How Immunotherapies Are Changing Biotech

T Cell-based Immunotherapy: Boosting Mitochondrial Health for Superior Antitumor Responses One of the major barriers to successful T cell-based immunotherapies is T cell exhaustion driven in part by mitochondrial loss and dysfunction. This may reduce the effectiveness of adoptive T cell therapies, particularly against solid tumors. I was thrilled to see the latest innovation from Luca Gattinoni and his team at Regensburg who were finally able to publish their paper in CELL after years of effort ... and nearly a year and a half of feverish revisions at the journal (Baldwin, et al, Cell, 2024). When I first heard about the notion that the mitochondria of T cells could be replenished by bone marrow stromal cells (BMSCs) several years ago, I was incredulous. I thought the observations were an artifact of the methods. But early observations have now been buttressed by a slew of experiments from a multi-institutional team of investigators. The final product published last week leaves me convinced that BMSCs establish nanotubular connections with T cells, that act as highways to transfer healthy mitochondria into exhausted CD8+ T cells. This process enhances mitochondrial respiration and bioenergetic capacity, supercharging the T cells for improved function. Notably, Talin 2 on both donor and recipient cells is required for optimal transfer. Not only does mitochondrial transfer occur, but it has a major impact on a T cells developmental trajectory and fate. CD8+ T cells that received mitochondria showed increased expansion, more efficient tumor infiltration, and fewer signs of exhaustion. These boosted T cells mediated superior antitumor responses in the highly realistic pmel-1 mouse tumor model, ultimately prolonging survival. Undoubtedly, this approach is a long way from clinical development, but it could ultimately revolutionize the field of organelle medicine, opening new avenues for next-generation T cell therapies to combat not just hematologic malignancies but solid tumors as well. For those who take a long view of the future of immunotherapy and cellular rejuvenation, mitochondrial transfer may someday be part of the solution for enhancing T cell therapies! #CancerResearch #Immunotherapy #Mitochondria #TCellTherapy #AdoptiveTCellTherapy #OrganelleMedicine #Bioenergetics #TCellExhaustion #TumorMicroenvironment #CellTherapyInnovation

This is a very compelling use of #AI... and get's me very excited to see the evolution in the field of #cancer treatment research. #Precision #medicine and precision immunotherapy are becoming a reality, not just a hope or dream. The investigators of this study use an AI platform to designs custom proteins in weeks rather than years. They create immune T cells to target and destroy cancer cells by recognizing peptides from viral proteins, tumor-associated proteins, or neoantigens (https://lnkd.in/g3yv_sic). Timothy Jenkins  High level view of how their platform works: ▪️ They leverage three AI models to design "minibinder" proteins that attach to T cells, giving them “molecular GPS” to locate cancers ( like melanoma). ▪️ Their model uses AlphaFold2 to predict proteins structure and function within weeks and not years. ▪️ The platform designs proteins for both common and patient-specific cancer markers, which allows for tailored treatments.  ▪️ Their system uses a virtual safety screening to predict and eliminate designs that might attack healthy cells before any lab testing begins. What exciting work like this means: 🟢 Accelerated personalized immunotherapy 🟢 Greater precision and reduced toxicity 🟢 Scalable approach for wider patient populations (a customizable library for multiple cancer types) 🟢 New therapeutic class emerging from protein design 🟢 Speed, specificity, and adaptability converge to create a platform capable of custom T cells to target tumors in clinically realistic and impactful timeframe (weeks not years). Exciting times. #UsingWhatWeHaveBetter

This article introduces a groundbreaking approach to cancer immunotherapy that addresses a key question: How can we overcome the ability of tumors to evade immune destruction? Tumors often block immune cells, such as dendritic cells and T cells, from attacking, which creates an environment that fosters cancer growth. Ascic et al. propose an innovative approach—reprogramming tumor cells directly into dendritic-like cells within the body using adenoviral delivery of transcription factors PU.1, IRF8, and BATF3. But could reprogramming tumor cells to trigger their own destruction be the key to improving cancer treatment outcomes? Their study demonstrates that this strategy reshapes the tumor microenvironment, enhances immune cell activation, and results in tumor regression and long-term immunity. Could this approach pave the way for a new era in cancer therapy, particularly for tumors that resist conventional immunotherapies? It’s truly exciting to see how this will unfold. https://lnkd.in/eBk6YhVd https://lnkd.in/efB8GeC3

#ScienceSaturday ❓ Can AI help us engineer better cancer therapies, one protein at a time? ➡️ A new study in Science reveals how generative AI is being used to rapidly create de novo protein minibinders to target cancer-associated peptide–MHC complexes (pMHCs), which are key triggers for T cell activation. ➡️ Using tools like RFdiffusion, AlphaFold2, and ProteinMPNN, researchers engineered minibinders that mimic T cell receptors and bind to tumor-specific pMHC targets like NY-ESO-1. When incorporated into CARs, these AI-designed molecules enabled T cells to kill #melanoma cells in lab experiments. 🌟 This approach could streamline and personalize T cell therapies, especially in cancers where conventional TCR discovery is too slow or difficult. It opens a path to designing synthetic proteins in weeks, not years, with built-in specificity and potency. 🔗 Read more in Science Magazine: https://lnkd.in/eWeGPbhU DTU - Technical University of Denmark Timothy Jenkins Kristoffer Haurum Johansen #CancerResearch #AI #Immunotherapy #CancerImmunotherapy

BioNTech SE recently launched Phase 1 trials for its mRNA lung cancer vaccine, one of ~70 clinical trials exploring using mRNA vaccines against cancer. Here’s a closer look at mRNA vaccines as a potential cancer therapy: The principle behind mRNA vaccines centers on identifying specific antigens within a patient's tumor, and crafting unique mRNA sequences for those antigens. When delivered, this instructs the patient's immune system to mount a response against the cancer. Recent clinical trials have showcased promising outcomes in patients, including those with types of cancers traditionally resistant to existing treatments – such as certain types of non-small cell lung cancer and aggressive melanomas. Although none have yet received regulatory approval, these vaccines have shown good tolerability and great potential for improving the immune system’s response to cancer. Leading the charge in this field are Moderna/Merck and BioNTech/Genentech, with promising mRNA cancer vaccine candidates in their pipelines. Moderna and Merck The collaboration between Moderna and Merck has yielded promising results, particularly with their mRNA-4157/V940 vaccine in combination with Keytruda for melanoma treatment. Phase 2 clinical trial results showed that this combination therapy led to a 49% lower risk of cancer recurrence or death compared to Keytruda treatment alone. mRNA-4157/V940 is now undergoing Phase 3 trials for melanoma with results expected in 2029, and is at the clinical trial stage for four additional cancer types. This underscores its versatility and potential for broad application across a wide range of cancers. Interestingly, Moderna’s close collaboration with Merck is highlighted by the fact that several of Moderna’s cancer-focused vaccines have 50-50 profit sharing with Merck. BioNTech BioNTech and Genentech are advancing cancer immunotherapy with their BNT122 vaccine. Phase 1 trials in pancreatic cancer patients showed that the vaccine induces lasting immune responses – up to 3 years post-administration – and is associated with extended recurrence-free survival. BNT122 is undergoing clinical trials for various cancers, with results from Phase 2 trials in pancreatic cancer expected in 2029, and Phase 2 trials in colorectal cancer in 2027. BioNTech currently has 11 mRNA vaccine candidates in its pipeline at the clinical trial stage for oncology indications. The company's ambitious roadmap includes launching a first wave of cancer immunotherapies by 2026, aiming for 10 approved cancer indications by 2030. The Future of mRNA Vaccines in Oncology With many highly anticipated trial results for mRNA vaccines as personalized cancer immunotherapies on the horizon, it will be intriguing to observe their effectiveness across different cancer types. Whether they are effective against a specific subset of cancers or a wide range of cancers, these early successes mark the beginning of a new era in cancer treatment.

New Review alert! AstraZeneca-based authors discuss key developments and innovative strategies for T-cell engaging antibody cancer treatments in a review newly published in mAbs. From the abstract: T cell engagers (TCEs) are a promising class of cancer immunotherapy that re-direct T cells to kill tumor cells. However, their clinical application is limited by several challenges, including cytokine release syndrome (CRS), on-target off-tumor toxicity and overcoming immunosuppression in both hematological and solid tumors. This review explores recent innovations in TCE design aimed at improving their safety and efficacy. Key developments include optimizing geometry to facilitate effective immune synapses, affinity optimization of the anti-CD3/TCR domain and targeting of specific T cell subsets which both aim to reduce CRS. Logic-gated approaches such as dual-targeted and conditional TCEs activated by tumor microenvironment factors have the potential to reduce on target, off tumor toxicity and potentially increase the depth and durability of response. Additionally, leveraging costimulatory signaling offers the potential to further improve efficacy across hematological and solid tumor settings. The next generation of TCEs is expected to overcome some of the limitations of conventional TCEs, enhancing their therapeutic window and enabling combination therapies. As the field advances, TCEs are poised to become a cornerstone of cancer immunotherapy, potentially improving outcomes for a broader range of patients than the ones currently benefiting from conventional immunotherapy. https://lnkd.in/ePRhXWEV

Cancer cells operate under a lot of stress and make do with what is available. Tryptophan is one of the heavily restricted ingredients due to overuse and overdemand (from prolonged interferon-gamma (IFNγ) exposure, resulting in upregulation of indoleamine 2,3-dioxygenase 1 (IDO1)). Insufficient amount induces tryptophan to phenylalanine substitutions "W>F" in multiple sequences, producing neoepitopes shared across different cancer types. Can one target resulting crippled proteins and their peptide presentation directly? Champagne et al. demonstrates how these neoepitopes become targets for adoptive T-cell therapy. A highly specific T-cell receptor is identified that recognizes one of these neoepitopes and effectively kills cancer cells. Other therapeutic formats will surely follow. This discovery opens new avenues for very tumor-specific and broadly applicable cancer immunotherapies, potentially overcoming current treatment limitations. https://lnkd.in/eDJwtkN5 #cancerimmunotherapy #neoepitopes #Tcelltherapy #immunooncology #research #immunology #

How does a "cancer vaccine" work? Several biotechnology companies are actively developing therapeutic cancer vaccines, particularly those using mRNA and self-amplifying RNA (saRNA) platforms, targeting various tumor types, including melanoma, non-small cell lung cancer (NSCLC), pancreatic and colorectal cancers, and head and neck squamous cell carcinoma. One of the most promising developments in oncology is mRNA-4157/V940, a personalized cancer vaccine co-developed by Moderna and Merck. Designed to target up to 34 tumor-specific neoantigens based on a patient’s unique mutational profile, this investigational therapy harnesses the power of mRNA to train the immune system to recognize and eliminate cancer cells. What makes this approach revolutionary is its precision. The vaccine is tailored to the molecular fingerprint of each tumor. Once administered, the encoded neoantigens are expressed as proteins, effectively turning the patient’s own biology into a therapeutic engine. In clinical trials, mRNA-4157/V940, particularly when combined with the checkpoint inhibitor pembrolizumab (Keytruda), has shown improved recurrence-free survival and distant metastasis-free survival in high-risk melanoma cancer patients. This type of immunotherapy is extremely complex. So, let's watch an animation of how it works, courtesy of Nature Videos. The full video can be seen here: https://lnkd.in/g4y9_2nD #CancerImmunotherapy #mRNA #PersonalizedMedicine #Melanoma #OncologyInnovation #Moderna #Merck #Keytruda

Where is Immuno Oncology heading? Has IO stalled? A review of the IO space circa 2025. Few key points- * PD-1 and CTLA-4 targeted drugs ushered in the era of IO, with Keytruda anti-PD-1 antibody becoming the massive blockbuster receiving ~$30 Bn in sales per year. * IO monotherapies hit a plateau of 30% efficacy, meaning 70% of patients do not respond. Expansion to other checkpoint inhibitors include LAG-3 with modest outcomes. Highly anticipated TIGIT antibodies held great promise but met difficulties in phase 3 clinical trials. Many cancers simply do not respond to IO therapies. * The focus for IO became everything in combo with PD1 in hopes to find better efficacy, culminating in Summit bispecific antibody anti-PD1 / VEGF showing stunning response in Chinese phase 3 clinical trials. Inadvertently, these results (yet to be confirmed in the US), has led to the stampede of interest in China as the new wellspring of biotech innovation. * Proponents of AI, the much publicized technology, continues to promise to save the pharma industry by identifying new checkpoint inhibitors as targets in drug discovery. At the end of the day, what really is needed is a refocus to detecting and treating cancers early, a subject that @Azra Raza (read - The First Cell) has been advocating for decades. https://lnkd.in/eMKRRrSs Unfortunately, headwinds to this approach are that pharma economics favor treatment of later stage cancers because of straightforward development and the needs of a desparate patient population. Heather McKinzie writes - " However it’s done, [Jeremy] Levin continued, the holy grail for IO is pre-emptively engaging the human body to defeat a cancer cell before it has even proliferated. “Immuno-oncology is the clue that you can do this,” he told BioSpace. “It says that you can absolutely galvanize the human tissue to reawaken attack on a cancer cell. The big question is, can you actually pre-emptively immunize us such that we can be ready for this?"" I contend that indeed, catching and treating the initiation of cancer is the Holy Grail, but we may need to posit that IO might be therapeutically limited as a modality. Newer innovative technologies and approaches could be necessary to detect and treat patients harboring the first cancer cells as they emerge. https://lnkd.in/epxYiKPa

This could be a huge immunotherapy development ... A new study from the University of Geneva shows that CD4+ T cells - long thought to be just “helpers” in the immune system - can actually kill cancer cells directly. The research, published in Science Immunology, found that: - These cells use the same tools as known killer cells (like granzyme B and perforin) - They also trigger tumor cell death through a second method involving the Fas pathway - And they carry a unique gene signature that could help identify them in the future This challenges the idea that CD4s only assist other immune cells. They may be much more active players in the fight against cancer, and could open up new possibilities for future treatments. Full story: https://lnkd.in/eGcMt3uq