Radically different
Nature Medicine, Published online: 20 April 2026; doi:10.1038/s41591-026-04365-y
As presented at the 2026 AACR Annual Meeting, in a phase 2 trial, treatment of patients with high-risk smoldering multiple myeloma with BCMA-targeting CAR T cell therapy ciltacabtagene autoleucel was safe and led to encouraging rates of clinical responses.
Leanna Stokes had gotten into the habit of asking her oncologist what might be next for her treatment, and for good reason. Stokes, a 36-year-old gymnastics manager from New Rochelle, New York, had received one of the most difficult diagnoses in oncology: metastatic pancreatic cancer. Her oncologist kept mentioning two syllables, KAY-ras, referring to her cancer’s mutation on the KRAS gene. Mutations in this gene can make cancers more aggressive. But for Stokes, it was a possible key to extending her life.
“She always mentioned this — KRAS, KRAS, KRAS,” Stokes said of her oncologist. As Stokes proceeded to receive line after line of chemotherapy, she would remind herself, “It’s there. It’s there. It’s there. Then finally, it was my turn.”
Just a few years ago, such a refrain might have sounded odd to pancreatic cancer experts. For most of the nearly 50 years since KRAS was first discovered, scientists struggled to effectively drug the cancer protein. When Kevan Shokat, a biochemist at University of California, San Francisco, finally discovered how to drug a rare subset of KRAS mutant cancers, the first-generation drugs were a clinical disappointment. For the roughly 1% of pancreatic cancer patients who could receive them, the drugs improved outcomes only marginally, with resistance forming rapidly.
“We did not have a home run on the first effort,” said Channing Der, a pancreatic cancer researcher at the University of North Carolina, Chapel Hill. “It’s fair to say we’ve been disappointed by the durability of the responses.”
But once Shokat had shown it could be done at all, more and more companies jumped into developing drugs for KRAS, with new agents now regularly moving into clinical trials. The company leading the field has been Revolution Medicines, with the drug daraxonrasib, which targets KRAS and related proteins.
This was the drug that Stokes got on her clinical trial. It transformed her life, she said, enabling her to live far longer than most patients with her diagnosis. It’s also generating immense excitement among oncologists and drug developers, who say it heralds a new era for pancreatic cancer medicine and could bring new treatments for other cancer types with KRAS mutations including lung, colorectal, endometrial, and more. Beyond Revolution Medicines, dozens of other companies are also testing promising KRAS inhibitors in the clinic.
Nature Medicine, Published online: 17 April 2026; doi:10.1038/s41591-026-04405-7
Author Correction: Obicetrapib in patients with heterozygous familial hypercholesterolemia: the BROOKLYN randomized clinical trial
Results from a Phase I/IIa trial show promise for an immune priming approach where donor immune cells are infused into liver transplant recipients before surgery. In the small-scale clinical trial, three patients were reported to remain completely off immunosuppression for over three years thanks to this treatment.
Recipients of organ transplants need to take lifelong medication to prevent the immune system from rejecting the transplant. In the case of end-stage liver disease patients, the serious side effects of immunosuppressants are considered acceptable in the face of a severe and life-threatening condition. Still, researchers have long been looking for strategies to at least reduce the intensity and duration of this treatment, which would significantly improve the health of these patients and the financial burden of long-term immunosuppression.
“Long-term use of immunosuppressive drugs can harm the kidneys, causes metabolic complications, makes patients more susceptible to infections and certain types of cancer, as well as diabetes,” said Angus Thomson, PhD, DSc, professor of surgery and immunology at the University of Pittsburgh’s School of Medicine (UPMC). “Sparing patients from these serious side effects has been a goal that Pittsburgh transplant scientists began pursuing three decades ago. It is an honor to achieve this important milestone toward finally realizing that dream.”
The immune priming approach developed by Thomson’s team makes use of regulatory dendritic cells (DCregs), a type of immune cell that regulate innate and adaptive immunity and have the ability to train the immune system to stop recognizing transplanted cells as foreign. The treatment is made by extracting monocytes from the donor’s blood and inducing them to turn into DCregs.
Launched in 2017, the clinical trial recruited a total of 13 patients who were infused with DCregs from their donor a week before surgery. A year after surgery, transplant recipients underwent a biopsy and an assessment to determine if they were eligible for immunosuppressant withdrawal.
Out of eight patients who stopped taking immunosuppressants, four achieved complete withdrawal and three of them remained off immunosuppression therapy for over three years. These findings represent a significant improvement compared to the rate of patients who successfully withdraw from immunosuppression without intervention, raising it from 16% to 37%.
“For as long as organ transplantation has been a field of medicine, tolerance has been its holy grail,” said Abhinav Humar, MD, clinical director of the Starzl Transplantation Institute and chief of the division of transplantation at UPMC. “While we haven’t hit a home run yet, we’ve definitely gotten on base by reliably and safely removing immunosuppression early after transplantation from a significant percentage of patients, which is a huge breakthrough.”
While preliminary efficacy results seem promising, the main objective of this small scale trial was to establish the treatment’s safety and feasibility. Based on these results, a larger scale, randomized trial will be designed and conducted with the purpose of establishing the efficacy of this immune priming approach.
In future studies, the researchers also want to explore the use of an alternative immunosuppressant medication that may be more likely to allow DCregs to stop immune rejection against the transplant, as well as studying the effects of infusing the donor cells after surgery and looking for ways of obtaining these cells from deceased donors to expand the potential applications of this approach.
“There are so many tantalizing paths we could take to help our findings benefit many more patients,” Thomson said. “We are very interested in collaborating with other transplantation centers to accelerate and scale our clinical research.”
The post Immune Priming Could End Immunosuppression After Liver Transplant appeared first on Inside Precision Medicine.
Background: Pediatric chronic pain affects up to one-third of youth and is associated with significant disruptions in social, emotional, and behavioral functioning. Although behavioral treatments are effective, access remains limited due to geographic, financial, and systemic barriers. Digital behavioral health interventions offer a promising solution, but many lack user-centered design, iterative refinement, and implementation-informed development strategies that support usability and scalability. Objective: This study aimed to develop and iteratively refine iGET Living, a digital graded exposure intervention for youth with chronic pain, using a combined user-centered and implementation-informed framework, and to evaluate its preliminary acceptability, feasibility, and user-perceived success. Methods: Guided by the Consolidated Framework for Implementation Research (CFIR) and the mHealth (mobile health) Agile Development and Lifecycle model, intervention development proceeded through 3 phases. Phase 0 translated an evidence-based in-person graded exposure treatment (GET Living) into an initial digital prototype. Phase 1 involved iterative user-centered refinement across 3 cycles of qualitative development sessions with youth with chronic pain (n=15), incorporating think-aloud usability testing, Likert-rated feedback, and rapid qualitative analysis mapped to CFIR constructs to guide real-time modifications to content, design, and functionality. Phase 2 piloted the refined intervention with a new sample of youth (n=38, n=30 completers) recruited from a tertiary pediatric pain clinic to evaluate feasibility, acceptability, treatment credibility and expectancy, and user-perceived functional improvements. Quantitative outcomes were summarized descriptively, and qualitative exit interview data were analyzed using rapid qualitative analysis. Results: Across development cycles, youth feedback informed substantive refinements to the intervention, including reducing text density, incorporating animated educational videos, enhancing interactive features, and improving navigation and layout. These changes resulted in progressive improvements in clarity, satisfaction, and acceptability across prototypes. In the Phase 2 pilot study, participants reported moderate-to-high treatment credibility (mean of 19.71 out of 30) and expectancy (mean of 17.96 out of 30), as well as high satisfaction (mean of 46.12 out of 60). Acceptability ratings across domains of the Theoretical Framework of Acceptability were favorable. Qualitative exit interviews highlighted the interventions’ perceived role in helping youth re-engage in valued activities. Conclusions: Using a combined CFIR and agile development approach, iGET Living emerged as a feasible, acceptable, engaging digital graded exposure intervention for youth with chronic pain. These findings highlight the value of integrating implementation frameworks and participatory design early in digital intervention development and support further evaluation in a preliminary efficacy trial. Trial Registration: ClinicalTrials.gov NCT05079984; https://clinicaltrials.gov/study/NCT05079984 International Registered Report Identifier (IRRID): RR2-10.1136/bmjopen-2022-065997
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Background: The prevalence of obesity is a global health challenge, as obesity is associated with various comorbidities, reduced quality of life, and increased mortality. Providing effective treatment to improve health and quality of life for people with obesity is a major health care concern. Internet-delivered treatment (IDT) is an alternative treatment that increases patient accessibility and reachability; however, pilot testing is required before such interventions are evaluated in full-scale studies or implemented. Objective: This study aims to investigate the feasibility and user-friendliness of an IDT program for obesity (IDT-O); to evaluate body weight, dietary habits, physical activity, psychosocial functioning, and experiences of treatment in those who completed the 6-month treatment; and to investigate the dropouts’ experiences of the treatment. Methods: A prospective 1-year observational approach, evaluated through a multimethod research design, was adopted. Inclusion criteria were age 18 years and older, BMI of ≥30 kg/m, or BMI of 28‐29.9 kg/m with obesity-related comorbidity. Participants were offered a 6-month therapist-assisted IDT-O program providing evidence-based obesity treatment, behavioral and lifestyle support, and strategies to address weight stigma. BMI, participants’ dietary habits, self-reported physical activity, psychosocial functioning, experiences of treatment effects, and treatment satisfaction were measured before treatment and after 6 and 12 months. Dropouts were followed up through qualitative interviews. Results: A total of 20 participants (17 females and 3 male; mean age 44.2, SD 16.4 years) started the IDT-O program, and 35% (7/20) completed all 12 modules. Ten (8 females) out of 13 dropouts were interviewed. Both quantitative and qualitative findings showed that participants were generally satisfied with the content and design of the intervention. Those who completed the IDT-O lost some weight (mean 2.0%, 95% CI −1.09 to 5.13), reported improved dietary habits (effect size [ES] 0.25, 95% CI −0.51 to 1.00), increased physical activity (ES 0.93, 95% CI −0.08 to 1.87), and improved psychosocial functioning (distress: ES 0.43, 95% CI 0.‐0.37 to 1.19; avoidance: ES 0.67, 95% CI −0.18 to 1.48), 6 months after completing the treatment. The qualitative analysis of the interviews revealed “The programme was OK, but it does not suit everyone” as the main theme. The main themes were based on the 3 subthemes: “It wasn’t for me,” “There were good things,” and “There are things to improve.” Conclusions: The findings indicate that the IDT-O holds potential as a treatment for people with obesity, although one limitation is that only 35% (7/20) of the participants completed the pilot program. Improvements in lifestyle habits and psychosocial functioning were observed in those who completed the IDT-O, but these findings are preliminary and need to be confirmed in a more comprehensive study. The issue of nonadherence underscores the importance of both thoroughly assessing patients before treatment and further development of IDT-O programs. Trial Registration: ClinicalTrials.gov NCT04150445; https://clinicaltrials.gov/study/NCT04150445
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