Project description:<p>The human immune system has evolved to interact with various commensal and pathogenic bacteria in intricate and nuanced ways. While the diversity of bacteria presents fundamental challenges in understanding immune-microbe interactions, it also offers ample opportunities for developing effective immunomodulatory therapies. We introduce microbial product cocktails as a novel class of immunotherapy for cancer. Using freshly resected tumors from bladder cancer patients, an immuno-comparative analysis of recruitment and enhancement assay, and an AI-guided optimization workflow, we established a personalized platform for identifying potent MPCs that promote recruitment, infiltration, and activation of immune cells for cancer treatment. In an orthotopic mouse bladder cancer model, MPCs demonstrated immunoenhancement and improved survival rates compared with standard bacillus Calmette–Guérin immunotherapy.</p>
2025-07-01 | MTBLS12666 | MetaboLights
Project description:Microbial Product Cocktails for Personalized Cancer Immunotherapy
Project description:Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. We developed a low-input proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy. Our data indicate that novel splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminated tumor cells in vitro. Targeting novel tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies. These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors.
Project description:Adoptive transfer of T cells expressing a transgenic T cell receptor (TCR) has the potential to revolutionize immunotherapy of infectious diseases and cancer. However, the generation of defined TCR-transgenic T cell medicinal products with predictable in vivo function still poses a major challenge and limits broader and more successful application of this ‘living drug’. Here, by studying 51 different TCRs, we show that conventional genetic engineering by viral transduction leads to variable TCR expression and functionality as a result of variable transgene copy numbers and untargeted transgene integration. In contrast, CRISPR/Cas9-mediated TCR replacement enables defined, targeted TCR transgene insertion into the TCR gene locus. Thereby, T cell products display more homogenous TCR expression similar to physiological T cells. Importantly, increased T cell product homogeneity after targeted TCR gene editing correlates with predictable in vivo T cell responses, which represents a crucial aspect for clinical application in adoptive T cell immunotherapy.
Project description:We present a pipeline, ObsERV, for the design of personalized cancer immunotherapies based on epitopes derived from endogenous retroviral elements (EVEs). We show that EVE-derived peptides are presented as antigens on tumors and can be predicted by ObsERV. Preclinical testing of ObsERV demonstrates elicitation of poly-functional CD4+ and CD8+ T-cell responses as well as long-term tumor protection and persistence of the responses.