Cancer Treatment Using mRNA-Lipid Nanoparticles

T-cell engager (TCE)-based immunotherapy is clinically validated in hematological cancers. However, application in solid tumors faces hurdles including T cell penetration, the immunosuppressive tumor microenvironment, and toxicity. We develop an mRNA-encoded TCE (MTS105) targeting Glypican-3, the hepatocellular carcinoma antigen, delivered via lipid nanoparticles directly to liver tissue. In mice, rats, and cynomolgus monkeys, MTS105 exhibits higher liver exposure versus plasma. Liver-orthotopic tumor-bearing mice achieve complete, dose-dependent regression, with fast intratumoral T cell activation owing to sustained higher liver and tumor functional TCE exposure versus conventional antibody-based TCE. In vivo, MTS105 induces intratumoral CD8 cell precursor and terminally differentiated memory subsets with high activation scores. In cynomolgus monkeys, MTS105 displays favorable, linear plasma pharmacokinetics including mRNA, ionizable lipid, and translated TCE following single and repeated-four-weekly dosing (up to 45 μg/kg). No severe adverse effects or gross pathology were observed. Our results thus support the advancement of MTS105 into clinical trials, with a first-in-human study currently underway. Paper and research by @Yan Huang,  Wei Xu and larger team

Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes. It lacks the three receptors (ER/PR/HER2) that enable targeted therapies in other forms of breast cancer and recurs early (often peaking ~3 years after diagnosis). Its genomic instability and immunogenic microenvironment make it a strong candidate for individualized immunotherapy. In a Phase 1 clinical trial led by Prof. Dr. med. Marcus Schmidt and investigators from Germany and Sweden, just published in Nature, we evaluated an individualized neoantigen mRNA vaccine approach in 14 patients with early-stage TNBC after surgery and (neo)adjuvant therapy. Each vaccine encoded up to 20 patient-specific neoantigens on two mRNA molecules, delivered intravenously via lipid nanoparticles to target dendritic cells. The results showed robust immune responses: • All patients in the clinical trial developed vaccine-induced T cell responses against multiple neoantigens. • Vaccine-induced CD8⁺ T cells reached frequencies commonly achieved with adoptive T cell therapies and persisted functionally for years without boosters – evolving into both "ready-to-act" cytotoxic effector cells and stem-like memory T cells. • 11 of 14 patients remained relapse-free for up to six years post-vaccination. Furthermore, the findings in three patients with relapses were instructive for potential future combination treatment strategies to overcome resistance – each revealing a distinct escape mechanism to be addressed: • Enhancing response magnitude: The patient with the weakest vaccine-induced response relapsed but achieved complete remission on subsequent anti–PD-1, suggesting a response threshold and supporting combination strategies. • Targeting antigen-presentation loss: One patient showed near-complete loss of MHC class I (likely via B2M downregulation), despite vaccine-induced T cells being present, highlighting the need to address HLA-loss escape (e.g., antibodies or strategies restoring recognition). • Comprehensive tumor sequencing: In another patient the relapse originated from a contralateral, genetically independent tumor not covered by the vaccine design, underscoring the importance of sequencing multiple lesions in hereditary settings. Overall, these results demonstrate feasibility and durable neoantigen-specific immunity in TNBC supporting personalized mRNA cancer vaccines as platform technology, while pointing to novel treatment strategies to overcome resistance – especially through informed treatment combinations. 𝐋𝐢𝐧𝐤 𝐭𝐨 𝐩𝐮𝐛𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧: https://lnkd.in/dk4fq6nA #CancerResearch #Oncology

🧬 #𝗟𝗡𝗣𝘀 𝗳𝗼𝗿 #𝗺𝗥𝗡𝗔 𝗱𝗲𝗹𝗶𝘃𝗲𝗿𝘆 𝗱𝗶𝗿𝗲𝗰𝘁𝗹𝘆 𝗶𝗻𝘁𝗼 𝘁𝘂𝗺𝗼𝗿𝘀 𝘁𝗼 𝗯𝗼𝗼𝘀𝘁 𝗶𝗺𝗺𝘂𝗻𝗲 𝗿𝗲𝘀𝗽𝗼𝗻𝘀𝗲 𝗶𝗻 𝗰𝗮𝗻𝗰𝗲𝗿 𝘁𝗵𝗲𝗿𝗮𝗽𝘆? ◽𝗛𝗮𝗺𝗼𝘂𝗱𝗮 𝗲𝘁 𝗮𝗹. 𝗶𝗻 𝗡𝗮𝘁𝘂𝗿𝗲 𝗖𝗼𝗺𝗺𝘂𝗻𝗶𝗰𝗮𝘁𝗶𝗼𝗻𝘀 (𝗢𝗽𝗲𝗻 𝗔𝗰𝗰𝗲𝘀𝘀, 𝗟𝗶𝗻𝗸 𝗶𝗻 𝗰𝗼𝗺𝗺𝗲𝗻𝘁𝘀) led by Damya Laoui from Vrije Universiteit Brussel just published (6th Dec 2024) a study about intratumorally injected "Triplet LNPs" for cancer immunotherapy. ◽𝗖𝗼𝗻𝘁𝗲𝗻𝘁 The team explored the use of "Triplet LNPs" to co-deliver an mRNA mixture encoding 3 immunomodulators (cytokines IL-21, IL-7 & co- stimulator 4-1BB ligand) directly into tumors. The aim: boost the presence and activity of CD8+ T cells to eradicate tumors and establish long-term immunological memory, while minimizing systemic exposure and associated toxicities through local administration. The result: Triplet LNP administration significantly enhanced the presence of tumor-infiltrating CD8+ T cells and their ability to produce granzyme B and IFN-γ, resulting in tumor elimination and the establishment of long-term immunological memory. Ultimately, the expression of immunomodulators (IL-21, IL-7 & TNFSF9 (gene name for the 4-1BB ligand)) correlates with improved overall survival in cancer patients (Kaplan-Meier estimates on Page 15, Fig.8). ◽ 𝗚𝗲𝗻𝗲 𝗗𝗲𝗹𝗶𝘃𝗲𝗿𝘆 ｜ 𝗖𝗲𝗹𝗹 & 𝗚𝗲𝗻𝗲 𝗧𝗵𝗲𝗿𝗮𝗽𝘆 𝗡𝗲𝘄𝘀 Follow me for more breaking research & news.

Excited to share our latest in Nature Nanotechnology Nature Portfolio led by Mitchell Lab Postdoctoral Fellow Qiangqiang Shi on a new class of ionizable lipid-like materials that act like prodrugs to reprogram the tumor immune microenvironment for in situ mRNA lipid nanoparticle cancer vaccination! Acting as both an mRNA carrier and a drug, we show that these prodrug-like LNPs drive complete regression of primary solid tumors by eliciting effector T cell infiltration and reducing T cell exhaustion, while also acting as an in situ vaccine to generate a systemic immune response and eradicate distant tumors! Free access to the article: https://rdcu.be/e8Lq6 University of Pennsylvania press release: https://lnkd.in/esHur9wY Congratulations to all authors: Ningqiang Gong, Jinjin Wang, Rohan Palanki, Qiuxian Zheng, Mohamad-Gabriel Alameh, Garima D., Benjamin Davis, Jilian Melamed, Zhangyi Luo, Junchao Xu, Christian G. Figueroa-Espada, Lulu Xue, Ye Zeng, Xuexiang Han, Dongyoon Kim, Qinyuan Chen, Hannah Yamagata, Hannah Geisler, Rakan El-Mayta, Il-Chul Yoon, and Drew Weissman!

A patient just received a personalized mRNA lung cancer vaccine. It could change the future of cancer care. In a groundbreaking step for cancer treatment, the UK has launched its first clinical trial of a personalized mRNA vaccine targeting non-small cell lung cancer (NSCLC). Developed by BioNTech — the biotech company behind one of the first COVID-19 vaccines — the new therapy, called BNT116, aims to train the immune system to detect and destroy cancer cells. Unlike chemotherapy, which attacks both healthy and cancerous tissue, this vaccine delivers precise genetic instructions via mRNA, helping the body recognize tumor-specific markers and respond with targeted immune action. Led by University College London Hospitals (UCLH), the trial involves only 20 participants, including 67-year-old Janusz Racz, the first to receive the vaccine after completing standard lung cancer treatment. While still in early stages, researchers hope BNT116 can prevent recurrence by transforming the immune system into a cancer-hunting ally. If successful, this could usher in a new era of personalized immunotherapy — where cancer treatment is tailored to the genetic profile of an individual’s tumor, offering new hope for one of the world’s deadliest cancers.

What a nice one: Zwitterionic lipids slash reactogenicity while supercharging expression A new study in Nature Biomedical Engineering unveils membrane-destabilizing zwitterionic ionizable lipids (known as MeDZ by the authors) that enhance endosomal escape for superior mRNA delivery, while minimizing inflammation—addressing key hurdles in translating mRNA-LNP cancer vaccines to the clinic. Let's break this one down: 1) Composition + enhanced expression: The MeDZ lipid features a hydrophilic headgroup composed of a pyridine-based carboxybetaine (PyCB), degradable hydrophobic multitailed alkyl chains and a tertiary amine-based linker. When formulated into LNPs, they boost mRNA expression in lymph node APCs by ~1.7-fold over BNT162b2, with 1.7-fold higher endosomal escape efficiency. 2) Reduced reactogenicity: The LNPs can cut pro-inflammatory cytokines (GM-CSF, IL-1β, IL-6) by 41.8-65.7% and neutrophil infiltration by 50% at injection sites + prevent tumor formation in 100% of mice (vs. 66.7% for BNT162b2) and eliminates lung metastases in melanoma models. 3) Therapeutic efficacy: The tech inhibits established tumor growth, achieving 40% survival (vs. 0% control); combined with anti-PD-1 yields 50% survival and complete remission in 50% of cases. Lastly, integrated with spleen-specific SORT LNPs, it increases splenic mRNA expression by 1.5-fold. While promising, challenges include validating reduced reactogenicity in larger models (NHP), optimizing lipid ratios for diverse mRNA payloads, scaling production for clinical-grade LNPs, and assessing long-term immunogenicity in larger models for broader cancer applications. Read more: https://lnkd.in/eaA7r9Ef #mRNACancerVaccine #LNPs #ZwitterionicLipids #Immunotherapy #EndosomalEscape #Nanomedicine #MedicalBreakthrough

In a first-ever human #clinicaltrial of four adult patients, an #mRNA #cancer #vaccine developed at the University of Florida reprogrammed the #immunesystem to attack #glioblastoma, the most aggressive and lethal #brain #tumor. Reported in the journal Cell, the discovery represents a potential new way to recruit the immune system to fight notoriously treatment-resistant cancers using an iteration of mRNA #technology and lipid #nanoparticles, similar to COVID-19 vaccines, but with two key differences: use of a patient's own tumor cells to create a personalized vaccine, and a newly engineered complex delivery mechanism within the vaccine. "Instead of us injecting single particles, we're injecting clusters of particles that are wrapping around each other like onions, like a bag full of onions," said senior author Dr Elias Sayour, M.D., Ph.D., a UF Health pediatric oncologist who pioneered the new vaccine, which like other #immunotherapies attempts to "educate" the immune system that a tumor is foreign. Among the most impressive findings was how quickly the new method, delivered intravenously, spurred a vigorous immune-system response to reject the tumor, said Sayour, principal investigator of the RNA Engineering Laboratory within UF's Preston A. Wells Jr. Center for Brain Tumor Therapy and a UF Health Cancer Center and McKnight Brain Institute of the University of Florida Institute investigator who led the multi-institution research team. Glioblastoma is among the most devastating diagnoses, with median survival around 15 months. The current standard of care involves surgery, radiation and some combination of #chemotherapy. https://lnkd.in/gKSfQpGv https://lnkd.in/g2wDQt9z

#GetTheMessage Now THIS is exciting—the power of mRNA Medicines! Australia just launched a world-first clinical trial to fight childhood brain cancer—and it could change everything for kids with the deadliest tumors. The PaedNEO-VAX trial will give children personalized mRNA vaccines designed specifically for their cancer. Here's the magic: Each child's tumor gets sequenced. Unique cancer markers are identified. A customized vaccine is manufactured in about 10 weeks. And that child's immune system learns to attack their specific cancer. This is happening now! At 8 pediatric hospitals across Australia. These are kids with medulloblastoma. High-grade glioma. Diffuse midline glioma. Cancers that have resisted everything else. Cancers that have taken too many children too soon. Professor Brandon Wainwright: "We might offer a glimmer of hope for children with some of the most aggressive and treatment-resistant tumours." Bravo, Australia. 🇦🇺 Your government invested $2.5 million to make this happen. You saw the promise of mRNA—precision medicine, personalized to each patient, built in weeks instead of years. That's leadership. That's what betting on science looks like. The world is watching. https://lnkd.in/e94XjV_7 #mRNA #PediatricCancer #BrainCancer #PrecisionMedicine #GetTheMessage, #HHS, Alliance for mRNA Medicines