Ressejac,

Derangère

et al. 2024

Preprint

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Background: mRNA-based cancer vaccines show promise in triggering antitumor immune responses. To combine them with existing immunotherapies, the intratumoral immune microenvironment needs to be deeply characterized. Here, we test the second generation of lipid nanoparticles (LNPs), nanostructured lipid carriers (so-called Lipidots), for delivering mRNA encoding Ovalbumin (OVA) antigen to elicit specific antitumor responses. Methods: We evaluated whether LNP OVA mRNA complexes activate dendritic cells (DCs) ex vivo and identified the involved signaling pathways using specific inhibitors. We tested the anti-tumoral impact of Ova mRNA vaccine in two murine tumor models as well as its synergy effect with an anti-PD-1 therapy by following the tumor growth and performing an immunophenotyping of innate and adaptive immune cells. The vaccine-related gene signature was assessed by RNA-sequencing. The immune memory response was assessed by re-challenging surviving treated mice with tumor cells. Results: We demonstrate in vitro that our LNPs deliver mRNA into DCs, when complexed with mRNA, activate DCs through the TLR4/8 and ROS signaling pathways and induce specific CD4+ and CD8+ T cell activation. Our vaccinal strategy exhibits significant antitumor efficacy both in the context of tumor prevention and as a therapeutic vaccine in B16OVA and E.G7-OVA cold tumors. The LNP-Ova mRNA vaccine induces a profound intratumoral remodeling of the innate and adaptive immunity associated with an increase in the gene expression of chemokines (Cxcl10, Cxcl11, Cxcl9) involved in CD8+ T cell attraction. Additionally, the vaccine induces the establishment of an escape mechanism mediated by PD-1/PDL-1 axis, making it an adjuvant therapy for optimized responses to the blocking of this signaling pathway. Finally, the combination of vaccine and anti-PD-1 therapy achieves a much higher rate of complete responses and memory immune responses compared to monotherapies. Conclusion: Our work demonstrates the capability of Lipidots as an effective platform for the development of preventive and therapeutic vaccines against cancer based on mRNA delivery and that combination with other immunotherapies such as immune checkpoint blockers could counter tumor resistance and promote long-term antitumor immunity.

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Section: Introductionmentioning

confidence: 99%

Second generation of LNP based mRNA vaccine leads to a T cell–inflamed tumor microenvironment favorable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumor model

Fournier,

Mercey-Ressejac,

Derangère

et al. 2024

Preprint

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Unlocking cancer vaccine potential: What are the key factors?

Grant,

Ni Lee,

Chinnakannan

et al. 2024

Human Vaccines & Immunotherapeutics

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Cancer is a global health challenge, with changing demographics and lifestyle factors producing an increasing burden worldwide. Screening advancements are enabling earlier diagnoses, but current cancer immunotherapies only induce remission in a small proportion of patients and come at a high cost. Cancer vaccines may offer a solution to these challenges, but they have been mired by poor results in past decades. Greater understanding of tumor biology, coupled with the success of vaccine technologies during the COVID-19 pandemic, has reinvigorated cancer vaccine development. With the first signs of efficacy being reported, cancer vaccines may be beginning to fulfill their potential. Solid tumors, however, present different hurdles than infectious diseases. Combining insights from previous cancer vaccine clinical development and contemporary knowledge of tumor immunology, we ask: who are the ‘right’ patients, what are the ‘right’ targets, and which are the ‘right’ modalities to maximize the chances of cancer vaccine success?

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Tumor infiltrating lymphocytes as an endpoint in cancer vaccine trials

Cited by 2 publications

References 79 publications

Second generation of LNP based mRNA vaccine leads to a T cell–inflamed tumor microenvironment favorable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumor model

Second generation of LNP based mRNA vaccine leads to a T cell–inflamed tumor microenvironment favorable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumor model

Unlocking cancer vaccine potential: What are the key factors?

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