Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4–6, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically ‘cold’ tumour microenvironment8. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone—a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma—generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.

Background The only definitive treatment for end-stage organ failure is orthotopic transplantation. Lung extracellular matrix (ECM) holds great potential as a scaffold for lung tissue engineering since it retains the complex architecture, biomechanics and topological specificity of the lung. Decellularization of human lungs rejected from transplantation could provide “ideal” biological scaffolds for lung tissue engineering, but the availability of such lungs remains limited. The present study was designed to determine whether porcine lung could serve as a suitable substitute of human lung to study tissue-engineering therapies. Methods Human and porcine lungs were procured, sliced into sheets, and decellularized using three different methods. Compositional, ultrastructural, and biomechanical changes to the ECM were characterized. The suitability of LECM for cellular re-population was evaluated by assessing the viability, growth, and metabolic activity of human lung fibroblasts (hMRC-5s), human small airway epithelial cells (hSAECs), and human adipose-derived mesenchymal stem cells (hMSCs) over a period of seven days. Results Decellularization using CHAPS, 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate, showed the best maintenance of both human and porcine LECM, with similar retention of ECM proteins, except for elastin. Human and porcine LECM supported the cultivation of pulmonary cells in a similar way, except that the human LECM was stiffer and resulted in higher metabolic activity of the cells than porcine LECM. Conclusions Porcine lungs can be decellularized using CHAPS to produce lung ECM scaffolds with properties resembling those of human lungs, for pulmonary tissue engineering. We propose that porcine lung ECM can be an excellent screening platform for the envisioned human tissue engineering applications of decellularized lungs.

Native extracellular matrix (ECM) that is secreted and maintained by resident cells is of great interest for cell culture and cell delivery. We hypothesized that specialized bioengineered niches for stem cells can be established using ECM-derived scaffolding materials. Kidney was selected as a model system because of the high regional diversification of renal tissue matrix. By preparing the ECM from three specialized regions of the kidney (cortex, medulla, and papilla; whole kidney, heart, and bladder as controls) in three forms: (i) intact sheets of decellularized ECM, (ii) ECM hydrogels, and (iii) solubilized ECM, we investigated how the structure and composition of ECM affect the function of kidney stem cells (with mesenchymal stem cells, MSCs, as controls). All three forms of the ECM regulated KSC function, with differential structural and compositional effects. KSCs cultured on papilla ECM consistently displayed lower proliferation, higher metabolic activity, and differences in cell morphology, alignment, and structure formation as compared to KSCs on cortex and medulla ECM, effects not observed in corresponding MSC cultures. These data suggest that tissue- and region-specific ECM can provide an effective substrate for in vitro studies of therapeutic stem cells.