Issues
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Cover Image
Cover Image
Targeted therapy and immunotherapy have significantly improved patient outcomes, but responses are not always durable and resistance is common. To effectively combine the benefits of both targeted therapy and immunotherapy, Hattori, Maso, and colleagues developed a generalizable technology platform that utilizes covalent targeted therapies conjugated to an intracellular oncoprotein fragment to create drug–peptide conjugates that serve as major histocompatibility complex (MHC)–restricted cancer neoantigens. Antibodies were engineered that recognize these MHC-bound neoantigens but not free drug, leading to targeted tumor cell killing through immune cell engagement. Antibodies targeting sotorasib and osimertinib were used as proof of concept and demonstrated potent killing of tumor cells resistant to these drugs. Overall, this study unifies targeted therapy and immunotherapy and suggests that targetable neoantigens may enhance therapeutic effectiveness against cancer. For more information, see the article by Hattori, Maso, and colleagues on page 132 - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
Review
Research Briefs
Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer
Colorectal cancer patients receiving KRASG12C and EGFR inhibitors develop resistance alterations that largely converge on ERK reactivation, with KRASG12C amplification standing out as a dominant mechanism that leads to oncogene-induced senescence off drug.
A Small Molecule Reacts with the p53 Somatic Mutant Y220C to Rescue Wild-type Thermal Stability
An allele-specific covalent small molecule was identified that selectively reacts with the mutant cysteine Y220C of p53 and leads to the rescue of wild-type thermal stability levels.
Human Papillomavirus 42 Drives Digital Papillary Adenocarcinoma and Elicits a Germ Cell–like Program Conserved in HPV-Positive Cancers
Human papillomavirus (HPV) 42 is a novel tumorigenic virus that drives a germ cell–like program conserved in all HPV-driven tumors that distinguishes HPV-driven from mutation-driven tumors and outperforms established clinical markers.
Cell Competition Shapes Metastatic Latency and Relapse
Cell competition triggers displacement of latent metastatic cells from the primary tumor that persist in distal organs and initiate metachronous metastasis.
Research Articles
Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor–Mutated, MET-Amplified Non–Small Cell Lung Cancer: TATTON
Savolitinib plus osimertinib combination therapy has an acceptable safety profile and demonstrated antitumor activity in patients with MET-amplified, EGFR-mutated advanced NSCLC who experienced disease progression on prior EGFR tyrosine kinase inhibitor therapy.
Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety
This first report of repeatedly dosed intracranial B7-H3 chimeric antigen receptor (CAR) T cells for patients with DIPG includes preclinical efficacy, preliminary clinical tolerability, and serial correlative biospecimen analysis of circulating CAR T cells, cytokine production, and targeted mass spectrometry.
Creating MHC-Restricted Neoantigens with Covalent Inhibitors That Can Be Targeted by Immune Therapy
Cancer-specific neoantigens created in the form of a covalent drug conjugated to a fragment of an intracellular oncoprotein selectively mark drug-resistant cancer cells for killing with bispecific T-cell engagers.
A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin–MLL Inhibition
Inhibition of Menin–MLL complexes allows tumor-suppressive MLL3/4–UTX chromatin-modifying complexes to bind target gene loci; reactivation of this program with CDK4/6 inhibitors can overcome intrinsic Menin inhibitor resistance.
Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance
Mutational scanning in base-edited IDH-mutant leukemia cells uncovered recurrent mutations that disable uncompetitive inhibition, which reveals a new class of pathogenic mutations and mechanisms for resistance to IDH-targeting therapies.
Identifying the Transcriptional Drivers of Metastasis Embedded within Localized Melanoma
An in vivo screen of a human melanoma transcriptional signature identified a role for free cholesterol in activating an AP-1 metastasis program.
An Aged/Autoimmune B-cell Program Defines the Early Transformation of Extranodal Lymphomas
Extranodal B-cell lymphoma founder mutations induce the clonal expansion of a traceable B-cell population reminiscent of that driving autoimmune disorders, setting the stage for early detection and targeted interventions.
News in Brief
News in Depth
Research Watch
Immunology
Intratumoral Heterogeneity
Clinical Trials
Immunotherapy
Cell Movement
Epigenetics
Prostate Cancer
Biotechnology
Gene Expression
Medulloblastoma
Colorectal Cancer
Early Detection
Microbiome
Immune Evasion
Acknowledgment to Reviewers
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