First anti-BCMA CAR-T cells for progressive MS show positive results

𝐀𝐧𝐭𝐢-𝐁𝐂𝐌𝐀 𝐂𝐀𝐑-𝐓 𝐓𝐡𝐞𝐫𝐚𝐩𝐲: 𝐀 𝐍𝐨𝐯𝐞𝐥 𝐀𝐩𝐩𝐫𝐨𝐚𝐜𝐡 𝐟𝐨𝐫 𝐏𝐫𝐨𝐠𝐫𝐞𝐬𝐬𝐢𝐯𝐞 𝐌𝐮𝐥𝐭𝐢𝐩𝐥𝐞 𝐒𝐜𝐥𝐞𝐫𝐨𝐬𝐢𝐬 (𝐏𝐌𝐒) Progressive multiple sclerosis (PMS), including primary (PPMS) and secondary (SPMS) forms, remains a major unmet clinical need. Current therapies rarely halt disease progression, which is driven by chronic CNS inflammation, plasmocytes, and microglia activation. 💡 𝐓𝐚𝐫𝐠𝐞𝐭𝐢𝐧𝐠 𝐩𝐥𝐚𝐬𝐦𝐨𝐜𝐲𝐭𝐞𝐬 𝐰𝐢𝐭𝐡 𝐂𝐀𝐑-𝐓 𝐜𝐞𝐥𝐥𝐬 In a phase 1 clinical trial, five patients with treatment-refractory PMS (1 PPMS, 4 SPMS) received autologous anti-BCMA CAR-T cells after lymphodepleting chemotherapy. Patients had previously received multiple MS therapies, including glucocorticoids, S1P modulators, DHODH inhibitors, and anti-CD20 antibodies. 𝐊𝐞𝐲 𝐂𝐥𝐢𝐧𝐢𝐜𝐚𝐥 𝐅𝐢𝐧𝐝𝐢𝐧𝐠𝐬: ✅ 𝐒𝐚𝐟𝐞𝐭𝐲: 4/5 patients experienced grade 1 cytokine release syndrome (CRS), with no grade ≥2 CRS. All grade ≥3 cytopenias occurred within 40 days; no severe anemia or thrombocytopenia was observed. ✅ 𝐅𝐮𝐧𝐜𝐭𝐢𝐨𝐧𝐚𝐥 𝐈𝐦𝐩𝐫𝐨𝐯𝐞𝐦𝐞𝐧𝐭: All patients showed improved EDSS scores, faster Nine-Hole Peg Test and Timed 25-Foot Walk performance, and decreased CSF neurofilament light-chain (NfL) levels. ✅ 𝐑𝐚𝐝𝐢𝐨𝐥𝐨𝐠𝐲: No new T1 gadolinium-enhancing or T2 lesions; T2 lesion volume decreased in 2 patients. 𝐂𝐀𝐑-𝐓 𝐂𝐞𝐥𝐥 𝐃𝐲𝐧𝐚𝐦𝐢𝐜𝐬: 🔹 Rapid peak expansion around day 10 in blood and bone marrow, with prolonged detection up to 3 months. 🔹 In CSF, CAR-T cells showed delayed but sustained expansion, preferential persistence of CD4+ effector memory cells, and a less exhausted phenotype compared to other compartments. 🔹 Single-cell multi-omics analyses revealed strong clonal expansion, intercompartmental trafficking, and effective killing of target plasmocytes. 𝐌𝐞𝐜𝐡𝐚𝐧𝐢𝐬𝐭𝐢𝐜 𝐈𝐧𝐬𝐢𝐠𝐡𝐭𝐬: 🔹 Anti-BCMA CAR-T cells depleted pathogenic PB/PCs across blood, CSF, and bone marrow. 🔹 This depletion normalized B cell lineages, reduced pro-inflammatory cytokines, and attenuated CSF immune dysregulation. 🔹 TSPO-PET imaging confirmed reduced microglial activation, indicating the therapy modulates CNS neuroinflammation. 𝐓𝐚𝐤𝐞𝐚𝐰𝐚𝐲: This proof-of-concept study demonstrates that targeting plasmocytes with anti-BCMA CAR-T cells is safe, induces meaningful clinical improvements, and reverses key mechanisms of CNS immune dysregulation in PMS. It opens a new avenue for treating CNS autoimmune diseases where conventional therapies fail. #CellTherapy #CART #MultipleSclerosis #Neuroinflammation #AutoimmuneDiseases #Immunotherapy #InnovationTherapeutics

The study below highlights an innovative approach using CAR-T (Chimeric Antigen Receptor T-cell) therapy not only for cancer treatment but also as a potential avenue for managing autoimmune diseases like multiple sclerosis (MS). In this specific research, the treatment involved five patients with progressive multiple sclerosis receiving anti-BCMA (B-cell maturation antigen) CAR-T therapy. Key findings from the study include: 1. Plasma Cell Depletion: The therapy successfully depleted plasma cells within the central nervous system (CNS), which are often implicated in autoimmunity. 2. CAR-T Cell Expansion: There was a notable prolonged expansion of CAR-T cells within the cerebrospinal fluid (CSF), indicating their sustained presence and potential effectiveness in the CNS environment. 3. Reduced Exhaustion: The CAR-T cells displayed reduced signs of exhaustion, which is critical for maintaining their functions and longevity in combating disease. 4. Alleviation of Microglial Activation: The treatment also alleviated microglial activation in the CSF. Microglia are resident immune cells in the CNS, and their overactivation is often associated with inflammatory conditions, including MS. This study suggests that CAR-T cells, initially developed for oncology, may offer a novel therapeutic option for autoimmune conditions by effectively modulating the immune response in the CNS. Further research is essential to establish long-term efficacy and safety in a broader patient population.

Reality Check: TILs in HNSCC Need Smarter Selection & Combos A recent Phase 2 C-145-03 (NCT03083873) sponsored by Iovance tested one-time autologous tumor-infiltrating lymphocyte (TIL) therapy across four cohorts in recurrent/metastatic head & neck SCC after prior ICI/chemo. ✳️ TL;DR – it’s feasible, almost safe(ish), but its efficacy is meh ✳️ https://lnkd.in/euwEPseW 👉🏼 Who: 53 patients treated (most stage IV; median 2 prior lines; 87% prior anti-PD-1/PD-L1). 🔴 What: Non-cryopreserved TIL; cryopreserved lifileucel (22-day vs 16-day process); and PD-1–selected TIL (LN-145-S1). Lymphodepletion with Cy/Flu → single TIL infusion → short-course high-dose IL-2. Cell Dose: Median 32.4×10⁹ TIL (range 2.4–98.8×10⁹); median 6 IL-2 doses. ⚠️ Efficacy (investigator-assessed RECIST v1.1): • ORR: 11% (6/53), all PRs, no CRs.  • Median PFS: ~2.0–2.8 mo (by cohort). • Median OS: ~8–10 months (by cohort). • Two patients had no progression for 12 months or longer after therapy. ⚠️ Safety: • TEAEs consistent with non-myeloablative LD + high-dose IL-2 (cytopenias, hypotension, fever, chills). • CRS low (4%) and largely attributed to IL-2, not the cells. • Grade ≥3: thrombocytopenia (62%), anemia (45%), febrile neutropenia (42%), neutropenia (30%). • Three patients experienced Grade 5 SAE’s (death). ✅ Takeaways: • Manufacturing feasibility in HNSCC reaffirmed, high success and large cell yields. • Clinical activity is modest in the post-ICI setting; authors conclude these specific TIL products don’t warrant further development as monotherapy in r/m HNSCC. • Signals (durable PRs in two patients) keep the door open for combinations (e.g., with checkpoint blockade/other agents) and product refinements (selection, process, biomarkers). 🔎 My read: In heavily pretreated HNSCC, TIL can stabilize disease, but DCR in the kinds of patients treated here is not unusual with PD-1 monotherapy or higher with salvage chemo/anti-EGFR regimens post ICI. TIL induced durable PRs in 2/53 patients, but LD + IL-2 toxicity remains non-trivial and response rates are low. ✊🏼 Hats off to Robert Ferris, colleagues Iovance Biotherapeutics, Inc. and academic collaborators for a well done and honestly presented trial. The next step is smarter patient/lesion selection, biomarker-guided manufacturing (e.g., PD-1⁺ or neoantigen-enriched TILs), and combination strategies tested in randomized designs. 🧐 What combinations or selection strategies would you prioritize for HNSCC TIL? 👇 #HNSCC #Iovance #Immunotherapy #TIL #CellTherapy #Oncology #ClinicalTrials #JITC #HeadAndNeckCancer

🚀 Breakthrough in Multiple Myeloma Treatment! Johnson & Johnson has announced encouraging results from their Phase 2 MajesTEC-5 study, exploring an induction therapy for newly diagnosed, transplant-eligible multiple myeloma patients. This novel regimen combines TECVAYLI®, DARZALEXFASPRO®, and lenalidomide, with some arms including bortezomib, offering a steroid-sparing approach. 🌟 Key Highlights: - 100% overall response rate across treatment cohorts - 100% minimal residual disease negativity among evaluable patients by Cycles 3 and 6 - 85.7% of patients achieved a complete response or better by Cycle 6 - Absence of severe neurological toxicity, with manageable side effects This immune-based combination demonstrates a powerful, sustained effect against cancerous plasma cells, signaling significant potential to improve early-stage outcomes for multiple myeloma patients. 🔬 Safety profiles reveal mainly hematologic side effects, no Grade 5 adverse events, and no treatment discontinuations due to toxicity, underscoring the regimen’s tolerability. While long-term benefits are still under investigation, these findings mark a promising step forward in tackling this challenging blood cancer. #Biotech #CancerResearch #ClinicalResearches #HealthcareInnovation #Immunotherapy #JohnsonAndJohnson #MedicalBreakthrough #MultipleMyeloma #Oncology #PatientCare #RegulatoryAgencies #MarketAccess #MarketAccessToday

The FDA recently approved cemiplimab for adjuvant cutaneous squamous cell carcinoma for patients at high risk of recurrence. This was based off the results of the C-POST trial, which demonstrated a disease-free survival benefit (Hazard ratio 0.32 [0.20-0.51]) for adjuvant cemiplimab vs placebo. Cemiplimab reduced the risk of both locoregional and distant recurrences. For distance recurrences, the main benefit was a reduction in distant nodal and lung recurrences, the two most common sites for distant recurrence in cutaneous squamous cell carcinoma. Do patients need to have this therapy adjuvant? There are positives and negatives. On the positive side, we are delaying progression and the immunotherapy-related adverse events appeared to be manageable. On the negative side, due to crossover, overall survival was essentially equivalent between the two arms. There was also no significant difference in quality-of-life between the two treatment arms. Overall, cemiplimab is probably worth discussing as adjuvant therapy for all patients. But the improvement in disease-free survival does not have appear to be associated with overall survival, as long as the patient crossed over to cemiplimab. One benefit from this trial is that adjuvant cemiplimab is given for 48 weeks, while cemiplimab on recurrence would typically be given indefinitely (though 24 months could be appropriate too, depending on response). Longer follow-up may be needed to determine the treatment-free interval after adjuvant therapy, and the time on cemiplimab after recurrence. #libtayo https://lnkd.in/e2KAge69

One of the hardest decisions in oncology isn’t WHICH drug to give, it’s WHEN to give it The explosion of new therapies is a gift, and presents a new challenge: sequencing therapy Deciding which treatment to use first, and which to save for later if the disease progresses or toxicities force a change The stakes are high. The right sequence maximizes efficacy and quality of life. Others may close off future options, especially in diseases that progress quickly or require careful toxicity management. This is especially relevant in metastatic disease where we have to balance efficacy and safety to ensure the patient can get a benefit from all available therapies, especially in diseases with a long life expectancy. For example, in metastatic renal cell carcinoma (RCC), there are 4 combination regimens preferred in the front line setting for any risk disease: 👉 Ipilimumab + nivolumab 👉 Cabozantinib + nivolumab 👉 Axitinib + pembrolizumab 👉 Lenvatinib + pembrolizumab Since they are all category 1 recommendations, which one is selected often comes down to provider and patient preference. We think about: 💰 Copay - double immunotherapy avoids oral copays 📈 Baseline blood pressure - VEGF TKIs can exacerbate 💊 Pill burden - axitinib is BID dosing vs other orals are daily 🏃♂️ Patient fitness - could they tolerate double immunotherapy? ❤️🩹 Skin comorbidities - cabozantinib can cause PPE (palmar-plantar erythrodysesthesia) 💨 High tumor burden/fast growing - VEGF TKIs are more likely to to produce faster response 🔍 Toxicity identification - axitinib has short half-life and can easily be held to identify AE causation In frontline disease, the guidelines have recommendations (arguably too many 😅) But in relapsed RCC we’re left with a menu of options and little evidence to guide the order. The lack of sequencing data is one of the biggest blind spots in oncology today. There are new data that does not support re-challenging immunotherapy when it fails in the frontline setting, but before this data, re-challenging these combinations was done and was supported in the guidelines Now the guidelines are not very helpful in relapsed disease, listing no preferred therapies at all There are some data that cabozantinib monotherapy should be preferred after immunotherapy Belzutifan is also a contender in those that got VEGF TKI combination therapy up front and is appealing as a second line agent with its unique mechanism This is why sequencing data is so important. If we knew that outcomes were better with those that received double IO followed by single agent VEGF TKI, we would use that to make decisions, but it’s pretty muddy right now. Until we have more data, decisions will continue to be guided by patient factors, toxicity profiles, and careful multidisciplinary discussion --- I’m the Kelley in KelleyCPharmD 👋 and I help pharmacists learn oncology

[Health Watch] #Zipalertinib Breaks New Ground: Encouraging #CNS Response in EGFR-Mutant NSCLC with Brain Metastases” ✅ Taiho Oncology, Inc. & Cullinan Therapeutics revealed CNS cohort data from the Phase 2b REZILIENT2 trial showing 31.3% intracranial objective response rate, and a disease control rate of 68.8% for NSCLC patients with EGFR mutations and active brain metastases. ✅ Systemic ORR in the cohort was ~27.6%, with median duration of response near 7.6 months, and intracranial DOR ~8.1 months. ✅ Safety profile was manageable: ~25% of patients experienced grade 3+ treatment-related adverse events (e.g. anemia, interstitial lung disease), and no new safety signals emerged. ✅ The data underscores zipalertinib’s potential to address CNS disease in a high-unmet-need population, supporting further clinical investigation and regulatory interest. #Oncology #NSCLC #EGFR #BrainMetastases #CNS-Therapeutics #CancerInnovation #Biotech #ClinicalTrials Tim Whitten Michael Schick Stephen E. Yoder, MD, MBA Tehseen Salimi Sushil Rijhwani Atsushi Azuma Nadim Ahmed Mary Kay Fenton Jeff Jones Patrick Baeuerle #Healthcare #HealthcareJobs #HealthTech #HealthcareHiring #MedicalJobs #PharmaJobs #Biotech #LifeSciences #PharmaceuticalIndustry #Biopharma #MedTech #MedicalDevices #MedTechJobs #MedicalTechnology #HealthcareCompliance #RegulatoryAffairs #PharmaCompliance #ClinicalResearch #MedicalAffairs #PatientCare #pharmajobs #medicaljobs #jobsinjapan https://lnkd.in/eRuXSEPR

In the randomized phase III NATALEE trial, recently published in JAMA Oncology, adjuvant #ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) continued to demonstrate sustained benefit beyond the 3-year treatment period in patients with hormone receptor–positive (HR+)/HER2– early #breast cancer at risk of recurrence. The trial enrolled 5101 patients with stage IIA (with high-risk features), IIB, or III disease. Participants were randomized 1:1 to receive ribociclib (400 mg daily, 3 years) plus NSAI (letrozole or anastrozole for 5 years) or NSAI alone. Premenopausal women and men also received goserelin. The primary endpoint was invasive disease-free survival (iDFS), with secondary endpoints including distant disease-free survival (DDFS), recurrence-free survival, and overall survival (OS). At a median follow-up of 44.2 months, ribociclib plus NSAI reduced the risk of invasive disease recurrence by 28.5% compared with NSAI alone (HR 0.72; 95% CI, 0.61–0.84). The absolute iDFS benefit increased over time, from 2.7% at 3 years (90.8% vs 88.1%) to 4.9% at 4 years (88.5% vs 83.6%). Consistent benefit was observed across disease stages and nodal subgroups. DDFS, recurrence-free survival, and distant recurrence-free survival all favored ribociclib. OS data remain immature, but a trend toward improvement was observed (HR 0.83; 95% CI, 0.64–1.07). Safety findings were consistent with prior analyses, and no new signals emerged with extended follow-up. The most frequent adverse events in the ribociclib arm were neutropenia, arthralgia, and nausea. Liver enzyme elevations were generally transient, and QT prolongation events were infrequent, with grade ≥3 prolongation observed in about 1% of patients. Early discontinuation of ribociclib due to adverse events occurred in 20% of patients, but the majority were able to complete the planned 3 years of therapy. The 4-year exploratory analysis of NATALEE reinforces that the addition of ribociclib to adjuvant endocrine therapy provides durable, clinically meaningful reductions in recurrence risk even after treatment cessation, supporting its role as a long-term strategy for patients with HR+/HER2– early breast cancer at risk of relapse. #Oncology #OncologyME #OncologyNewsletter #نشرة_أخبار_الأورام #سرطان_الثدي #العلاج_الهرموني

🔬🔴 Can Immunotherapy Improve Outcomes in High-Risk ER+/HER2− Breast Cancer? The KEYNOTE-756 Phase 3 trial, recently published in Nature Medicine, marks a potential paradigm shift for a traditionally immune-resistant subtype — early-stage, high-risk, ER+/HER2− breast cancer. 🧪 This double-blind, randomized study evaluated the addition of pembrolizumab (anti–PD-1) to standard neoadjuvant chemotherapy, followed by adjuvant pembrolizumab and endocrine therapy. 📊 Key Findings: Pathologic complete response (pCR) rate (ypT0/Tis ypN0): 🔹 Pembrolizumab + chemo: 24.3% 🔹 Placebo + chemo: 15.6% 🔸 Absolute difference: 8.7% (P = 0.00005) Benefit was more pronounced in patients with: ▪ High PD-L1 expression ▪ ER-low tumors (ER staining <10%) ▪ Node-positive disease Pembrolizumab also led to a higher proportion of patients achieving RCB-0 or RCB-1, indicating deeper responses beyond pCR. 📌 Safety: Treatment-related Grade ≥3 adverse events were more common in the pembrolizumab arm (52.5% vs 46.4%), with immune-related events consistent with prior PD-1 inhibitor data. One treatment-related death was reported. ⏳ What’s Next? While the improvement in pCR is statistically and clinically meaningful, event-free survival (EFS) data — a co-primary endpoint — remain immature, with follow-up ongoing. 📖 Full study: https://lnkd.in/dwnD5cyS #BreastCancer #OncologyResearch #Immunotherapy #Pembrolizumab #ERPositive #HER2Negative #CancerTrials #PrecisionOncology #AcademicMedicine #CancerCare

ESMO Abstract “1709MO - Multi-center NCI-sponsored phase I study of triapine in combination with 177Lu-dotatate in patients with well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NETs)” Mini Oral session Speakers: Aman Chauhan (Deerfield Beach, United States of America) Lecture Time: 08:53 - 08:58 Background 177Lu-Dotatate is an FDA-approved somatostatin receptor-targeted radiopharmaceutical shown to improve progression-free survival (PFS) in patients with metastatic well-differentiated neuroendocrine tumors (NETs). Benchmark NETTER-1 trial established a median PFS of 28.4 months and an objective response rate (ORR) of 14% for Lu-177 dotatate. Triapine, an oral ribonucleotide reductase inhibitor, is a potent radiation sensitizer. This phase 1 study evaluated the safety and efficacy of combining triapine with 177Lu-Dotatate in patients with progressive NETs. Methods ETCTN 10388 is a multi-center, investigator-initiated, NCI-sponsored phase 1 trial conducted at six academic institutions in the United States. Eligible patients had metastatic, well-differentiated GEP-NETs and had progressed on at least one prior line of therapy. The study included a dose-escalation phase (Part A, n=15) utilizing a Bayesian Optimal Interval (BOIN) design, followed by a dose-expansion phase (Part B, n=16). All patients received 177Lu-Dotatate 200 mCi on Day 1 of each 8-week cycle, along with oral triapine (50–200 mg) on Days 1–14, for a total of four cycles. Results Thirty-one patients received study treatment. The most common treatment-related adverse events were anemia (94%), lymphopenia (88%), and thrombocytopenia (81%), which were largely transient and resolved within two weeks without impacting treatment continuity. Dose-limiting toxicities (DLTs) were observed in nine patients. Based on integrated safety and pharmacokinetic data, the recommended phase 2 dose (RP2D) of triapine was established at 150 mg. Among 28 patients evaluable for efficacy, the confirmed ORR was 21.4%, and the median PFS was 38.03 months. In the RP2D cohort, median PFS has not yet been reached and may exceed 40 months. Conclusions Triapine in combination with 177Lu-Dotatate was well tolerated and demonstrated encouraging signs of clinical activity in GEPNET patients. Triapine (150 mg) is the RP2D. A randomized phase 2 trial (ETCTN 10558) comparing the combination to 177Lu-dotatate monotherapy is currently enrolling at 14 sites across the United States. Clinical trial identification NCT 04234568. https://lnkd.in/eWQXaJ-V