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Cell Aug 2023Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential...
Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune evasion of T cell immunity involving aberrant major histocompatibility complex class I (MHC-I) antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR-Cas9 screens in AML. The top-ranked negative regulators were surface protein sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in a CD8 T cell-dependent manner. Mechanistically, SUSD6 forms a trimolecular complex with TMEM127 and MHC-I, which recruits WWP2 for MHC-I ubiquitination and lysosomal degradation. Together with the SUSD6/TMEM127/WWP2 gene signature, which negatively correlates with cancer survival, our findings define a membrane-associated MHC-I inhibitory axis as a potential therapeutic target for both leukemia and solid cancers.
Topics: Humans; Antigen Presentation; CD8-Positive T-Lymphocytes; Histocompatibility Antigens Class I; HLA Antigens; Neoplasms; Ubiquitin-Protein Ligases; Tumor Escape
PubMed: 37557169
DOI: 10.1016/j.cell.2023.07.016 -
Journal of Clinical Oncology : Official... Oct 2023This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel...
First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.
PURPOSE
This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS
Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics.
RESULTS
Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. This population had a median of three prior lines of therapy. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the recommended dose for further development was 6 mg/kg once every 3 weeks. In patients receiving 6 mg/kg (n = 50), median duration on study, including follow-up, and median exposure were 13.3 and 3.5 months, respectively. The most frequent any-grade treatment-emergent adverse events (TEAEs) were nausea (64%), stomatitis (60%), and alopecia (42%). Grade ≥3 TEAEs and treatment-related AEs occurred in 54% and 26% of patients, respectively. Interstitial lung disease adjudicated as drug-related (two grade 2 and one grade 4) occurred in three of 50 patients (6%). The ORR was 26% (95% CI, 14.6 to 40.3), and median duration of response was 10.5 months; median progression-free survival and overall survival were 6.9 months (95% CI, 2.7 to 8.8 months) and 11.4 months (95% CI, 7.1 to 20.6 months), respectively. Responses occurred regardless of TROP2 expression.
CONCLUSION
Promising antitumor activity and a manageable safety profile were seen with Dato-DXd in heavily pretreated patients with advanced NSCLC. Further investigation as first-line combination therapy in advanced NSCLC and as monotherapy in the second-line setting and beyond is ongoing.
Topics: Adult; Humans; Carcinoma, Non-Small-Cell Lung; Immunoconjugates; Trophoblasts; Antibodies, Monoclonal, Humanized; Lung Neoplasms; Antineoplastic Agents; Antigens, Surface
PubMed: 37327461
DOI: 10.1200/JCO.23.00059 -
Immunology Jul 2023The cell surface antigen CD14 is primarily understood to act as a co-receptor for toll-like receptors (TLRs) to activate innate immunity responses to pathogens and... (Review)
Review
The cell surface antigen CD14 is primarily understood to act as a co-receptor for toll-like receptors (TLRs) to activate innate immunity responses to pathogens and tissue injury in macrophages and monocytes. However, roles for CD14 are increasingly being uncovered in disease responses in epithelial and endothelial cells. Consistent with these broader functions, CD14 expression is altered in a variety of non-immune cell types in response to a several of disease states. Moreover, soluble CD14 activated by factors from both pathogens and tissue damage may initiate signalling in a variety of non-immune cells. This review examined the current understanding CD14 in innate immunity as well as its potential functions in nonimmune cells and associated human diseases.
Topics: Humans; Endothelial Cells; Toll-Like Receptor 4; Lipopolysaccharides; Toll-Like Receptors; Macrophages; Lipopolysaccharide Receptors
PubMed: 36840585
DOI: 10.1111/imm.13634 -
Immunity Oct 2023Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has achieved tremendous success treating B cell malignancies; however, some patients fail to respond due...
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has achieved tremendous success treating B cell malignancies; however, some patients fail to respond due to poor autologous T cell fitness. To improve response rates, we investigated whether disruption of the co-inhibitory receptors CTLA4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion of CTLA4 in preclinical models of leukemia and myeloma improved CAR T cell proliferation and anti-tumor efficacy. Importantly, this effect was specific to CTLA4 and not seen upon deletion of CTLA4 and/or PDCD1 in CAR T cells. Mechanistically, CTLA4 deficiency permitted unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under conditions of high antigen load. In clinical studies, deletion of CTLA4 rescued the function of T cells from patients with leukemia that previously failed CAR T cell treatment. Thus, selective deletion of CTLA4 reinvigorates dysfunctional chronic lymphocytic leukemia (CLL) patient T cells, providing a strategy for increasing patient responses to CAR T cell therapy.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; CTLA-4 Antigen; T-Lymphocytes; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Antigens, CD19
PubMed: 37776850
DOI: 10.1016/j.immuni.2023.09.001 -
Molecular Cancer Dec 2023The molecules of Major histocompatibility class I (MHC-I) load peptides and present them on the cell surface, which provided the immune system with the signal to detect... (Review)
Review
The molecules of Major histocompatibility class I (MHC-I) load peptides and present them on the cell surface, which provided the immune system with the signal to detect and eliminate the infected or cancerous cells. In the context of cancer, owing to the crucial immune-regulatory roles played by MHC-I molecules, the abnormal modulation of MHC-I expression and function could be hijacked by tumor cells to escape the immune surveillance and attack, thereby promoting tumoral progression and impairing the efficacy of cancer immunotherapy. Here we reviewed and discussed the recent studies and discoveries related to the MHC-I molecules and their multidirectional functions in the development of cancer, mainly focusing on the interactions between MHC-I and the multiple participators in the tumor microenvironment and highlighting the significance of targeting MHC-I for optimizing the efficacy of cancer immunotherapy and a deeper understanding of the dynamic nature and functioning mechanism of MHC-I in cancer.
Topics: Humans; Histocompatibility Antigens Class I; Neoplasms; Immunotherapy; Cell Membrane; Tumor Microenvironment
PubMed: 38041084
DOI: 10.1186/s12943-023-01899-4 -
Cancer Immunology, Immunotherapy : CII Sep 2023The use of treatments, such as programmed death protein 1 (PD1) or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies, that loosen the natural checks upon... (Review)
Review
The use of treatments, such as programmed death protein 1 (PD1) or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies, that loosen the natural checks upon immune cell activity to enhance cancer killing have shifted clinical practice and outcomes for the better. Accordingly, the number of antibodies and engineered proteins that interact with the ligand-receptor components of immune checkpoints continue to increase along with their use. It is tempting to view these molecular pathways simply from an immune inhibitory perspective. But this should be resisted. Checkpoint molecules can have other cardinal functions relevant to the development and use of blocking moieties. Cell receptor CD47 is an example of this. CD47 is found on the surface of all human cells. Within the checkpoint paradigm, non-immune cell CD47 signals through immune cell surface signal regulatory protein alpha (SIRPα) to limit the activity of the latter, the so-called trans signal. Even so, CD47 interacts with other cell surface and soluble molecules to regulate biogas and redox signaling, mitochondria and metabolism, self-renewal factors and multipotency, and blood flow. Further, the pedigree of checkpoint CD47 is more intricate than supposed. High-affinity interaction with soluble thrombospondin-1 (TSP1) and low-affinity interaction with same-cell SIRPα, the so-called cis signal, and non-SIRPα ectodomains on the cell membrane suggests that multiple immune checkpoints converge at and through CD47. Appreciation of this may provide latitude for pathway-specific targeting and intelligent therapeutic effect.
Topics: Humans; CD47 Antigen; Antigens, Differentiation; Receptors, Immunologic; Neoplasms; Antibodies; Carrier Proteins; Phagocytosis
PubMed: 37217603
DOI: 10.1007/s00262-023-03465-9 -
Nature Sep 2023Certain bacterial strains from the microbiome induce a potent, antigen-specific T cell response. However, the specificity of microbiome-induced T cells has not been...
Certain bacterial strains from the microbiome induce a potent, antigen-specific T cell response. However, the specificity of microbiome-induced T cells has not been explored at the strain level across the gut community. Here, we colonize germ-free mice with complex defined communities (roughly 100 bacterial strains) and profile T cell responses to each strain. The pattern of responses suggests that many T cells in the gut repertoire recognize several bacterial strains from the community. We constructed T cell hybridomas from 92 T cell receptor (TCR) clonotypes; by screening every strain in the community against each hybridoma, we find that nearly all the bacteria-specific TCRs show a one-to-many TCR-to-strain relationship, including 13 abundant TCR clonotypes that each recognize 18 Firmicutes. By screening three pooled bacterial genomic libraries, we discover that these 13 clonotypes share a single target: a conserved substrate-binding protein from an ATP-binding cassette transport system. Peripheral regulatory T cells and T helper 17 cells specific for an epitope from this protein are abundant in community-colonized and specific pathogen-free mice. Our work reveals that T cell recognition of commensals is focused on widely conserved, highly expressed cell-surface antigens, opening the door to new therapeutic strategies in which colonist-specific immune responses are rationally altered or redirected.
Topics: Animals; Mice; Antigens, Surface; Bacteria; Firmicutes; Gastrointestinal Microbiome; T-Lymphocytes, Regulatory; Th17 Cells; T-Lymphocytes; Symbiosis; Germ-Free Life; Receptors, Antigen, T-Cell; Hybridomas; Cell Separation
PubMed: 37587342
DOI: 10.1038/s41586-023-06431-8 -
Journal of Nanobiotechnology Nov 2023Pancreatic cancer is a highly aggressive malignancy with limited treatment options and a poor prognosis. Trophoblast cell surface antigen 2 (TROP2), a cell surface...
BACKGROUND
Pancreatic cancer is a highly aggressive malignancy with limited treatment options and a poor prognosis. Trophoblast cell surface antigen 2 (TROP2), a cell surface antigen overexpressed in the tumors of more than half of pancreatic cancer patients, has been identified as a potential target for antibody-drug conjugates (ADCs). Almost all reported TROP2-targeted ADCs are of the IgG type and have been poorly studied in pancreatic cancer. Here, we aimed to develop a novel nanobody-drug conjugate (NDC) targeting TROP2 for the treatment of pancreatic cancer.
RESULTS
In this study, we developed a novel TROP2-targeted NDC, HuNb-MMAE, for the treatment of TROP2-positive pancreatic cancer. HuNb-MMAE is characterized by the use of nanobodies against TROP2 and human serum albumin (HSA) and has a drug-antibody ratio of 1. HuNb-MMAE exhibited specific binding to TROP2 and was internalized into tumor cells with high endocytosis efficiency within 5 h, followed by intracellular translocation to lysosomes and release of MMAE to induce cell apoptosis in TROP2-positive pancreatic cancer cells through the caspase-3/9 pathway. In a xenograft model of pancreatic cancer, doses of 0.2 mg/kg and 1 mg/kg HuNb-MMAE demonstrated significant antitumor effects, and a dose of 5 mg/kg even eradicated the tumor.
CONCLUSION
HuNb-MMAE has desirable affinity, internalization efficiency and antitumor activity. It holds significant promise as a potential therapeutic option for the treatment of TROP2-positive pancreatic cancer.
Topics: Humans; Antigens, Surface; Cell Line, Tumor; Immunoconjugates; Pancreatic Neoplasms; Xenograft Model Antitumor Assays; Animals
PubMed: 37932752
DOI: 10.1186/s12951-023-02183-9 -
Journal of Hepatology Oct 2023Current therapy for chronic hepatitis B virus (cHBV) infection involves lifelong treatment. New treatments that enable HBV functional cure would represent a clinically...
BACKGROUND & AIMS
Current therapy for chronic hepatitis B virus (cHBV) infection involves lifelong treatment. New treatments that enable HBV functional cure would represent a clinically meaningful advance. ALN-HBV and VIR-2218 are investigational RNA interference therapeutics that target all major HBV transcripts.
METHODS
We report on: i) the safety of single doses of VIR-2218 (modified from ALN-HBV by enhanced stabilization chemistry plus technology to reduce off-target, seed-mediated binding while maintaining on-target antiviral activity) and ALN-HBV in humanized mice; ii) a cross-study comparison of the safety of single doses of VIR-2218 and ALN-HBV in healthy human volunteers (n = 24 and n = 49, respectively); and iii) the antiviral activity of two doses of 20, 50, 100, 200 mg of VIR-2218 (total n = 24) vs. placebo (n = 8), given 4 weeks apart, in participants with cHBV infection.
RESULTS
In humanized mice, alanine aminotransferase (ALT) levels were markedly lower following administration of VIR-2218 compared with ALN-HBV. In healthy volunteers, post-treatment ALT elevations occurred in 28% of participants receiving ALN-HBV compared with none in those receiving VIR-2218. In participants with cHBV infection, VIR-2218 was associated with dose-dependent reductions in hepatitis B surface antigen (HBsAg). The greatest mean reduction of HBsAg at Week 20 in participants receiving 200 mg was 1.65 log IU/ml. The HBsAg reduction was maintained at 0.87 log IU/ml at Week 48. No participants had serum HBsAg loss or hepatitis B surface antibody seroconversion.
CONCLUSIONS
VIR-2218 demonstrated an encouraging hepatic safety profile in preclinical and clinical studies as well as dose-dependent HBsAg reductions in patients with cHBV infection. These data support future studies with VIR-2218 as part of combination regimens with a goal of HBV functional cure.
TRIAL REGISTRATION
ClinicalTrials.gov identifiers: NCT02826018 and NCT03672188.
IMPACT AND IMPLICATIONS
A significant unmet need exists for therapies for chronic HBV (cHBV) infection that achieve functional cure. We report clinical and non-clinical data on two investigational small-interfering RNAs that target HBx, ALN-HBV and VIR-2218, demonstrating that incorporation of enhanced stabilization chemistry plus technology in VIR-2218 reduces its propensity to cause ALT elevations relative to its parent compound, ALN-HBV. We also show that VIR-2218 reduces hepatitis B surface antigen levels in a dose-dependent manner in participants with cHBV infection. These studies support the continued development of VIR-2218 as part of therapeutic regimens for cHBV infection, with the goal of a functional cure, and are important for HBV researchers and physicians.
Topics: Humans; Animals; Mice; Hepatitis B, Chronic; Hepatitis B virus; Hepatitis B Surface Antigens; RNAi Therapeutics; Randomized Controlled Trials as Topic; Antiviral Agents; DNA, Viral; Hepatitis B e Antigens; Hepatitis B
PubMed: 37290591
DOI: 10.1016/j.jhep.2023.05.023