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Nature Jun 2024Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and...
Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted β- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.
Topics: Animals; Humans; Male; Mice; Antigens, Surface; Cell Line, Tumor; Fluorides; Glutamate Carboxypeptidase II; Ligands; Membrane Proteins; Molecular Targeted Therapy; Pilot Projects; Prostatic Neoplasms; Radioisotopes; Radiopharmaceuticals; Sulfur Compounds; Tyrosine; Xenograft Model Antitumor Assays
PubMed: 38778111
DOI: 10.1038/s41586-024-07461-6 -
Cancer Treatment Reviews Feb 2024Antibody-drug conjugates (ADCs) represent a novel class of molecules composed of a recombinant monoclonal antibody targeted to a specific cell surface antigen,... (Review)
Review
Antibody-drug conjugates (ADCs) represent a novel class of molecules composed of a recombinant monoclonal antibody targeted to a specific cell surface antigen, conjugated to a cytotoxic agent through a cleavable or non-cleavable synthetic linker. The rationale behind the development of ADCs is to overcome the limitations of conventional chemotherapy, such as the narrow therapeutic window and the emergence of resistance mechanisms. ADCs had already revolutionized the treatment algorithm of HER2-positive breast cancer. Currently, emergent non-HER2 targeted ADCs are gaining momentum, with special focus on triple-negative disease therapeutic landscape. Sacituzumab govitecan (SG) is an ADC consisting of a humanized monoclonal antibody hRS7 targeting trophoblast cell surface antigen 2 (Trop2), linked to the topoisomerase I inhibitor SN-38 by a hydrolysable linker. It currently stands as the only non-HER2 targeted ADC that already received approval for the treatment of unresectable locally advanced or metastatic triple negative breast cancer (TNBC) in patients who had received two or more prior systemic therapies, with at least one for advanced disease. The purpose of these review is to analyze the available evidence regarding ADCs in TNBC, alongside with providing an overview on the ongoing and future research horizons in this field.
Topics: Humans; Female; Triple Negative Breast Neoplasms; Breast Neoplasms; Irinotecan; Camptothecin; Immunoconjugates; Antibodies, Monoclonal; Antigens, Surface
PubMed: 38118302
DOI: 10.1016/j.ctrv.2023.102672 -
Nature Cancer Jul 2023The limited efficacy of chimeric antigen receptor (CAR) T cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an...
The limited efficacy of chimeric antigen receptor (CAR) T cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an immunosuppressive environment. Herein, we use c-Kit signaling, a physiological pathway associated with stemness in hematopoietic progenitor cells (T cells lose expression of c-Kit during differentiation). CAR T cells with intracellular expression, but no cell-surface receptor expression, of the c-Kit D816V mutation (KITv) have upregulated STAT phosphorylation, antigen activation-dependent proliferation and CD28- and interleukin-2-independent and interferon-γ-mediated co-stimulation, augmenting the cytotoxicity of first-generation CAR T cells. This translates to enhanced survival, including in transforming growth factor-β-rich and low-antigen-expressing solid tumor models. KITv CAR T cells have equivalent or better in vivo efficacy than second-generation CAR T cells and are susceptible to tyrosine kinase inhibitors (safety switch). When combined with CD28 co-stimulation, KITv co-stimulation functions as a third signal, enhancing efficacy and providing a potent approach to treat solid tumors.
Topics: CD28 Antigens; Cell Line, Tumor; Immunotherapy, Adoptive; Interleukin-2; Receptor Protein-Tyrosine Kinases; T-Lymphocytes; Proto-Oncogene Proteins c-kit
PubMed: 37336986
DOI: 10.1038/s43018-023-00573-4 -
The Journal of Experimental Medicine Aug 2023Interest in MHC-E-restricted CD8+ T cell responses has been aroused by the discovery of their efficacy in controlling simian immunodeficiency virus (SIV) infection in a...
Interest in MHC-E-restricted CD8+ T cell responses has been aroused by the discovery of their efficacy in controlling simian immunodeficiency virus (SIV) infection in a vaccine model. The development of vaccines and immunotherapies utilizing human MHC-E (HLA-E)-restricted CD8+ T cell response requires an understanding of the pathway(s) of HLA-E transport and antigen presentation, which have not been clearly defined previously. We show here that, unlike classical HLA class I, which rapidly exits the endoplasmic reticulum (ER) after synthesis, HLA-E is largely retained because of a limited supply of high-affinity peptides, with further fine-tuning by its cytoplasmic tail. Once at the cell surface, HLA-E is unstable and is rapidly internalized. The cytoplasmic tail plays a crucial role in facilitating HLA-E internalization, which results in its enrichment in late and recycling endosomes. Our data reveal distinctive transport patterns and delicate regulatory mechanisms of HLA-E, which help to explain its unusual immunological functions.
Topics: Animals; Humans; Histocompatibility Antigens Class I; CD8-Positive T-Lymphocytes; Antigen Presentation; Vaccines; HLA-E Antigens
PubMed: 37140910
DOI: 10.1084/jem.20221941 -
Cancer Gene Therapy Feb 2024Antibody-Drug Conjugates (ADCs) represent a rapidly advancing category of oncology therapeutics, spanning the targeted therapy for both hematologic malignancies and...
Antibody-Drug Conjugates (ADCs) represent a rapidly advancing category of oncology therapeutics, spanning the targeted therapy for both hematologic malignancies and solid cancers. A crucial aspect of ADC research involves the identification of optimal surface antigens that can effectively differentiate target cells from most mammalian cell types. Herein, we have devised an algorithm and compiled an extensive dataset annotating cell membrane proteins. This dataset is derived from comprehensive transcriptomic, proteomic, and genomic data encompassing 19 types of solid cancer as well as normal tissues. The aim is to uncover potential therapeutic surface antigens for precise ADC targeting. The resulting target landscape comprises 165 combinations of targets and indications, along with 75 candidates of cell surface proteins. Notably, 35 of these candidates possess characteristics suitable for ADC targeting, and have not been previously reported in ADC research and development. Additionally, we have identified a total of 159 ADCs from a pool of 760 clinical trials. Of these, 72 ADCs are presently undergoing interventional evaluation for a variety of solid cancer types, targeting 36 unique antigens. We conducted an analysis of their expression in normal tissues using this comprehensive annotation dataset, revealing a diverse range of profiles for the current ADC targets. Moreover, we emphasize that the biological impacts of target antigens have the potential to enhance their clinical effectiveness. We propose a comprehensive assessment of the drugability of target antigens, considering multiple facets. This study represents a thorough exploration of pan-cancer ADC targets over the past two decades, underscoring the potential of a comprehensive solid cancer target atlas to broaden the scope of ADC therapies.
Topics: Animals; Humans; Immunoconjugates; Proteomics; Neoplasms; Antigens, Surface; Antineoplastic Agents; Mammals
PubMed: 38129681
DOI: 10.1038/s41417-023-00701-3 -
Nature Immunology Sep 2023The development of CD4 T cells and CD8 T cells in the thymus is critical to adaptive immunity and is widely studied as a model of lineage commitment. Recognition of...
The development of CD4 T cells and CD8 T cells in the thymus is critical to adaptive immunity and is widely studied as a model of lineage commitment. Recognition of self-peptide major histocompatibility complex (MHC) class I or II by the T cell antigen receptor (TCR) determines the CD8 or CD4 T cell lineage choice, respectively, but how distinct TCR signals drive transcriptional programs of lineage commitment remains largely unknown. Here we applied CITE-seq to measure RNA and surface proteins in thymocytes from wild-type and T cell lineage-restricted mice to generate a comprehensive timeline of cell states for each T cell lineage. These analyses identified a sequential process whereby all thymocytes initiate CD4 T cell lineage differentiation during a first wave of TCR signaling, followed by a second TCR signaling wave that coincides with CD8 T cell lineage specification. CITE-seq and pharmaceutical inhibition experiments implicated a TCR-calcineurin-NFAT-GATA3 axis in driving the CD4 T cell fate. Our data provide a resource for understanding cell fate decisions and implicate a sequential selection process in guiding lineage choice.
Topics: Mice; Animals; CD8-Positive T-Lymphocytes; Cell Lineage; CD4-Positive T-Lymphocytes; Thymocytes; Multiomics; Mice, Transgenic; Cell Differentiation; Receptors, Antigen, T-Cell; Thymus Gland; Histocompatibility Antigens Class I; CD4 Antigens
PubMed: 37580604
DOI: 10.1038/s41590-023-01584-0 -
Cancer Cell Jun 2024In acral melanoma (AM), progression from in situ (AMis) to invasive AM (iAM) leads to significantly reduced survival. However, evolutionary dynamics during this process...
In acral melanoma (AM), progression from in situ (AMis) to invasive AM (iAM) leads to significantly reduced survival. However, evolutionary dynamics during this process remain elusive. Here, we report integrative molecular and spatial characterization of 147 AMs using genomics, bulk and single-cell transcriptomics, and spatial transcriptomics and proteomics. Vertical invasion from AMis to iAM displays an early and monoclonal seeding pattern. The subsequent regional expansion of iAM exhibits two distinct patterns, clonal expansion and subclonal diversification. Notably, molecular subtyping reveals an aggressive iAM subset featured with subclonal diversification, increased epithelial-mesenchymal transition (EMT), and spatial enrichment of APOE/CD163 macrophages. In vitro and ex vivo experiments further demonstrate that APOECD163 macrophages promote tumor EMT via IGF1-IGF1R interaction. Adnexal involvement can predict AMis with higher invasive potential whereas APOE and CD163 serve as prognostic biomarkers for iAM. Altogether, our results provide implications for the early detection and treatment of AM.
Topics: Humans; Melanoma; Epithelial-Mesenchymal Transition; Skin Neoplasms; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Neoplasm Invasiveness; Apolipoproteins E; Macrophages; Male; Female; Receptor, IGF Type 1; Tumor Microenvironment; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Spatial Analysis; Middle Aged; Prognosis; Disease Progression; Aged; Receptors, Cell Surface
PubMed: 38759655
DOI: 10.1016/j.ccell.2024.04.012 -
Journal of Clinical Oncology : Official... May 2024JCO Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over... (Randomized Controlled Trial)
Randomized Controlled Trial
Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression.
JCO Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physician's choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.
Topics: Humans; Triple Negative Breast Neoplasms; Female; Middle Aged; Antigens, Neoplasm; Adult; Receptor, ErbB-2; Antibodies, Monoclonal, Humanized; Cell Adhesion Molecules; Aged; Immunoconjugates; Camptothecin; Progression-Free Survival; Neoplasm Metastasis
PubMed: 38422473
DOI: 10.1200/JCO.23.01409 -
Journal of Clinical Oncology : Official... Mar 2024Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface...
Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of Ac-J591.
PURPOSE
Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225.
METHODS
Following investigational new drug-enabling preclinical studies, we enrolled patients with progressive mCRPC that was refractory to or who refused standard treatment options (including androgen receptor pathway inhibitor and had received or been deemed ineligible for taxane chemotherapy). No selection for PSMA was performed. Patients received a single dose of Ac-J591 at one of seven dose-escalation levels followed by expansion at the highest dose. Primary end point of dose-escalation cohort was determination of dose-limiting toxicity (DLT) and RP2D.
RESULTS
Radiochemistry and animal studies were favorable. Thirty-two patients received Ac-J591 in an accelerated dose-escalation design (22 in dose escalation, 10 in expansion). One patient (1 of 22; 4.5%) experienced DLT in cohort 6 (80 KBq/kg) but none in cohort 7; MTD was not reached, and RP2D was the highest dose level (93.3 KBq/kg). The majority of high-grade adverse events (AEs) were hematologic with an apparent relationship with administered radioactivity. Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: 46.9% had at least 50% PSA decline at any time (34.4% confirmed PSA response), and protocol-defined CTC count response occurred in 13 of 22 (59.1%).
CONCLUSION
To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway.
Topics: Animals; Humans; Male; Androgen Receptor Antagonists; Antibodies, Monoclonal; Antigens, Surface; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome
PubMed: 37922438
DOI: 10.1200/JCO.23.00573 -
European Urology Nov 2023Prostate-specific Membrane Antigen Reporting and Data System (PSMA-RADS) was introduced for standardized reporting, and PSMA-RADS version 1.0 allows classification of...
Prostate-specific Membrane Antigen Reporting and Data System (PSMA-RADS) was introduced for standardized reporting, and PSMA-RADS version 1.0 allows classification of lesions based on their likelihood of representing a site of prostate cancer on PSMA-targeted positron emission tomography (PET). In recent years, this system has extensively been investigated. Increasing evidence has accumulated that the different categories reflect their actual meanings, such as true positivity in PSMA-RADS 4 and 5 lesions. Interobserver agreement studies demonstrated high concordance among a broad spectrum of Ga- or F-labeled, PSMA-directed radiotracers, even for less experienced readers. Moreover, this system has also been applied to challenging clinical scenarios and to assist in clinical decision-making, for example, to avoid overtreatment in oligometastatic disease. Nonetheless, with an increasing use of PSMA-RADS 1.0, this framework has shown not only benefits, but also limitations, for example, for follow-up assessment of locally treated lesions. Thus, we aimed to update the PSMA-RADS framework to include a refined set of categories in order to optimize lesion-level characterization and best assist in clinical decision-making (PSMA-RADS version 2.0).
Topics: Humans; Male; Antigens, Surface; Data Systems; Glutamate Carboxypeptidase II; Positron-Emission Tomography; Prostatic Neoplasms
PubMed: 37414701
DOI: 10.1016/j.eururo.2023.06.008