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T cell receptor (TCR)-engineered T cells offer great promise for targeting tumor antigens in cancer therapy. A synthetic fusion protein termed 80BB, which can simultaneously activate the CD28 and 4-1BB co-stimulatory pathways, is now shown to enhance overall functionality of therapeutic TCR/CD3-dependent T cells in an antigen-agnostic manner.
Targeted therapies that use small-molecule inhibitors for the treatment of T cell blood cancer exist only for certain subtypes, and the development of immunologically based CAR T cell therapies has been challenging. A study now exploits the fact that malignant T cells express one of two T cell receptor-β variants and investigates strategies for targeting these malignant cells while sparing half of the non-malignant T cells.
Puissant and colleagues identify a myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis as a therapeutic vulnerability in acute myeloid leukemia and develop a proteolysis-targeting chimera to potently degrade PIK3CG and suppress AML progression.
Gemcitabine is a widely used chemotherapy drug that acts by targeting DNA replication. Understanding why many tumors are unresponsive to gemcitabine is a clinical challenge. A new study in Nature Cancer reports that upregulation of the cytidine deaminases APOBEC3C and APOBEC3D facilitates resistance to gemcitabine by protecting cells against DNA replication stress.
We profiled microglia using single-cell multi-omics techniques in lymphoma-bearing mice and patients who developed neurotoxicity after CAR19 T cell transfer. We discovered that microglial activation after CAR19 T cell infusion was mediated mainly by the kinase TAK1, which suggests that targeting TAK1 in patients receiving CAR19 T cell-based cancer immunotherapy could treat neurotoxicity.
As quantum technology advances, it holds immense potential to accelerate oncology discovery through enhanced molecular modeling, genomic analysis, medical imaging, and quantum sensing.
Rezvan and colleagues profile the infusion product from individuals with DLBCL treated with CAR T cells and integrate functional profiling by timelapse imaging microscopy and scRNA-seq to identify a signature of migratory CD8+ T cells associated with response.
Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.
Vousden and colleagues discuss the multifactorial role of mitochondrial folate metabolism in cancer and metastasis and reflect on potential therapeutic opportunities.
We performed a proof-of-concept study showing that single-cell RNA sequencing, a method for capturing rich tumor information (not yet in clinics owing to high costs), can be used to identify patients likely to respond to targeted therapy and to monitor the emergence of resistance.
Sarcomas are heterogeneous connective tissue tumors that occur at various anatomic sites and are generally difficult to treat. Cell states in sarcoma ecosystems are now shown to be conserved across multiple subtypes and associated with response to immunotherapy and patient outcome.
Arginine methylation is crucial for tumor maintenance. PRMT9 levels are elevated in acute myeloid leukemia, and its inhibition eradicates leukemia by diminishing arginine methylation of proteins involved in DNA damage response and RNA translation. This activates the cGAS–STING pathway, which triggers immune responses directed against leukemia. Epigenetic targeting of DNA-damage-response mechanisms may bolster anti-tumor immunity.
In this phase 1 trial, Hegde et al. treat 13 individuals with advanced sarcoma with lymphodepletion followed by HER2-specific CAR T cells, which were found to be safe and showed antitumor activity.
Barker and colleagues discuss the interplay between circadian rhythm, the tumor microenvironment and stem cells and how these are linked to metastasis as well as how these interactions could be clinically relevant.
Merz and colleagues perform single-cell multiomic analysis of mononuclear cells isolated from individuals receiving BCMA-directed CAR T cell therapy for myeloma and show that nonresponders are characterized by an immune-suppressive microenvironment.
Sinha and colleagues present PERCEPTION, a precision oncology computational pipeline that can predict the response and resistance of patients by analyzing single-cell transcriptomic data from their tumor samples.