Exercise with cancer: it’s about more than fitness
Retrospective observational studies very frequently highlight the correlation of various lifestyle characteristics with outcomes, but most of the time, randomized controlled trials whereby one arm gets a lifestyle intervention vs. another arm remains status quo fail to show a clear benefit on hard clinical endpoints. This is why a Canadian trial that shows a survival advantage with exercise (hazard ratio for death 0.63) in cancer patients is so interesting. The study population consisted in colon cancer patients who were fully resected, but with significant risk of a recurrence leading to the use of adjuvant chemotherapy. These 889 subjects were randomized to a structured exercise program vs. just health education and followed at least 5 years. The beneficial difference in risk of death was principally driven by lower colon cancer recurrence, but also by fewer other primary cancers (and not by a cardiovascular benefit as one might have expected). This is not about overall stamina and fitness which could allow better resilience to illness and the often arduous therapies inflicted on cancer patients: there is mysterious biology at the cellular level going on here. Structured Exercise after Adjuvant Chemotherapy for Colon Cancer
Lights at the end of the DM1 tunnel?
In the last highlights for Q2 2025, I noted the encouraging results from the initial phase 1 trial for the implantation of Vertex’s allogeneic islet cells derived from pluripotent embryonic stem cells, but also complained of the lack of description of the immunosuppressive regimen (I am still waiting to see if there will be letters to the Editor about that, nothing so far). Now comes a new approach also based on allogeneic beta cells (harvested from a donor, presumably cadaveric though that’s not specified) which are then edited by removing expression of both MHC class I and II, and adding in overexpression of CD47 to evade “missing-self” innate killing. After extensive testing in mice and NHPs, a first in human study with a small number of cells implanted in the forearm of a type I diabetic volunteer showed the following: 1) the cells that were successfully edited survived for at least 12 weeks, while partially/non-edited cells died (as expected from the underlying process driving β cells destruction in DM1) 2) the surviving cells produced insulin in response to blood glucose levels. Because the implantation was only with a small number of cells, the patient remained dependent on exogenous insulin, but a dose 15x larger should, in theory, be sufficient for insulin independence (presumably this is a next step that the company, Sana Biotechnology is working on). Looking ahead, one can hope these two approaches will merge – β cells grown from a pluripotent master (instead of from one donor at a time), and edited to be invisible to the immune system (presumably this is what Sana, the company, is working on). If concerns of potential malignant transformation can be allayed, now that would really be solving Type I diabetes. Survival of Transplanted Allogeneic Beta Cells with No Immunosuppression
Exploiting accidents of nature
About 16 years ago, a hyper-functional mutant variant of Factor IX (the protein whose deficiency causes hemophilia B) was discovered in a patient in Padua, Italy, and reported in the Journal under the name of the Padua variant. This gain of function (~8x activity relative to wild-type) has been exploited for the gene therapy Hemgenix (UniQure) enabling the use of a much lower, and therefore safer, dose of viral vector. Now a group out of the University of Colorado reports on a single patient with an analog gain-of-function (3x) mutation for Factor VIII (the protein whose deficiency causes hemophilia A) that they have called the Aurora variant. Whether it can be applied to gene therapy in hemophilia A remains to be seen, but it highlights the value of mining the natural experiments that randomly emerge in large populations, in this case, by an undergraduate student (first time I have noticed a NEJM author with no degree after their name)! A Naturally Occurring Gain-of-Function Mutation in Factor VIII
GLP-1 agonists galore
This quarter’s issues contained a veritable tidal wave of late stage clinical data from would be successors to Ozempic/Wegovy and Mounjaro/Zepbound. Targeted improvements include: higher weight-loss (CagriSema, Novo), reduced frequency (MariTide, Amgen), oral administration (orforglipron Lilly, megadose semaglutide Novo) and there is way more in the pipeline. While an army of Wall Street analysts are parsing the details of weight loss (10-20%), adverse events and tolerability (GI upsets widespread but generally tolerable), I wonder if the old pharma adage that you have to either be “first in class” or “best in class” to win will apply in this particular context (for a paper on this see here). These drugs blur the line between lifestyle and health (cf. the many jokes at the Oscars or Golden Globes). Payers are very nervous about reimbursement, with major DTC efforts from the manufacturers (and let’s not forget the compounders…). Relative to other drug classes, price and access will be a major consideration – would you be willing to accept a bit less weight loss to save $3K a year? The calculus of 30 vs. 40 lbs of expected weight loss may be quite different from 30 vs. 40 months of expected survival. This will be a fight for the consumer at least as much as a fight for the prescribers. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity; Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes; Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity — A Phase 2 Trial; Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes; Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity