Strategies for Targeting Tumor Microenvironment

CAR-T cell therapy has revolutionized blood cancer treatment, but solid tumors remain challenging due to limited efficacy and safety concerns from systemic cytokine release. Current "armored" CAR-T cells that secrete inflammatory cytokines like IL-12 show promise but cause dangerous toxicities when these factors are expressed throughout the body. Existing synthetic promoter systems (like NFAT) fail to adequately restrict expression to tumor sites. Researchers developed a CRISPR knock-in strategy that leverages endogenous gene regulatory mechanisms to drive transgene expression in a tumor-localized manner. By screening endogenous genes with tumor-restricted expression, they identified the NR4A2 and RGS16 promoters as promising candidates to support the delivery of cytokines such as IL-12 and IL-2 directly to the tumor site. Key Results: - Enhanced antitumour efficacy and long-term survival in both syngeneic and xenogeneic models - Improved CAR T cell polyfunctionality and activation of endogenous antitumour immunity - Superior tumor restriction compared to synthetic NFAT promoters - Favourable safety profile without the toxicities seen with conventional approaches - Applicable in CAR T cells from patients Clinical Impact: This approach addresses a critical barrier in solid tumor CAR-T therapy by providing precise spatial control over cytokine expression. The use of endogenous tumour-restricted promoters provides enhanced regulatory control compared with synthetic promoter systems, coupling transgene expression to an endogenous gene and enabling control by not only the promoter but all trans- and cis-regulatory elements. The technology offers a path toward safer, more effective CAR-T cell therapies for solid tumors while maintaining the therapeutic benefits of cytokine armoring. Paper and research by @Amanda Chen and larger team

Exosome-derived Nanoparticles in Activating NK and T Cells Exosome-derived nanoparticles are emerging as a powerful tool in immunotherapy, particularly in enhancing the activity of natural killer (NK) and T cells. These nanoparticles are naturally derived from cells, are biocompatible, and can be designed to deliver immunostimulatory signals, making them ideal for activating the immune system to fight cancer and other diseases. Exosome-derived nanoparticles can carry ligands, cytokines, or proteins that stimulate NK cells. For example, exosomes loaded with interleukin 15 (IL-15) or interleukin 12 (IL-12) can enhance NK cell proliferation, survival, and cytotoxicity. They can also deliver stress ligands that bind to activation receptors on NK cells, triggering their anti-tumor response. These nanoparticles overcome inhibitory signals in the tumor microenvironment (TME), allowing NK cells to effectively target tumor cells. Exosome-derived nanoparticles can deliver tumor antigens or co-stimulatory molecules to T cells, promoting their activation and proliferation. For example, exosomes from dendritic cells (DCs) can present tumor antigens directly to T cells, bridging innate and adaptive immunity. In addition, nanoparticles loaded with immune checkpoint inhibitors (e.g., anti-PD-1) can restore the function of exhausted T cells, enhancing their ability to attack tumors. Exosome-derived nanoparticles can stimulate both NK and T cells simultaneously, providing a dual immune response. They reprogram the TME by delivering immunostimulants while neutralizing inhibitory factors, creating a supportive environment for immune cell activity. In summary, by enhancing NK and T cell activation, exosome-derived nanoparticles offer a targeted and effective approach for cancer immunotherapy. Ongoing research focuses on optimizing their design, delivery, and clinical application, making them a promising frontier for next-generation immunotherapy. References [1] Dhanashree Murugen et al., Cancers 2022 (DOI: 10.3390/cancers14215438) [2] Jiarong Ye et al., Biomedicine & Pharmacotherapy 2024 (https://lnkd.in/eRM9uXQQ) #Immunotherapy #ExosomeNanoparticles #NKCells #TCells #CancerResearch #TumorMicroenvironment #PrecisionMedicine #CancerImmunology #BiomedicalInnovation #Nanomedicine #CancerTreatment #OncologyBreakthroughs #LifeSciences

🔓Unlocking the Full Potential of CAR-T Therapy with Small-Molecule Inhibitors! 🔬 An interesting recently published review explores how small-molecule inhibitors (SMIs) are enhancing CAR-T therapies at every stage—manufacturing, efficacy, and safety—offering hope for wider and more effective clinical applications. 📌Key Highlights from the Review: 1️⃣ Facilitating CAR-T Manufacturing: ▪️SMIs like lenalidomide (LEN) and rapamycin preserve a less-differentiated T-cell phenotype, enhancing CAR-T fitness and persistence. ▪️Dasatinib, used during manufacturing, mitigates tonic signaling and suppresses fratricide when CAR targets are expressed on T cells. 2️⃣ Boosting Anti-Tumor Efficacy: ▪️FLT3 inhibitors increase target expression and improve the engagement of FLT3-directed CARs in AML models. ▪️PI3K/AKT/mTOR inhibitors promote a central memory T-cell phenotype, improving CAR-T longevity and performance in both hematologic and solid tumors. ▪️γ-Secretase inhibitors enhance BCMA expression on tumor cells, optimizing CAR-T targeting in multiple myeloma. 3️⃣ Mitigating Toxicity: ▪️JAK inhibitors (e.g., ruxolitinib, itacitinib) reduce CRS and ICANS while preserving CAR-T functionality. ▪️Dasatinib precisely controls cytokine release and prevents immune exhaustion when administered post-infusion. 4️⃣ Epigenetic Modulation for CAR-T Fitness: ▪️HDAC inhibitors (e.g., panobinostat) enhance memory phenotypes and CAR-T infiltration into solid tumors. ▪️EZH2 inhibitors improve CAR-T polyfunctionality, reduce exhaustion markers, and boost anti-tumor efficacy, particularly in lymphomas. 5️⃣ Transforming the Tumor Microenvironment (TME): ▪️TGF-β inhibitors protect CAR-T cells from TME-induced suppression, expanding their utility in solid tumors. ▪️Adenosine blockers counteract immune suppression, enabling CAR-T cells to sustain activity even in challenging environments. 6️⃣ Innovative Combinations: Dual approaches, such as combining VIP receptor antagonists with PI3K inhibitors, show promise in overcoming resistance mechanisms and enhancing synergies. 📊 Clinical Impact: Although most data are preclinical, early-phase trials combining SMIs and CAR-T cells have demonstrated promising results, especially in AML, multiple myeloma, and solid tumors like glioblastoma. For instance, clinical trials using ibrutinib alongside CD19 CAR-T showed enhanced T-cell expansion and reduced CRS toxicity. 💡 The Road Ahead: Combining SMIs with CAR-T therapies offers a personalized and multifaceted strategy to tackle cancer. While cost and patient variability remain challenges, integrating SMIs could reduce CAR-T doses, improve accessibility, and enhance safety profiles. #CART #Immunotherapy #SmallMolecules #CancerResearch

Published in Nature (2023), Bastian Kruse et al. (Thomas Tüting lab) demonstrate that adoptively transferred CD4+ T cells alone—but not CD8+ T cells—can eradicate melanoma tumors completely lacking both MHC class I and II expression. These findings challenge the current paradigm of cancer immunotherapy, which predominantly focuses on CD8+ cytotoxic T cells whose effectiveness is limited by MHC loss and immunosuppressive TME. Historically viewed merely as ‘helper’ cells, CD4+ T cells instead have a critical yet underappreciated capacity for antitumor immunity independent of CD8+ cells. Intriguingly, CD4+ T cells do not directly infiltrate tumors in the same way CD8+ T cells do. Rather, they profoundly reshape the tumor immune landscape by recruiting and functionally reprogramming myeloid cells. These myeloid cells mature into potent interferon-activated APCs and robust iNOS-expressing tumoricidal effectors. This study uncovers exciting therapeutic opportunities by revealing the potential of CD4+ T cells to complement CD8+ T cells and NK cells, paving the way for innovative strategies against immune-evasive cancers.

Can we make CAR T cells smarter and safer for solid tumours? Imagine CAR T for solid tumours without collateral damage. CAR T therapies work well in haematological cancers, but solid tumours have long been a challenge. Arming CAR T cells with cytokines like IL-2 or IL-12 can enhance efficacy - but often at the cost of systemic toxicity. A recent article published in Nature shows a new approach to making CAR T cells more effective for solid tumours, while reducing toxicity. The authors used CRISPR to rewire endogenous genes in CAR T cells, enabling tumour-restricted cytokine expression. Instead of relying on synthetic promoters, they used natural tumour-responsive genes - NR4A2 and RGS16 - to regulate IL-12 and IL-2 production. The results? Minimal off-target toxicity Stronger anti-tumour responses Improved survival in preclinical models This strategy was effective in both mouse and human CAR T cells, including patient-derived samples. Could this redefine the future of immunotherapy for solid tumours? #science #drjojo ---------- Hi! I am Joanna, and my friends call me Dr Jojo 🌸 𝐈 𝐡𝐞𝐥𝐩 𝐬𝐭𝐚𝐫𝐭𝐮𝐩𝐬 𝐚𝐧𝐝 𝐞𝐧𝐭𝐫𝐞𝐩𝐫𝐞𝐧𝐞𝐮𝐫𝐬 𝐦𝐚𝐫𝐤𝐞𝐭 𝐭𝐡𝐞𝐢𝐫 𝐯𝐚𝐥𝐮𝐞 𝐚𝐧𝐝 𝐢𝐧𝐧𝐨𝐯𝐚𝐭𝐢𝐨𝐧 🔔 Follow for insights ♻️ Share if you find it interesting 📩 Book a consultation to grow your business and generate leads

This animation takes us on a tour through a landscape known as the 𝘁𝘂𝗺𝗼𝗿 𝗺𝗶𝗰𝗿𝗼𝗲𝗻𝘃𝗶𝗿𝗼𝗻𝗺𝗲𝗻𝘁 (TME). But beware, it's a haunted neighborhood. 🧌 Inside the #TME; it's always a stormy night, and Vincent Price can always be found playing his organ around town. Despite advances in immunotherapy and targeted treatments, many breast and lung cancers remain resistant to therapy — 𝗮𝗻𝗱 𝗮 𝗯𝗶𝗴 𝗽𝗮𝗿𝘁 𝗼𝗳 𝘁𝗵𝗲 𝗽𝗿𝗼𝗯𝗹𝗲𝗺 𝗹𝗶𝗲𝘀 𝗶𝗻 𝘁𝗵𝗲 𝗧𝗠𝗘, 𝘄𝗵𝗲𝗿𝗲 𝘄𝗲 𝗳𝗶𝗻𝗱 𝗮 𝗱𝘆𝗻𝗮𝗺𝗶𝗰 𝗻𝗲𝘁𝘄𝗼𝗿𝗸 𝗼𝗳 𝗴𝗵𝗼𝘂𝗹𝘀. 𝗙𝗼𝗿 𝗲𝘅𝗮𝗺𝗽𝗹𝗲, 𝗳𝗶𝗯𝗿𝗼𝗯𝗹𝗮𝘀𝘁𝘀, 𝗶𝗺𝗺𝘂𝗻𝗲 𝗰𝗲𝗹𝗹𝘀, 𝗯𝗹𝗼𝗼𝗱 𝘃𝗲𝘀𝘀𝗲𝗹𝘀, 𝗮𝗻𝗱 𝗲𝘅𝘁𝗿𝗮𝗰𝗲𝗹𝗹𝘂𝗹𝗮𝗿 𝗺𝗮𝘁𝗿𝗶𝘅 𝘁𝗵𝗮𝘁 𝗰𝗼𝗻𝘀𝘁𝗶𝘁𝘂𝘁𝗲 𝘁𝗵𝗲 𝗧𝗠𝗘 𝗰𝗮𝗻 𝗮𝗰𝘁𝗶𝘃𝗲𝗹𝘆 𝗵𝗲𝗹𝗽 𝘁𝘂𝗺𝗼𝗿𝘀 𝗴𝗿𝗼𝘄, 𝘀𝗽𝗿𝗲𝗮𝗱, 𝗮𝗻𝗱 𝗲𝘃𝗮𝗱𝗲 𝘁𝗿𝗲𝗮𝘁𝗺𝗲𝗻𝘁. Recent studies show that cells like cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) secrete signals that shield cancer cells, limit drug penetration, and suppress the immune system’s ability to fight back. In 𝗯𝗿𝗲𝗮𝘀𝘁 𝗮𝗻𝗱 𝗹𝘂𝗻𝗴 cancers, the TME also alters immune responses through myeloid-derived suppressor cells (MDSCs), regulatory T cells, and PD-L1 expression, creating an “immune cold” environment—one where even the best immunotherapies struggle to gain traction. Add to that a dense, fibrotic stroma and hypoxic pockets with irregular blood flow, and you've got a recipe for therapy resistance. But there’s hope. New TME-targeted strategies that include reprogramming TAMs, blocking CAF-derived signals, normalizing tumor vasculature, and 𝗰𝗼𝗺𝗯𝗶𝗻𝗶𝗻𝗴 𝗶𝗺𝗺𝘂𝗻𝗼𝘁𝗵𝗲𝗿𝗮𝗽𝗶𝗲𝘀 𝘄𝗶𝘁𝗵 𝗰𝘆𝘁𝗼𝗸𝗶𝗻𝗲 𝗯𝗹𝗼𝗰𝗸𝗲𝗿𝘀 (like IL-6 or TGF-β inhibitors). There's even momentum around nanoparticle-based delivery systems to get treatments deeper into tough-to-reach tumors. The future of cancer treatment isn't just about smarter drugs — it's about tackling the environment that helps tumors thrive. As we shift toward personalized, combination-based approaches targeting the TME, we open new doors to improve outcomes for patients with therapy-resistant breast and lung cancers. #CancerResearch #Immunotherapy #TumorMicroenvironment #Oncology #PrecisionMedicine Credit for Video to Hybrid Medical Animation

Is Osteopontin, OPN a therapeutic target in breast cancer and possibly other solid tumors? Researchers have identified OPN as a major factor in breast cancer recurrence, influencing tumor growth and immune modulation within the tumor microenvironment. OPN's role becomes crucial as its secreted protein levels significantly rise in recurrent tumors, promoting cell proliferation and accelerating growth, especially when β1 integrin is absent. 🧬 OPN accumulates in the tumor microenvironment, recruiting receptor-positive macrophages that adopt pro-tumorigenic traits. These macrophages create an extracellular matrix-rich environment, closely associated with proliferating tumor cells. The therapeutic potential of targeting OPN early in tumor development shows promise, potentially reducing growth and metastasis. In recurrent tumors, inhibiting OPN and depleting macrophages can mimic reduced tumor burden, emphasizing their roles in promoting recurrence. 🔬 The study highlights the immune tumor microenvironment's role in immunotherapy success. Targeting OPN can enhance cytotoxic T cell activity, improving responses to treatments like anti-PD-1. This combination therapy leads to higher T cell recruitment and tumor cell death, although further investigation into the clinical pharmacodynamics of anti-OPN is needed. Could this be the key to addressing aggressive recurrent tumors and improving patient outcomes? Find more insights in the comments below. 🔗 #RecurrentTumors #Osteopontin #Immunotherapy #CancerResearch #TumorMicroenvironment