RNA aggregates harness the danger response for potent cancer immunotherapy.

in Cell by Hector R Mendez-Gomez, Anna DeVries, Paul Castillo, Christina von Roemeling, Sadeem Qdaisat, Brian D Stover, Chao Xie, Frances Weidert, Chong Zhao, Rachel Moor, Ruixuan Liu, Dhruvkumar Soni, Elizabeth Ogando-Rivas, Jonathan Chardon-Robles, James McGuiness, Dingpeng Zhang, Michael C Chung, Christiano Marconi, Stephen Michel, Arnav Barpujari, Gabriel W Jobin, Nagheme Thomas, Xiaojie Ma, Yodarlynis Campaneria, Adam Grippin, Aida Karachi, Derek Li, Bikash Sahay, Leighton Elliott, Timothy P Foster, Kirsten E Coleman, Rowan J Milner, W Gregory Sawyer, John A Ligon, Eugenio Simon, Brian Cleaver, Kristine Wynne, Marcia Hodik, Annette M Molinaro, Juan Guan, Patrick Kellish, Andria Doty, Ji-Hyun Lee, Tara Massini, Jesse L Kresak, Jianping Huang, Eugene I Hwang, Cassie Kline, Sheila Carrera-Justiz, Maryam Rahman, Sebastian Gatica, Sabine Mueller, Michael Prados, Ashley P Ghiaseddin, Natalie L Silver, Duane A Mitchell, Elias J Sayour

TLDR

  • RNA-LPAs are a new technology that can improve the way our bodies fight cancer. They work by packaging tumor mRNA antigens into multi-layered particles that activate immune cells and reprogram the tumor microenvironment. The study found that RNA-LPAs improved cancer immunogenicity and reprogrammed the TME in client-owned canines with terminal gliomas and in a first-in-human trial for glioblastoma patients. This technology has the potential to improve cancer immunotherapy, but more research is needed to determine the optimal dosage and duration for different types of cancer and to determine the long-term safety and efficacy in humans.

Abstract

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Overview

  • The study aims to enhance the payload packaging and immunogenicity of tumor mRNA antigens using multi-lamellar RNA lipid particle aggregates (LPAs).
  • The study compares the outcomes observed under different experimental conditions, specifically the systemic administration of RNA-LPAs versus current mRNA vaccine designs. The study seeks to answer the question of whether RNA-LPAs can improve cancer immunogenicity and reprogram the tumor microenvironment (TME).
  • The primary objective of the study is to demonstrate the safety and efficacy of RNA-LPAs in client-owned canines with terminal gliomas and in a first-in-human trial for glioblastoma patients.

Comparative Analysis & Findings

  • The study found that RNA-LPAs elicited a massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provoked cancer immunogenicity and mediated rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became
  • . In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Implications and Future Directions

  • The study's findings suggest that RNA-LPAs have the potential to improve cancer immunogenicity and reprogram the TME, which could lead to more effective cancer immunotherapy. However, the study also identified limitations, such as the need for further research to determine the optimal dosage and duration of RNA-LPAs for different types of cancer. Future research could also explore the use of RNA-LPAs in combination with other immunotherapies to enhance their efficacy. Additionally, the study highlights the need for further research to determine the long-term safety and efficacy of RNA-LPAs in humans.
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