Innovative Cancer Immunotherapy Approaches

"Somatic mutations in cancer cells can generate tumour-specific neoepitopes, which are recognized by autologous T cells in the host. As neoepitopes are not subject to central immune tolerance and are not expressed in healthy tissues, they are attractive targets for therapeutic cancer vaccines. Because the vast majority of cancer mutations are unique to the individual patient, harnessing the full potential of this rich source of targets requires individualized treatment approaches. Many computational algorithms and machine-learning tools have been developed to identify mutations in sequence data, to prioritize those that are more likely to be recognized by T cells and to design tailored vaccines for every patient. In this Review, we fill the gaps between the understanding of basic mechanisms of T cell recognition of neoantigens and the computational approaches for discovery of somatic mutations and neoantigen prediction for cancer immunotherapy. We present a new classification of neoantigens, distinguishing between guarding, restrained and ignored neoantigens, based on how they confer proficient antitumour immunity in a given clinical context. Such context-based differentiation will contribute to a framework that connects neoantigen biology to the clinical setting and medical peculiarities of cancer, and will enable future neoantigen-based therapies to provide greater clinical benefit." Great review for those interested in personalized cancer vaccines, by Franziska Lang, @Barbara Schrörs, @Martin Löwer, @Özlem Türeci & Ugur Sahin https://lnkd.in/e_uhzEJa

🔬 Have we been trying to Starve Cancer in the Wrong Way? A groundbreaking new study just shared from the National Cancer Institute (NCI) shared a new concept of turning fat into a tool! Scientists have just taken a bold step forward in cancer therapy by using genetically engineered fat cells to slow tumor growth—not by attacking cancer directly, but by outcompeting it for fuel. 💥 The concept? Cancer cells need nutrients—especially glucose, fatty acids, and specific molecules like uridine—to grow. What if we introduced cells that were even hungrier than cancer? That’s exactly what researchers at UCSF did. Using gene editing tools like CRISPRa, they transformed ordinary white fat cells into beige fat cells—a more metabolically active type of fat that aggressively consumes energy. This engineered fat was then implanted into mice with various cancers, including breast, pancreatic, colon, and prostate tumors. The result? ➡ Tumors grew slower—even when the engineered fat was implanted far away from the tumor. ➡ The fat cells behaved like “energy vacuums,” draining the fuel cancer needs to thrive. ➡ In some cases, tumor cells were completely depleted of nutrients. This experimental therapy is being called Adipose Manipulation Transplantation (AMT)—and it could represent the first cellular therapy using fat cells instead of immune cells, like CAR-T or TIL therapy. 🧠 Why does this matter? Most cancer therapies—chemo, radiation, immunotherapy—aim to kill cancer cells. But AMT takes a different approach: it changes the nutrient environment so cancer can’t grow. And this has some big advantages: ✔️ Potentially less toxic than traditional treatments ✔️ Customizable—engineered fat cells can target specific nutrient pathways ✔️ Uses a patient’s own fat, which may reduce the risk of immune rejection ✔️ Adds to the growing field of metabolic therapies that complement lifestyle interventions 🌡️ The inspiration for AMT actually came from a previous study showing that cold temperatures slowed tumor growth in mice. Why? Because cold activates brown fat—which burns glucose for heat. But like all exciting innovations, there are limitations and unanswered questions: ⚠️ The treatment was less effective in mice fed high-fat or high-sugar diets—reminding us that what we eat matters in cancer care. ⚠️ Scientists still need to study how long these fat cells remain active, and whether cancer could eventually adapt. ⚠️ More research is needed to understand how this strategy might affect healthy cells and overall metabolism. Still, the potential is huge. This could become a new therapeutic option not just for cancer, but possibly for metabolic conditions like diabetes as well. #science #keepfundingresearch #lifestylemedicine

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

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

A #Breakthrough Year for T Cells This year has been transformative for T cell therapies in the fight against cancer, as reviewed by Rigel Kishton and me in today’s issue of Nature Cancer (https://rdcu.be/d3R8D). With three FDA approvals, 2024 has underscored the clinical power of #Tcells -- living #immunotherapies capable of achieving results where all other treatments fail. Key Approvals of 2024 -> #Lifileucel (Amtagvi): The first #TIL-based therapy for unresectable/metastatic melanoma, approved in February. -> Afamitresgene (Tecelra): The first #TCR-engineered therapy for solid tumors, approved in August for synovial sarcoma. -> Obecabtagene (Aucatzyl): The 7th #CAR T therapy for B cell hematologic malignancies, approved last month. 🚀 These therapies are clinically remarkable. Engineered from a patient’s own T cells, they deliver life-changing responses for patients with no other options. I’ve had the privilege of contributing to these advancements and witnessing their profound impact. The Promise of TIL Therapies TIL-based therapies hold transformative potential. By recognizing tumor #neoantigens -- expressed #mutations, cancer germline antigens, and even “#darkgenome” products like #HERVs or #pseudogenes -- T cells can achieve durable, complete responses. CD4+ and CD8+ T cells bring the ability to directly or indirectly eliminate tumors where traditional therapies fall short. Despite these advances, the oncology capital markets remain skeptical. Cell therapy companies face immense challenges: -> Development Costs: Complex manufacturing, high trial expenses, and stringent regulations. -> Safety Concerns: Risks like cytokine release syndrome and lymphodepletion-associated toxicities. -> Commercialization Hurdles: High prices, uncertain reimbursement, and cumbersome logistics. The result? T cell-based immunotherapies can land with a thud from investors concerned about small target markets and costly treatment delivery. ⚡ Technology as a Solution The future of T cell-based therapies looks brighter with technological innovation: -> #AI/ML for Transcriptomics and Genomics: Personalizing T cell products for individual patients. -> Cheaper #Sequencing: Accelerating tumor neoantigen target discovery. -> Improved Culture Methods: Enhancing T cell #stem cell qualities for durable efficacy. While #Tcellengagers and #bispecificantibodies gain investor interest for their transient solid tumor activity, these treatments are rarely curative. TIL therapies, on the other hand, stand on the cusp of delivering transformative, long-term responses in patients with common solid tumors. The journey isn’t easy—financial skepticism, logistical hurdles, and scientific complexity remain—but the horizon for T cell therapies is filled with extraordinary possibility. Here’s to the progress we've made and the breakthroughs that lie ahead. 🎇 #immunotherapy #celltherapy #carT #TIL #oncology

Our team just published our latest work in Nature revealing how patients' own antibodies can make or break their response to checkpoint immunotherapy. The Question: Why do some cancer patients experience dramatic tumor shrinkage when they received immunotherapy while others see no benefit? Our Approach: Using REAP (Rapid Extracellular Antigen Profiling), we screened blood samples from 374 cancer patients for autoantibodies against 6,000+ proteins. Key Findings: · Cancer patients have an extraordinarily diverse “autoantibody reactome.” We detected ~3,000 unique autoantibody reactivities and clearly had not achieved saturation. · Patients with anti-interferon antibodies were up to 40x more likely to respond to treatment. This is a complete reversal from COVID-19 where these same antibodies increase mortality by 20-200 fold. · Novel finding: Anti-TL1A antibodies enhance treatment by preventing T cell apoptosis in the TME · Red flag: 10% of non-responders had antibodies against BMP receptors, revealing a previously unknown barrier to treatment success Conclusions: Treatment-modifying autoantibodies act as a roadmap for developing better therapies. We can now design drugs that mimic beneficial antibodies or counteract harmful ones, potentially improving outcomes for any patient who receives immunotherapy. This work was only possible through incredible collaboration between the Fred Hutchinson Cancer Center, the Yale Cancer Center, and my company Seranova Bio. Special recognition to lead author Yile Dai and the entire team who made this vision a reality. Read the full paper here: https://lnkd.in/dRxYd4bC

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.

Sooo, why doesn't cell therapy work against solid tumors? And what's being done to fix it? --- Let's get straight to the point. Cell therapy doesn't work in solid tumors for three main reasons: i) Heterogeneous antigen expression - targetable protein antigens are less likely to be widely expressed throughout a solid tumor. Antigen expression is also often lost. ii) Poor tumor-trafficking of therapeutic cells - in order for the cells to kill the tumor, they have to get there first. This can get tricky. iii) Immunosuppressive microenvironment - once inside the tumor, the therapeutic cells have to persist and maintain cytotoxic functionality. The tumor does everything it can to stop them. The solution? I have been embarking on a journey through the natural killer cell therapy landscape and have noticed five main strategies that are being deployed to enhanced NK cell therapy against solid tumors. Here's my thoughts. 1️⃣ Biologic cell engagers such as bispecific antibodies and innate cell engagers are used to help diversify the potential antigens recognized by the cell therapy and enhance antigen binding affinity. ➡ See Cytovia Therapeutics, Dragonfly, and Coeptis Therapeutics for key examples. 2️⃣ The expression of custom activation surface receptors such as CARs, TCRs, and hybrid fusion receptors expand and enhance the immunological potential of therapeutic cells. ➡ Many platforms incorporate CAR expression but check out FATE Therapeutics, Zelluna Immunotherapy, and CytoImmune for other innovative technologies. 3️⃣ Innovative signal inverters have been developed that can translate an immunosuppressive signaling molecule, such as TGF-ß, into a immuno-stimulatory signaling cascade (these are insanely cool). ➡ Senti Bio and Catamaran Bio deserve some serious props for their highly innovative signaling circuits. Definitely check these platforms out. 4️⃣ Expression of enhanced cytokines ("superkines") or constitutively active cytokine receptors enables persistent activation and effector functionality. ➡ FATE Therapeutics, NKarta, and ImmunityBio are absolutely crushing the "Cell Therapy + Cytokine" game. 5️⃣ Genetic deletion of key inhibitory receptors renders cells resistant to immunosuppressive signaling within the tumor. ➡ ONK Therapeutics really put these inhibitory signaling molecules on the CLEARANCE rack with their highly genetically modified NK cell platforms. Everything must go! I should note that the list of "notable platforms" that I have mentioned is by no means an exhaustive list. If you or your team have questions and would like more insight into this market, feel free to reach out to me. 📩 Also, I have a newsletter (https://lnkd.in/eTQTkH9n). Subscribe and get my thoughts and insights delivered straight to your inbox (Saturday mornings 9AM EST).

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

Unlocking the "First-Dose Effect" in T-Cell Engager Therapies. The risk of Cytokine Release Syndrome (CRS) is primarily confined to the initial dose of the CD3 engager, the perplexing "first-dose effect". Ling et al. unveils a fascinating shift in T-cell biology between the first and subsequent treatments: Initial dose primarily activates existing T effector memory (Tem) cells, leading to moderate cytolytic activity and high cytokine production associated with CRS risk. A novel population of central memory CD8+ T cells (CD8-Tcm-TCF7) takes over for the subsequent doses. These cells, potentially originating from stimulated naïve T cells, exhibit a crucial shift: high cytolytic activity with significantly lower cytokine production. This distinct T-cell response explains why CRS risk diminishes after the first dose. Furthermore, tumor-killing capacity can be uncoupled from cytokine release, even when cytokine production is blocked (e.g., with dasatinib). These findings are pivotal for designing next-generation T-cell engagers and mechanism-based strategies to mitigate CRS risk, paving the way for safer, equally effective cancer immunotherapies. https://lnkd.in/e-rvffU5 #Immunotherapy #TCellEngagers #CRS #CancerResearch #Oncology #SingleCell #Biotechnology #DrugDevelopment #Immunology #Cytokine #Cytotoxicity