Nature Medicine最新文献

The limitations of current immune checkpoint inhibitor therapies highlight a need for improved strategies to expand tumor-reactive T cell repertoires in a way that is safe, selective and efficient. Cancer vaccines hold potential to achieve this goal, but the profound success of vaccines for infectious diseases has not yet translated to the cancer setting. Recently, however, encouraging preliminary results from phase 1 and 2 clinical trials have renewed enthusiasm and spurred the initiation of large-scale cancer vaccine trials. In this Review, we highlight insights from recent clinical trials, translational studies and preclinical models, which reveal critical factors for optimizing cancer vaccines. Key strategies include definition of improved proxies to estimate vaccine efficacy, selection of high-quality antigens-particularly neoantigens-using modular vaccine platforms with innate immunostimulatory capabilities, and a focus on early-stage cancer, as exemplified by (neo)adjuvant therapies. We discuss each of these in detail, outlining a roadmap for future cancer vaccine development.

Chimeric antigen receptor (CAR) T cell therapy was recently proposed as a treatment for adults with B-cell-mediated autoimmune diseases (ADs) refractory to conventional immunomodulatory therapy. We present a case series of eight children with severe/refractory AD (four systemic lupus erythematosus, three dermatomyositis, one systemic sclerosis) treated at Ospedale Pediatrico Bambino Gesù, Rome, and University Hospital Erlangen with a single infusion of 1 × 10⁶ kg^-1 point-of-care manufactured autologous CD19 CAR T cells (zorpocabtagene autoleucel), in a hospital exemption (HE) program. In Europe, the HE pathway offers the opportunity to treat patients with life-threatening or seriously debilitating disorders who lack valid therapeutic options, using an advanced therapy medicinal product (ATMP) authorized on a nonroutine, single-patient basis. In contrast to the 'compassionate use' pathway, the ATMP does not necessarily need to have undergone clinical trials or marketing authorization applications. Manufacturing was successful in all patients, yielding several drug product bags. Once infused after lymphodepletion, zorpocabtagene autoleucel cells expanded in vivo, promoting prompt B cell clearance. Grade 1 cytokine release syndrome was reported in six patients, and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in one patient. Late-hematotoxicity was limited to grade 1 in two patients. All these adverse events were manageable and no severe infections occurred. With a median follow-up of 16.5 months (range = 9-24 months), all patients experienced a clinically substantial improvement/resolution of AD, as evidenced by reduction in disease activity scores and signs of reversal of organ damage. This improvement enabled sustained discontinuation of immunomodulators, even after B cell reconstitution. The activation of formal clinical trials enrolling children and adolescents is urgently needed to confirm these preliminary results and to assess the long-term safety of this approach.

Patient-facing large language models (LLMs) hold potential to streamline inefficient transitions from primary to specialist care. We developed the preassessment (PreA), an LLM chatbot co-designed with local stakeholders, to perform the general medical consultations for history-taking, preliminary diagnoses, and test ordering that would normally be performed by primary care providers and to generate referral reports for specialists. PreA was tested in a randomized controlled trial involving 111 specialists from 24 medical disciplines across two health centers, where 2,069 patients (1,141 women; 928 men) were randomly assigned to use PreA independently (PreA-only), use it with staff support (PreA-human), or not use it (No-PreA) before specialist consultation. The trial met its primary end points with the PreA-only group showing significantly reduced physician consultation duration (28.7% reduction; 3.14 ± 2.25 min) compared to the No-PreA group (4.41 ± 2.77 min; P < 0.001), alongside significant improvements in physician-perceived care coordination (mean scores 113.1% increase; 3.69 ± 0.90 versus 1.73 ± 0.95; P < 0.001) and patient-reported communication ease (mean scores 16.0% increase; 3.99 ± 0.62 versus 3.44 ± 0.97; P < 0.001). Equivalent outcomes between the PreA-only and PreA-human groups confirmed the autonomous operation capability. Co-designed PreA outperformed the same model with additional fine-tuning on local dialogues across clinical decision-making domains. Co-design with local stakeholders, compared to passive local data collecting, represents a more effective strategy for deploying LLMs to strengthen health systems and enhance patient-centered care in resource-limited settings. Chinese Clinical Trial Registry identifier: ChiCTR2400094159 .