CAR T Cell Therapy Advancements

Autologous vs. Allogeneic: A Paradigm Shift in Clinical Impact While autologous cell therapies (patient-specific) have demonstrated remarkable efficacy (90%+ in indications like B-cell malignancies), their limitations are increasingly untenable: weeks-long manufacturing delays, 10–15% production failures, and costs exceeding $500K. These bottlenecks restrict patient access, particularly in rapidly progressing diseases or resource-limited settings. 2025: The Allogeneic Tipping Point Next-generation allogeneic "off-the-shelf" therapies are poised to dominate the cell therapy landscape, driven by three transformative advancements: 1) Immune Evasion Breakthroughs: CRISPR-Cas9 and base-editing technologies (e.g., Beam Therapeutics’ cytosine base editing) enable precise disruption of HLA and TCR genes, reducing immune rejection risks. Clinical data from Allogene Therapeutics’ ALPHA2 trial (NCT04416984) show 76% objective response rates in relapsed/refractory lymphoma, mirroring autologous CAR-T outcomes. 2) Elimination of GvHD: Tools like TALEN-edited cells (Cellectis’ UCART19) report 0% Grade 3–4 GvHD in pediatric B-ALL patients (NCT02808442), with durability extending to 24+ months. 3) Scalable Manufacturing: Automated closed-system bioreactors (Lonza’s Cocoon®) and master cell banks reduce batch variability by 85% and costs by ~60% (per-dose estimates: 150K vs. 150 K vs. 400K for autologous). - Recent trials underscore allogeneic therapies’ expanding utility: 1) Solid Tumors: CRISPR Therapeutics’ CTX110 (anti-CD19 allogeneic CAR-T) achieved 57% CR rates in CD19+ B-cell malignancies (Phase 1, ASH 2022). 2) Autoimmune Diseases: Cabaletta Bio’s DSG3-CAART (for pemphigus vulgaris) eliminated pathogenic antibodies in 100% of Phase 1 patients (NCT04422912). 3) Acute Indications: Atara Biotherapeutics’ tabelecleucel (off-the-shelf EBV T-cell therapy) delivered 50% 1-year survival in post-transplant lymphoproliferative disorder (PTLD), addressing urgent unmet needs. - Market Landscape: A $23.6B Opportunity by 2030, fueled by: 1) Pipeline Expansion: 250+ allogeneic candidates in clinical trials (60% in oncology, 25% in autoimmune diseases). 2) Regulatory Tailwinds: FDA RMAT designation granted to 15 allogeneic programs (e.g., Precision Biosciences’ PBCAR0191), accelerating pathways to approval. 3) The ability to treat 10–100x more patients per batch vs. autologous therapies creates a winner-takes-most market dynamic. Don’t wait for the market to mature—dominate the inflection point. What are your thoughts? I read you in the comments ____________________________________________________________________________ 🔔 Follow for insights ♻️ Share if you find it interesting #celltherapy #biotech #investment #investor

Johnson & Johnson’s cilta-cel just rewrote the multiple myeloma playbook. Fresh five-year data shows this CAR-T therapy is doing what most thought impossible: holding the line long-term. - 1 in 3 patients remain myeloma-free five years post-treatment - Many needed no further therapy in that time - Clinicians are calling this the first real shot at using the word “cure” in myeloma Why it matters: multiple myeloma has been notoriously relentless. Relapse after relapse. Patients cycling through lines of therapy until options run out. A durable remission window this long changes the narrative entirely. Every biotech in the CAR-T race should take note: the bar just got raised. And every hematology CEO needs to ask—are we still chasing incremental progress, or swinging for transformative outcomes? Because if “cure” is even on the table now, the standard of ambition in oncology marketing just shifted overnight.

🚀 Bristol Myers Squibb #Reports #Mezigdomide #Cuts #Risk of Disease #Progression or #Death by 52% in #Relapsed/ #Refractory #Multiple #Myeloma — First Phase 3 CELMoD Success at #ASCO26 A potentially major breakthrough in relapsed or refractory multiple myeloma (RRMM): Bristol Myers Squibb announced positive Phase 3 SUCCESSOR-2 results showing mezigdomide + carfilzomib + dexamethasone (MeziKd) significantly outperformed standard therapy in RRMM. The headline result: ✅ 52% reduction in risk of disease progression or death ✅ Median PFS: 18 months vs. 8.3 months ✅ First-ever Phase 3 success for a CELMoD therapy 1️⃣ Why this matters in RRMM Patients in SUCCESSOR-2 were heavily pretreated: 📌 92.1% triple-class exposed 📌 85.8% refractory to anti-CD38 antibodies 📌 75.8% refractory to lenalidomide As @Paul Richardson, MD, Director of Clinical Research and Clinical Program Leader at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and RJ Corman Professor of Medicine at Harvard Medical School, highlighted, achieving 18 months progression-free survival in resistant RRMM is especially meaningful, where durable disease control becomes increasingly difficult after each relapse. 2️⃣ Strong efficacy signal beyond PFS Compared with standard Kd therapy: ✅ Overall response rate: 80.2% vs. 53.4% ✅ Complete response or better: 26.7% vs. 8.9% ✅ Benefit observed across second-line, third-line, and higher-risk patients 3️⃣ CELMoD may become the next myeloma backbone According to Cristian Massacesi, M.D., Executive Vice President, Chief Medical Officer and Head of Development at Bristol Myers Squibb, these data further validate cereblon-targeted protein degradation as a powerful therapeutic strategy in multiple myeloma. 🧩 My takeaway After IMiDs, anti-CD38 antibodies, and BCMA therapies, CELMoDs may emerge as the next important treatment backbone for RRMM, particularly for patients facing increasing resistance after multiple prior therapies. 📌 Bottom line Bristol Myers Squibb may have a future new standard-of-care contender in RRMM, while simultaneously validating targeted protein degradation as a scalable oncology platform with broader hematology potential. #ASCO26 #MultipleMyeloma #Hematology #Oncology #Biotech #Pharma #CancerResearch https://lnkd.in/giZzv38s

Stop what you're doing and read this paper.  Carl June's group just answered one of the biggest questions in CAR-T: "Is this actually a cure?" The Challenge: - Previous types of immunotherapy(mAbs, biologics, etc) have had a distressing problem - long-term datasets have shown late relapses, quashing early optimism.  - For CAR-T specifically, data beyond 5 years have been almost entirely absent. - Therefore, clinicians have been uncertain about whether to use the word "cure" with patients. What June's Group Did: - Evaluated 38 patients with relapsed/refractory B-cell NHL (24 with large B-cell lymphoma, 14 with follicular lymphoma) treated with the CAR-T therapy called CTL019 (tisagenlecleucel) - Median follow-up of 10.1 years (range 7.9 to 11.5) - Assessed lymphoma-free survival, progression-free survival, overall survival, non-relapse mortality, and second primary cancers - Analyzed CAR-transgene persistence as a correlate of long-term response Key Results: - No relapses occurred beyond 5.4 years post-infusion (!!) - 10-year lymphoma-free survival was 32% for LBCL and 47% for follicular lymphoma. - 10-year overall survival was 17% for LBCL and 50% for follicular lymphoma (mostly due to the patients being a heavily pretreated cohort, CAR-T therapy is often the last kind of treatment tried). - Notably, second primary cancer developed in 9 patients (21% cumulative incidence at 10 years), so long term monitoring is still needed - A large portion of patients still have ONGOING CAR-T cell activity almost a DECADE after infusion Implications: This is, arguably, the most consequential clinical data readout in CAR-T cell therapy's history.  Especially the absence of relapses beyond 5.4 years.   And 47% 10-year lymphoma-free survival (in a heavily pretreated population) is, frankly, remarkable.  (This particular cancer is well-known for relapse) CAR-T works.  One single infusion can produce a functional cure. Kudos to the team at the University of Pennsylvania, and to the patients who contributed data for over a decade.  The future is bright. What are your thoughts on this?  Drop them in the comments. Full paper link: https://lnkd.in/gPniizFM

🚨 In vivo CAR-T just took a big step forward — but the story is complicated. AstraZeneca (via EsoBiotec) just reported first-in-human clinical data for an in vivo lentiviral CAR-T platform (ESO-T01) in Nature Medicine — and it’s one of the most important datasets in this space so far. What’s exciting: ⚡ No leukapheresis. No ex vivo manufacturing. No lymphodepletion. ⚡ Vein-to-vein time: ~8.5 hours ⚡ Low dose (0.2 × 10⁹ TU) → still achieved robust in vivo expansion ⚡ ORR 80% (4/5), with rapid responses (~15 days) ⚡ Deep responses: MRD-negative (10⁻⁵) by day 60 ⚡ CAR-T expansion up to ~59% of CD3+ T cells This is a massive step toward making CAR-T faster, simpler, and scalable. But here’s the reality check: ⚠️ 100% of patients had ≥ Grade 3 adverse events ⚠️ CRS in 80% (mostly Grade 3) ⚠️ Clear biphasic inflammation: • Early innate immune surge (vector-driven) • Later adaptive CAR-T expansion ⚠️ A hyperacute CRS case within 2 hours post-infusion ⚠️ One death linked to anatomical risk (extramedullary disease + spinal compression) This is not just “CAR-T toxicity” — it’s vector biology + immune activation colliding in vivo. What’s scientifically fascinating: 🧬 Lentiviral vector engineering is doing heavy lifting: • TCR-targeting for selective delivery • Mutated VSV-G to reduce tropism • CD47 overexpression → evade clearance • MHC-I knockout → reduce immunogenicity 🧬 Distinct mechanism vs ex vivo CAR-T: → First: vector-triggered innate immunity → Then: CAR-T–driven adaptive response This is a fundamentally different therapeutic paradigm. My take: ✅ Efficacy: not the bottleneck ❗ Safety: the real frontier Key questions going forward: - How do we tune down innate immune sensing (TLR pathways, glycan shielding?) - Can we better control early cytokine bursts without compromising expansion? - Do we need additional activation signals — or is TCR targeting enough? - How do we risk-stratify patients (especially extramedullary disease)? Reference In vivo generation of anti-BCMA CAR-T cells in relapsed or refractory multiple myeloma: a phase 1 study https://lnkd.in/e-RRWSkh Phase I clinical trial https://lnkd.in/e5xS3mCH

MYC has long been considered “undruggable.” Rather than targeting the protein directly, we targeted its RNA—part of our broader effort to expand the druggability of genetically defined disease targets using small molecules that bind messenger RNA and induce its degradation. I am excited to share an important paper in Blood arising from our long-term collaboration with Nikhil C. Munshi, Eugenio Morelli, first author Domenico Maisano, Chungen Li, Tenghui Wang, Mehmet Kemal Samur, Yuquan Tong, Jessica Disney, Michael Cameron, and many others This study establishes a comprehensive preclinical package for MYC-RiboTAC, a small-molecule RNA degrader that binds the MYC IRES and recruits RNase L to degrade MYC mRNA. MYC-RiboTAC reduces MYC RNA and protein, suppresses MYC-driven transcriptional programs, kills multiple myeloma cells, remains active within the protective bone marrow microenvironment, and demonstrates significant antitumor activity in two of the most important preclinical mouse models of multiple myeloma. It also shows favorable pharmacokinetic and safety profiles. One of the most important findings is that FDA-approved multiple myeloma therapies can increase RNase L expression—even in cells with little or no detectable RNase L at baseline—and enhance the activity of MYC-RiboTAC. This suggests that existing medicines may do more than simply combine with an RNA degrader: they may induce the cellular machinery needed to enable RNA degradation. This work provides strong evidence that disease-driving mRNAs encoding historically “undruggable” proteins can be directly targeted and degraded with small molecules. Congratulations to the entire collaborative team. Read the paper: https://lnkd.in/epeXxtp6 #RiboTAC #RNADegradation #MultipleMyeloma #MYC #DrugDiscovery #ChemicalBiology Dana-Farber Cancer Institute, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, UF Health Cancer Institute Scripps Research

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.

𝗧𝗵𝗲 𝗙𝗗𝗔 𝗰𝗵𝗮𝗻𝗴𝗲𝗱 𝘁𝗵𝗲 𝗿𝘂𝗹𝗲𝘀 𝗳𝗼𝗿 𝗖𝗔𝗥-𝗧 𝗰𝗹𝗶𝗻𝗶𝗰𝗮𝗹 𝘁𝗿𝗶𝗮𝗹𝘀 You might have missed it in the end-of-year noise. But this is a big shift. FDA is moving CAR-T development toward randomized, superiority-based trials, raising the evidence bar for future approvals. Single-arm response rates built the CAR-T field. This chapter is closing. And developers will feel it fast. 🔍 𝗪𝗵𝗮𝘁’𝘀 𝗰𝗵𝗮𝗻𝗴𝗶𝗻𝗴  • Randomized trials are becoming the default  • Superiority over control is now the expectation  • Overall survival or strong time-to-event endpoints matter more  • Single-arm studies will be limited to rare or hard-to-study settings  • Accelerated approval may still happen, but confirmatory trials are no longer optional 💡 𝗪𝗵𝘆 𝘁𝗵𝗶𝘀 𝘀𝗵𝗶𝗳𝘁 𝗶𝘀 𝗵𝗮𝗽𝗽𝗲𝗻𝗶𝗻𝗴  • Clearer proof that a new CAR-T is actually better  • Stronger data for clinicians, payers, and patients  • Less reliance on response rates that don’t always predict durability  • Better long-term credibility for the field ⚠️ 𝗖𝗵𝗮𝗹𝗹𝗲𝗻𝗴𝗲𝘀  • Trials will be larger, longer, and more expensive  • Choosing the right control arm is tricky as standards evolve Crossover can mask true survival differences  • Manufacturing and site readiness become real bottlenecks At the same time, FDA removed REMS for approved autologous CAR-Ts. So this isn’t more regulation per se. It’s higher evidence for new products — and less friction for approved ones. 👉 𝗘𝗳𝗳𝗲𝗰𝘁𝘀 𝗼𝗻 𝗖𝗔𝗥-𝗧 𝗱𝗲𝘃𝗲𝗹𝗼𝗽𝗺𝗲𝗻𝘁 The bar is higher now. But clarity is better than ambiguity.  • Superiority needs to be built into the program early  • Trial design becomes (even more) a strategic asset  • Endpoint choice may decide success more than the construct itself ❓𝗢𝗽𝗲𝗻 𝗾𝘂𝗲𝘀𝘁𝗶𝗼𝗻𝘀  • Will these new rules apply also to K cells, γδ T cells, macrophages, and other next-gen cell therapies?  • Will EMA, MHRA, and other regulators move in the same direction?  • If randomized superiority trials become the norm, how do we protect innovation while still moving fast enough for patients who can’t wait? 𝗜𝘀 𝘁𝗵𝗶𝘀 𝘁𝗵𝗲 𝗿𝗶𝗴𝗵𝘁 𝗺𝗼𝘃𝗲 𝗳𝗼𝗿 𝗽𝗮𝘁𝗶𝗲𝗻𝘁𝘀? 𝗢𝗿 𝗮𝗿𝗲 𝘄𝗲 𝗮𝗯𝗼𝘂𝘁 𝘁𝗼 𝗺𝗮𝗸𝗲 𝗯𝗿𝗲𝗮𝗸𝘁𝗵𝗿𝗼𝘂𝗴𝗵 𝘁𝗵𝗲𝗿𝗮𝗽𝗶𝗲𝘀 𝗵𝗮𝗿𝗱𝗲𝗿 𝘁𝗼 𝗿𝗲𝗮𝗰𝗵?

Natural killer cell biology and therapy in multiple myeloma: challenges and opportunities Despite therapeutic advancements, multiple myeloma (MM) remains incurable. NK cells have emerged as a promising option for the treatment of MM. NK cells are heterogenous and typically classified based on the relative expression of their surface markers (e.g., CD56 and CD16a). These cells elicit an antitumor response in the presence of low mutational burden and without neoantigen presentation via germline-encoded activating and inhibitory receptors that identify the markers of transformation present on the MM cells. Higher NK cell activity is associated with improved survival and prognosis, whereas lower activity is associated with advanced clinical stage and disease progression in MM. Moreover, not all NK cell phenotypes contribute equally toward the anti-MM effect; higher proportions of certain NK cell phenotypes result in better outcomes. In MM, the proportion, phenotype, and function of NK cells are drastically varied between different disease stages; this is further influenced by the bone marrow microenvironment, proportion of activating and inhibitory receptors on NK cells, expression of homing receptors, and bone marrow hypoxia. Antimyeloma therapies, such as autologous stem cell transplant, immunomodulation, proteasome inhibition, and checkpoint inhibition, further modulate the NK cell landscape in the patients. Thus, NK cells can naturally work in tandem with anti-MM therapies and be strategically modulated for improved anti-MM effect. This review article describes immunotypic and phenotypic differences in NK cells along with the functional changes in homeostatic and malignant states and provides expert insights on strategies to harness the potential of NK cells for improving outcomes in MM. https://lnkd.in/eunurXi5

#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 |