CAR T Cell Therapy Advancements

Yale University just cracked one of CAR-T’s biggest limitations. Most FDA-approved CAR-Ts struggle when tumors don’t wave enough “cancer flags.” Low-antigen cancers slip through. But Yale researchers may have found a fix: Intrinsically Disordered Regions (IDRs). - In culture dishes, IDR-CAR-Ts showed far stronger killing activity, even against cells with low CD19, CD22, or HER2. - In mouse models, FUS-IDR CAR-Ts suppressed both blood cancers and low-HER2 colorectal tumors, with reduced exhaustion markers (PD1, LAG3). - IDRs are found in ~50% of human proteins - an untapped toolkit for immune engineering. Why it matters: CAR-T’s problem has never been promise - it’s persistence. If this approach holds, we’re talking broader reach, longer durability, and a new modular playbook for solid tumors. Every biotech working in immunotherapy should be watching Yale. The door to low-antigen cancers might finally be opening.

Just out: A new paper showing LNP-mRNAs can produce CAR-T cells inside the body. CAR-T therapy is transforming cancer treatment, but it presents several new challenges. And there are a lot of brilliant scientists (and companies) focused on improving access to this therapeutic approach. So far, it requires taking a patient's T cells (a white blood cell) and modifying them to attack their cancer. This currently occurs outside the patient's body, and the modified cells are reintroduced into the patient, where they attack tumour cells. --- But an interesting new approach was just described in Science. Building on the mRNA COVID-19 vaccine approach, they developed lipid nanoparticles (LNPs) that target specific T cells when injected into patients (in vivo). In the mouse model used, this approach successfully produced CAR-T cells, which controlled tumour growth. There are companies already adapting the mRNA vaccine approach to target tumours, but those approaches are based on expressing multiple tumour-specific proteins. This new method utilises the CAR-T approach and targets specific T cells. --- This new method is interesting because, over the long term, it could make CAR-T therapy more accessible to patients. That said, it will present new production challenges. And we'll need to see detailed clinical trials (which are underway).

A comprehensive update and status for CAR-T cell therapy for the treatment of adult high-grade gliomas, #Nature Precision Oncology Treatment for malignant primary brain tumors, including glioblastoma, remains a significant challenge despite advances in therapy. CAR-T cell immunotherapy represents a promising alternative to conventional treatments. This review discusses the landscape of clinical trials for CAR-T cell therapy targeting brain tumors, highlighting key advancements like novel target antigens and combinatorial strategies designed to address tumor heterogeneity and immunosuppression, with the goal of improving outcomes for patients with these aggressive cancers. Engineering CAR-T cells to overcome the brain tumor microenvironment One of the main challenges in treating brain tumors is the immune-suppressive nature of the tumor microenvironment. Several approaches are being developed to enable the delivery of immune-modulating factors, such as cytokines, directly to the TME. For example, CAR-T cells engineered to secrete cytokines IL-12 and IL-18 have shown increased activation of surrounding immune cells, such as NK, NKT, and γδ T cells169. Similarly, CAR-T cells designed to secrete IL-15 have exhibited improved effector functions, elevated levels of the anti-apoptotic protein Bcl-2, decreased expression of PD-1, and superior tumor control and persistence in preclinical GBM models170. Additionally, CRISPR-Cas9 genome editing techniques have been used to engineer CAR-T cells that resist TGF-β-mediated immunosuppression, a common feature of the GBM tumor microenvironment171. Also, CAR-T cells have been engineered to prevent the expression of immune checkpoint molecules such as PD-1, which are often upregulated in the TME of GBM and contribute to T cell exhaustion. By knocking out these checkpoint molecules, CAR-T cells can resist the suppressive signals in the TME, improving their persistence and anti-tumor efficacy172. https://lnkd.in/g2GnbBhZ

𝗖𝗔𝗥-𝗧 𝗶𝗻 𝘀𝗼𝗹𝗶𝗱 𝘁𝘂𝗺𝗼𝗿𝘀 - 𝗮 𝗿𝗲𝘃𝗶𝗲𝘄 🧠 𝗔 𝗽𝗮𝗽𝗲𝗿 𝗮 𝗱𝗮𝘆 𝗸𝗲𝗲𝗽𝘀 𝗯𝗿𝗮𝗶𝗻 𝗱𝗲𝗰𝗮𝘆 𝗮𝘄𝗮𝘆 🧠 Monday 16 March 2026 𝘚𝘰𝘭𝘪𝘥 𝘵𝘶𝘮𝘰𝘳 𝘊𝘈𝘙-𝘛 𝘤𝘦𝘭𝘭 𝘵𝘩𝘦𝘳𝘢𝘱𝘺 𝘪𝘴 𝘴𝘵𝘢𝘳𝘵𝘪𝘯𝘨 𝘵𝘰 𝘨𝘦𝘯𝘦𝘳𝘢𝘵𝘦 𝘳𝘦𝘢𝘭 𝘤𝘭𝘪𝘯𝘪𝘤𝘢𝘭 𝘳𝘦𝘴𝘱𝘰𝘯𝘴𝘦𝘴, 𝘣𝘶𝘵 𝘥𝘶𝘳𝘢𝘣𝘭𝘦 𝘴𝘶𝘤𝘤𝘦𝘴𝘴 𝘸𝘪𝘭𝘭 𝘥𝘦𝘱𝘦𝘯𝘥 𝘰𝘯 𝘰𝘷𝘦𝘳𝘤𝘰𝘮𝘪𝘯𝘨 𝘢𝘯𝘵𝘪𝘨𝘦𝘯 𝘩𝘦𝘵𝘦𝘳𝘰𝘨𝘦𝘯𝘦𝘪𝘵𝘺, 𝘱𝘰𝘰𝘳 𝘵𝘳𝘢𝘧𝘧𝘪𝘤𝘬𝘪𝘯𝘨, 𝘰𝘯-𝘵𝘢𝘳𝘨𝘦𝘵 𝘰𝘧𝘧-𝘵𝘶𝘮𝘰𝘳 𝘵𝘰𝘹𝘪𝘤𝘪𝘵𝘺, 𝘢𝘯𝘥 𝘵𝘩𝘦 𝘴𝘶𝘱𝘱𝘳𝘦𝘴𝘴𝘪𝘷𝘦 𝘵𝘶𝘮𝘰𝘳 𝘮𝘪𝘤𝘳𝘰𝘦𝘯𝘷𝘪𝘳𝘰𝘯𝘮𝘦𝘯𝘵. 💡𝗧𝗮𝗸𝗲 𝗵𝗼𝗺𝗲 𝗺𝗲𝘀𝘀𝗮𝗴𝗲  • Clinical efficacy: While response rates in solid tumors remain modest overall, clear “pockets of promise” exist in neuroblastoma (GD2), sarcoma (HER2), and glioblastoma (IL-13Rα2), with some trials reporting complete response rates up to ~31%.  • Biological barriers: Major challenges include antigen heterogeneity, on-target off-tumor toxicity, poor T cell trafficking, and an immunosuppressive tumor microenvironment. The field is moving toward armored CARs (for example IL-12 or IL-15 secreting cells) and logic-gated circuits such as SynNotch to improve specificity and persistence.  • Manufacturing innovation: New ex vivo strategies — including metabolic priming with L-arginine and shortened vein-to-vein production (24–72 h) — aim to preserve T cell stemness and reduce exhaustion.  • Emerging platforms: Allogeneic “off-the-shelf” CAR-T products and in vivo CAR engineering using lipid nanoparticles are being explored to overcome scalability and manufacturing complexity. 🔥𝗜𝗺𝗽𝗮𝗰𝘁  • Future progress will likely come from integrated cell engineering and tumor-specific clinical strategies, not receptor design alone. ❓𝗢𝗽𝗲𝗻 𝗾𝘂𝗲𝘀𝘁𝗶𝗼𝗻𝘀  • Which antigen combinations best balance tumor coverage and safety?  • Which armored CAR payloads enhance efficacy without systemic toxicity?  • How should conditioning, delivery route, and combinations differ by tumor type? 𝗖𝘂𝗿𝗿𝗲𝗻𝘁 𝘀𝘁𝗮𝘁𝗲 𝗼𝗳 𝗖𝗔𝗥-𝗧 𝗰𝗲𝗹𝗹 𝘁𝗵𝗲𝗿𝗮𝗽𝗶𝗲𝘀 𝗳𝗼𝗿 𝘀𝗼𝗹𝗶𝗱 𝘁𝘂𝗺𝗼𝗿𝘀 Reginaldo Rosa, MBA, PhD et al. Med, February 2026 Corresponding author: Saul Priceman 🔗 𝘓𝘪𝘯𝘬 𝘵𝘰 𝘵𝘩𝘦 𝘱𝘶𝘣𝘭𝘪𝘤𝘢𝘵𝘪𝘰𝘯 𝘪𝘯 𝘤𝘰𝘮𝘮𝘦𝘯𝘵𝘴 𝘐𝘭𝘭𝘶𝘴𝘵𝘳𝘢𝘵𝘪𝘰𝘯 𝘢𝘥𝘢𝘱𝘵𝘦𝘥 𝘧𝘳𝘰𝘮 𝘵𝘩𝘦 𝘢𝘳𝘵𝘪𝘤𝘭𝘦.  𝘛𝘩𝘦 𝘰𝘱𝘪𝘯𝘪𝘰𝘯𝘴 𝘴𝘩𝘢𝘳𝘦𝘥 𝘰𝘯 𝘓𝘪𝘯𝘬𝘦𝘥𝘐𝘯 𝘢𝘳𝘦 𝘮𝘺 𝘰𝘸𝘯.

In my latest article, published in Cancer World, I outlined where immunotherapy stands today and where the next decade is heading. 🌐 Beyond PD-1: Mapping the Next Era of Immunotherapy More than a decade ago, durable responses to checkpoint inhibitors signaled a turning point in oncology. Anti–CTLA-4 opened the door; anti–PD-1 therapies reshaped the entire field. For patients with advanced melanoma and other cancers, long-lasting remissions became a realistic possibility. But we are now at a crossroads. PD-1 inhibitors remain foundational, yet the field has plateaued: not all patients respond, some relapse, and access across Europe remains uneven. So, what comes next? 𝗡𝗲𝘄 𝗜𝗺𝗺𝘂𝗻𝗲 𝗧𝗮𝗿𝗴𝗲𝘁𝘀 Beyond LAG-3, TIGIT and TIM-3. Some combinations show promise but are unlikely to replicate the disruptive impact of early checkpoint inhibitors. “𝗦𝗺𝗮𝗿𝘁” 𝗖𝘆𝘁𝗼𝗸𝗶𝗻𝗲𝘀 Engineered IL-2, IL-15, IL-18 and others designed to empower effector cells while reducing toxicity — ideal partners for reshaping immunity in “cold” tumors. 𝗣𝗲𝗿𝘀𝗼𝗻𝗮𝗹𝗶𝘇𝗲𝗱 𝗺𝗥𝗡𝗔 𝗩𝗮𝗰𝗰𝗶𝗻𝗲𝘀 A potential paradigm shift. In melanoma, V940 + pembrolizumab significantly reduced recurrence risk by rebuilding immune priming and expanding T-cell diversity. 𝗖𝗲𝗹𝗹 𝗧𝗵𝗲𝗿𝗮𝗽𝘆 𝗳𝗼𝗿 𝗦𝗼𝗹𝗶𝗱 𝗧𝘂𝗺𝗼𝗿𝘀 TIL therapy demonstrates benefit even in heavily pretreated, PD-1–resistant melanoma. Infrastructure remains a crucial bottleneck for widespread adoption. 𝗧𝗵𝗲 𝗥𝗶𝘀𝗲 𝗼𝗳 𝗧-𝗖𝗲𝗹𝗹 𝗘𝗻𝗴𝗮𝗴𝗲𝗿𝘀 By physically bridging T cells to tumor cells, next-generation TCEs create immune synapses independently of pre-existing priming - a powerful strategy against PD-1 resistance. 𝗡𝗔𝗗𝗜𝗡𝗔 and the Evolution of Neoadjuvant Immune Priming The NADINA studies highlight a pivotal shift: activating and educating the immune system before surgery. This approach yields deeper pathological responses, stronger immune activation, improved long-term outcomes and enables potential post-surgical therapy de-escalation. 𝗧𝗵𝗲 𝗖𝗼𝗿𝗲 𝗜𝗻𝘀𝗶𝗴𝗵𝘁 The future of immunotherapy will not come from multiplying checkpoints, but from integrating strategies that rebuild priming, shape activation and sustain immune memory. 𝗧𝗵𝗲 𝗘𝘂𝗿𝗼𝗽𝗲𝗮𝗻 𝗖𝗵𝗮𝗹𝗹𝗲𝗻𝗴𝗲 Rapid innovation requires equally rapid solutions for access, infrastructure and sustainable reimbursement to avoid widening disparities. 𝗖𝗼𝗻𝗰𝗹𝘂𝘀𝗶𝗼𝗻 We are entering the second phase of immunotherapy - a phase defined by therapies that teach the immune system, not merely release it. Melanoma will remain the natural testing ground, but the implications are far broader.

#ScienceSaturday ❓How can we help CAR T cells survive longer and fight tumors more effectively? ➡️ In this study, Bailey et al. found that deleting the interferon-γ receptor (IFN-γR) in CAR T cells prevents IFN-γ–induced cell death, especially in CD28-based CARs, leading to better and more durable responses. ➡️ IFN-γR knockout CAR T cells showed enhanced persistence and memory, and delivered more potent tumor control in both liquid and solid tumor models, even protecting against tumor rechallenge. 🌟 This approach shows removing IFN-γ signaling can rewire CAR T cells for greater durability and antitumor activity, offering a promising path to improve cell therapy for cancer. 🔗 Read the full study in Science Magazine: https://lnkd.in/eskqWKzm

"Time 2EVOLVE: predicting efficacy of engineered T-cells – how far is the bench from the bedside?" Immunotherapy with gene engineered CAR and TCR transgenic T-cells is a transformative treatment in cancer medicine. There is a rich pipeline with target antigens and sophisticated technologies that will enable establishing this novel treatment not only in rare hematological malignancies, but also in common solid tumors. The T2EVOLVE consortium is a public private partnership directed at accelerating the preclinical development of and increasing access to engineered T-cell immunotherapies for cancer patients. A key ambition in T2EVOLVE is to assess the currently available preclinical models for evaluating safety and efficacy of engineered T cell therapy and developing new models and test parameters with higher predictive value for clinical safety and efficacy in order to improve and accelerate the selection of lead T-cell products for clinical translation. Here, we review existing and emerging preclinical models that permit assessing CAR and TCR signaling and antigen binding, the access and function of engineered T-cells to primary and metastatic tumor ligands, as well as the impact of endogenous factors such as the host immune system and microbiome. Collectively, this review article presents a perspective on an accelerated translational development path that is based on innovative standardized preclinical test systems for CAR and TCR transgenic T-cell products. Factors affecting efficacy of engineered T cells. CAR-T or TCR-T efficacy can be influenced by several factors, that can improve (in green) or dampen (in red) clinical outcomes. The immunosuppressive tumor microenvironment and the heterogeneity and loss of antigen expression are an important causes of treatment failure. Specific baseline qualities of the infusion product, including optimal differentiation potential, metabolic profile and low expression of inhibitory molecules are key to mediate tumor control. Effective treatment with engineered T cells, especially in the context of solid tumors may require the activation of an endogenous T cell response, in a process known as epitope spreading. Finally, viral integration and clonal imbalance may have a favorable or deleterious impact on T cell efficacy. https://lnkd.in/eBXgi9xs #Immunotherapy #CAR_transgenic_Tcells #TCR_transgenic_Tcells

Our lab's new paper (https://lnkd.in/gQa53Bqv) is now out at @NatureBiotech. We discovered that IL-10-expressing CAR T cells resist T cell dysfunction and mediate durable clearance of solid tumors and metastases (https://rdcu.be/duW2h) (1/) CAR T cells are remarkably effective in treating blood cancers, but not solid tumors. Antigen stimulation and immune suppressors cause T cell exhaustion and eventually dysfunction. Countering T cell exhaustion is required to enhance CAR T cell therapy for solid tumors. (2/) We previously reported that T cells upregulate IL-10-receptor expression when they become terminally exhausted (TCF1-TIM3+). IL-10–Fc fusion protein could reinvigorate terminally exhausted T cells and induce durable complete responses in solid tumors. https://lnkd.in/d7g34_i. (3/) However, to maintain adequate concentrations, multiple intratumoral injections of IL-10–Fc were necessary limiting the application. We designed and prepared IL-10-secreting CAR T using both mouse and human CAR T cells. (4/) We show that treatment with IL-10-CAR T cells leads to complete regression of established solid tumors and metastatic cancers across several cancer types in syngeneic and xenograft models, including colon cancer, breast cancer, melanoma, lymphoma, and pancreatic cancer. (5/) The superior antitumor effects of IL-10-producing CAR T cells challenge the conventional view that IL-10 is solely an immunosuppressive cytokine. Insights into the complex functions of cytokines could lead to further biomedical applications. (9/) The IL-10-secreting CAR T cell described here can potentially be a generalizable approach to prevent T cell exhaustion and metabolic dysfunction, which we term ‘metabolic armoring’. Extension to TCR-T, TIL, and other cell therapy can be expected. (10/) Clinical trials of IL-10-CD19-CAR T cells in patients with relapsed/refractory DLBCL or B-cell ALL are currently underway (NCT05715606, NCT05747157, NCT06120166). 12/12 patients have reached complete remission so far with 1-5% of typical CAR-T doses. (11/) We are thrilled that Research Briefing has highlighted our work (https://lnkd.in/g7UPWhB3). @Hongbo Chi, St Jude Children's Research Hospital comments “this is an interesting study with strong therapeutic relevance”. (12/) This work was led by Yang Zhao and Jiangqing Chen, and in close collaboration with Jie Sun lab Jie Sun, and @YugangGUO2 Lab, at Zhejiang University. We also thank the Santiago Carmona lab, and Pedro Romero lab, and other Li Tang lab members,  and core facilities - it was a real team effort! (13/) We are also grateful for the support from @EPFL and our funding sources @snf_ch, @krebsliga, @Krebs_Forschung, @ERC_Research, @XtalPi, #Kristian Gerhard Jebsen Foundation, #Anna Fuller Fund Grant, (14/)

#AdoptiveCellTherapy | Engineered #NKcells for #Cancer Therapy | "Off-the-Shelf" Solutions for #Solid #Tumours | Tremendous In-Depth Expert Review at latest Cancer Cell by Cell Press by Alexander Biederstädt, & Katy Rezvani | Allogeneic natural killer (NK) cell immunotherapy is emerging as a promising and scalable, off-the-shelf platform for treating relapsed and refractory cancers. Early-phase clinical trials have demonstrated remarkable safety and encouraging therapeutic efficacy of chimeric antigen receptor (CAR)-NK cells in heavily pretreated patients with lymphoid malignancies. Current efforts are expanding these therapies to solid tumors, with translational research increasingly leveraging precision gene editing to enhance effector function, persistence, and resistance to the immunosuppressive tumor microenvironment. In this review*, the authors summarise findings from early-phase clinical trials and discuss emerging synthetic biology and engineering approaches to improve NK cell potency. They also highlight advances in high-throughput discovery platforms that have identified actionable gene targets for NK cell reprogramming, offering a path to design multi-engineered CAR-NK cells to overcome the challenges of solid tumors. Together, these translational innovations define the trajectory of next-generation NK cell therapies and their integration into the broader cancer immunotherapy landscape. *https://lnkd.in/eb9HPFUA Celentyx Ltd #immunotherapy #drugdiscovery #CRO www.celentyx.com Professor Nicholas Barnes PhD, FBPhS Omar Qureshi Catherine Brady FIGURE | Upper: Synthetic biology and precision genome editing strategies to enhance NK cell-based immunotherapies: Schematic representation highlighting seven distinct engineering approaches to optimize NK cell function and tumor-targeting capabilities | Lower: Genome-wide CRISPR screening approaches to optimize NK cell therapeutics: Schematic representation of emerging CRISPR-based discovery platforms, highlighting their utility, method of CRISPR editor delivery, potential challenges, and current developments |

Researchers are developing a treatment that can transform a patient’s own T cells into cancer killing machines with just one injection. Traditional CAR T therapy involves removing immune cells, genetically engineering them in a lab, and returning them to the patient after chemotherapy. While effective, the process is lengthy, expensive, and can be harsh on the body. The new approach programs T cells inside the body, avoiding months of lab work and potentially reducing side effects. In a small trial, four patients with multiple myeloma, a blood cancer affecting bones and kidneys, received a single injection that reprogrammed their T cells. The cells were equipped with “homing beacons” to track and attack cancer cells efficiently. After one month, the patients showed no signs of cancer in their bone marrow, and for one, remission lasted at least five months. Side effects were mostly mild, including manageable immune reactions. This in body method uses a harmless virus to deliver the therapy specifically to T cells, triggering cancer fighting genes without permanently altering DNA. Previous animal studies showed similar results, with injected RNA or virus carriers transforming T cells into CAR T cells within hours. These approaches used nanoparticles or viruses engineered to target T cells while avoiding other organs. While early results are promising, scientists caution that long term effects, durability, and potential risks, including rare immune complications, still need careful study. Ongoing trials aim to expand patient numbers and test safety and efficacy over time. Research Paper 📄 DOI: 10.1016/S0140-6736(25)01030-X