The Rounds Report
November 2025: Don’t Call It A Comeback… For COVID Vaccines.
Your cancer patients' COVID vaccines might be saving their lives. And nobody planned it that way.
Every few months, medicine reminds us how quickly today’s “settled science” can flip on its head.
Between August and November, five studies landed that we think every internist and subspecialist should see not because they tweak our practice, but because they change the playing field. We’re talking about mRNA vaccines unexpectedly boosting cancer survival, CRISPR delivering one-and-done cholesterol correction, and T-cell engagers pulling off drug-free remissions in autoimmune disease.
We sifted through the quarter’s top journals so you don’t have to, filtering for what’s real, replicable, and immediately relevant to clinical practice. What follows isn’t hype. It’s the short list of studies that will actually matter when you’re back on the wards Monday morning.
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The Big Five Game-Changers
1. COVID Vaccines Double Cancer Survival in Most Counterintuitive Discovery of the Year
Remember telling immunotherapy patients that their PD-L1-negative tumors probably wouldn't respond? The MD Anderson COVID vaccine study just turned that prediction upside down.
Among 884 non-small cell lung cancer patients starting immunotherapy between 2018-2022, those who received mRNA COVID vaccines within 100 days had median overall survival of 37.33 months versus 20.6 months in unvaccinated patients, effectively doubling 3-year survival. Most remarkably, the benefit was greatest in exactly the wrong patients: those with PD-L1-negative tumors (<1%) showed the most dramatic improvement.
This completely counterintuitive finding, published October 2025 in Nature and presented at ESMO, suggests the mechanism defies conventional wisdom. COVID vaccines activate innate immunity, causing "cold" tumors to upregulate PD-L1 expression and become responsive to checkpoint inhibitors. It's like the vaccine primes the tumor microenvironment to recognize immunotherapy.
Clinical reality check: Multi-center Phase III randomized trials are being designed to validate these retrospective findings. If confirmed, this represents an inexpensive, readily available intervention that could expand the immunotherapy-responsive population exponentially.
Bottom line: An unexpected synergy between pandemic vaccines and cancer treatment may revolutionize immunotherapy for traditionally resistant tumors.
2. Ketamine's Disappointing Reality Check: The Negative Trial Psychiatry Needed
The KARMA-Dep 2 trial just delivered a sobering wake-up call to the ketamine enthusiasm sweeping psychiatry. In hospitalized patients with depression, serial ketamine infusions showed no significant benefit over midazolam through 6 months.
65 patients received up to 8 infusions over 4 weeks added to standard inpatient care, far more intensive than typical protocols, yet found no differences in depression severity, cognition, quality of life, or economic outcomes. Despite the modest sample size, this well-conducted negative trial earned publication in JAMA Psychiatry specifically because it challenges the proliferation of off-label ketamine clinics.
Blinding was severely compromised with most participants correctly guessing their treatment, suggesting previous single-infusion efficacy estimates may reflect placebo enhancement rather than pharmacologic effect.
This well-conducted negative result earned publication in JAMA Psychiatry specifically because it challenges the proliferation of off-label ketamine clinics and highlights critical gaps between preliminary evidence and real-world effectiveness.
Practice implication: The trial doesn't disprove acute single-dose efficacy for suicidal ideation in controlled settings. It does question serial infusion protocols and suggests the ketamine clinic boom may have outpaced the evidence base.
What this means: Sometimes the most important studies are the ones that make us reconsider what we thought we knew. This forces evidence-based recalibration of ketamine's role beyond acute contexts.
3. One Injection Permanently Fixes Cholesterol: CRISPR Enters Clinical Cardiology
CTX310 represents the first CRISPR gene editing therapy to reach human testing for cardiovascular disease. A single intravenous infusion permanently modified cholesterol metabolism.
The November 8, 2025 NEJM report showed 0.8 mg/kg targeting the ANGPTL3 gene produced sustained reductions of 49% in LDL cholesterol and 55% in triglycerides through 60+ days in 15 patients with refractory dyslipidemia. Maximum reductions reached 87% for LDL and 84% for triglycerides.
Among patients with baseline triglycerides exceeding 150 mg/dL, reductions averaged 60%. ANGPTL3 levels decreased 73% on average (maximum 89%), with effects appearing dose-dependent starting at 0.6 mg/kg.
The permanent genetic modification eliminates adherence challenges inherent to daily medications, a paradigm shift from chronic pharmacotherapy to single-treatment intervention. Safety proved excellent with no treatment-related serious adverse events; three infusion reactions (fever, nausea, back pain) at higher doses resolved with temporary pausing.
Clinical reality check: This opens the door to one-time curative approaches for conditions currently requiring lifelong medication. Phase 2 trials are expanding enrollment to broader dyslipidemia populations.
Bottom line: CRISPR moves from theoretical possibility to cardiovascular reality, potentially solving adherence problems that plague lipid management.
4. T-Cell Engager Achieves Drug-Free Remission in "Untreatable" Autoimmune Diseases
An October 2025 NEJM letter reported shocking results using teclistamab, a bispecific antibody targeting CD3 on T cells and BCMA on B cells/plasma cells, in patients who had failed everything else.
10 patients with severe refractory autoimmune diseases (systemic sclerosis, inflammatory myositis, IgG4-related disease, Sjögren's, rheumatoid arthritis, and Graves disease) who had failed more than three prior immunomodulatory drugs received compassionate-use teclistamab. 60% achieved drug-free remission.
Interstitial lung disease improved in 4 of 5 affected patients. Six of seven patients discontinued glucocorticoids, and 8 of 10 stopped all immunosuppressants at last follow-up. B-cell aplasia lasted a median 157 days, with free kappa/lambda light chains dropping below detection in all patients.
This represents an entirely novel mechanism, T-cell engaging therapy, imported from oncology into autoimmunology. While cytokine release syndrome occurred in 8 of 10 patients, it remained mild and manageable with tocilizumab within 2 days. No grade 3-4 cytokine release or neurotoxicity emerged.
What this means: T-cell engagers could rescue patients with devastating refractory autoimmune conditions who have exhausted conventional options. This compassionate-use experience demands formal clinical trials.
5. Telitacicept Doubles Response Rates in Systemic Lupus Erythematosus
The October 16, 2025 NEJM publication of a Chinese Phase 3 trial showed telitacicept produced 67% modified SRI-4 response rates versus 33% with placebo, unprecedented efficacy in SLE treatment.
335 patients received the dual BAFF/APRIL inhibitor as 160 mg subcutaneous weekly or placebo for 52 weeks. The treatment also achieved 70% response on SELENA-SLEDAI score reductions ≥4 points (versus 40% placebo), extended median time to flare from 115 to 198 days, and enabled 45% of patients to reduce glucocorticoids to ≤7.5 mg daily versus 35% on placebo.
Among patients with proteinuria, 72% achieved reductions compared to 55% with standard care. The treatment difference of 34.5 percentage points (95% CI: 24.3-44.7) represents more than double the clinical response versus standard therapy, establishing a potential new benchmark for SLE management.
Practice implication: Global Phase 3 trials are underway for US, European, and Japanese regulatory submissions. This magnitude of benefit, if replicated in broader populations, will likely transform treatment algorithms.
Bottom line: After decades of marginal improvements in SLE therapy, a dual BAFF/APRIL inhibitor achieves response rates that fundamentally change what's possible in lupus treatment.
The Clinical Pearls That Matter
Fish oil halves cardiovascular events in dialysis patients. The PISCES trial (n=1,228) showed daily fish oil supplementation (4g containing 1.6g EPA + 0.8g DHA) reduced serious cardiovascular events by 43% (HR 0.57, P<0.001) in maintenance hemodialysis patients over 3.5 years, with consistent protection across cardiac death, MI, stroke, and peripheral vascular disease requiring amputation. PISCES trial
Capillary refill time-targeted resuscitation improves outcomes in early septic shock. 2. Capillary refill time-targeted resuscitation improves outcomes in early septic shock. In the ANDROMEDA-SHOCK-2 trial (n=1,467), using CRT >3 seconds as the primary resuscitation target reduced the composite outcome of major organ support at day 5 compared to usual care (50.1% vs 56.0%, P=0.02).ANDROMEDA-SHOCK-2 trial
Triple lipid therapy accelerates LDL-C reduction in acute coronary syndrome. Triple lipid therapy in ACS proves safe but not superior to dual therapy. The ES-BempeDACS trial tested adding bempedoic acid 180 mg to high-intensity statin + ezetimibe 10 mg within 24-72 hours post-ACS, but found no significant difference in achieving LDL-C <55 mg/dL at 8 weeks (59.4% vs 53.1%, P=0.376). While the triple therapy approach proved safe with similar adverse event rates, dual therapy (statin + ezetimibe) remains appropriate initial management for most ACS patients. ES-BempeDACS trial
Amylin agonist achieves 20% weight loss without incretin receptor targeting. Eloralintide, a selective amylin receptor agonist, produced 20% weight loss at 48 weeks with 9 mg weekly subcutaneous dosing in adults with obesity (n=263), matching GLP-1/GIP efficacy through an entirely different mechanism. This offers critical alternatives for patients who don't respond to or tolerate incretin therapies. Eloralintide weight loss study
Monday Morning Rounds: 5 Key Discussion Points
1. COVID vaccines as cancer adjuvants - mRNA COVID vaccination within 100 days of starting immunotherapy doubled median overall survival (37.33 vs 20.6 months) in NSCLC patients, with greatest benefit in PD-L1-negative tumors previously considered immunotherapy-resistant.
2. Ketamine serial infusions fail rigorous testing - KARMA-Dep 2 showed no benefit of up to 8 ketamine infusions over midazolam placebo through 6 months in hospitalized depression patients, challenging the proliferation of ketamine clinic protocols.
3. CRISPR permanently corrects cholesterol - Single-dose CTX310 gene editing produced sustained 49% LDL and 55% triglyceride reductions through permanent ANGPTL3 modification, eliminating daily medication adherence challenges.
4. T-cell engagers rescue refractory autoimmune disease - Teclistamab achieved 60% drug-free remission rates in patients with severe autoimmune conditions who had failed three or more prior therapies, importing oncology mechanisms into rheumatology.
5. Lupus treatment finally breaks through - Telitacicept doubled SRI-4 response rates (67% vs 33%) in SLE, representing the most significant therapeutic advance in lupus treatment in decades.
Before You Go...
This quarter delivered breakthroughs that span the spectrum from completely unexpected (COVID vaccines boosting cancer treatment) to long-awaited (CRISPR entering cardiovascular medicine) to sobering reality checks (ketamine's disappointing performance). The COVID-immunotherapy synergy exemplifies how understanding mechanism can repurpose existing safe interventions for dramatic new benefits. The ketamine trial demonstrates equal importance, rigorous methodology exposing overstated efficacy estimates that could otherwise misdirect resources and patient care.
From permanent genetic cholesterol fixes to T-cell engagers rescuing refractory autoimmune patients, these advances point toward more durable, convenient, and precisely targeted treatments. The clinical pearls provide immediately implementable guidance on fish oil for dialysis patients, septic shock resuscitation, aggressive lipid lowering post-ACS, and weight loss alternatives, all backed by Level 1 evidence from the past 90 days.
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The convergence of precision targeting, mechanistic understanding, and one-time interventions signals internal medicine's evolution toward more effective therapeutics. The question isn't whether these breakthroughs will change your practice; it's how quickly you'll integrate them to optimize patient outcomes.
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Essential Reading for Deep Dives
Oncology Breakthroughs: • COVID Vaccines and Immunotherapy Synergy
Psychiatry & Neuroscience: • KARMA-Dep 2 Ketamine Trial
Cardiology & Gene Therapy: • CTX310 CRISPR Gene Editing for Cholesterol • ES-BempeDACS Triple Lipid Therapy in ACS
Nephrology: • PISCES Fish Oil Trial for Dialysis Patients
Critical Care: • ANDROMEDA-SHOCK-2 Capillary Refill Trial
Rheumatology & Immunology: • Teclistamab for Refractory Autoimmune Disease • Telitacicept Phase 3 Trial for SLE
Endocrinology & Metabolism: • Eloralintide Amylin Agonist for Weight Loss
Disclaimer: The content provided in The Rounds Report is for educational and informational purposes only and does not constitute medical advice, diagnosis, treatment recommendations, or professional medical guidance. This newsletter presents summaries and analysis of published medical research and should not be used as a substitute for professional medical judgment, clinical decision-making, or consultation with qualified healthcare providers. Always consult with appropriate medical professionals and refer to original research sources before making any clinical decisions. The Rounds Report does not establish a doctor-patient relationship and readers should not rely on this content for patient care decisions.