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Journal For Immunotherapy of Cancer Jul 2024Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood...
BACKGROUND
Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation.
METHODS
We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice.
RESULTS
Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer.
CONCLUSION
Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.
Topics: Animals; Mice; Antigens, CD19; Interleukin-15; Immunotherapy, Adoptive; Humans; Disease Models, Animal; Cell Line, Tumor; Female; Interleukin-15 Receptor alpha Subunit; Receptors, Chimeric Antigen; Lymphoma; Mice, Inbred BALB C; T-Lymphocytes
PubMed: 38955421
DOI: 10.1136/jitc-2023-008572 -
Journal For Immunotherapy of Cancer Jul 2024Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and...
BACKGROUND
Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking.
METHODS
We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis.
RESULTS
Overall, NRs exhibited drastically lower CD8, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3).
CONCLUSIONS
These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.
Topics: Humans; Female; Immune Checkpoint Inhibitors; Endometrial Neoplasms; DNA Mismatch Repair; Tumor Microenvironment; Middle Aged; Aged
PubMed: 38955419
DOI: 10.1136/jitc-2024-009143 -
Journal For Immunotherapy of Cancer Jul 2024Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in...
Extensive-stage small-cell lung cancer in patients receiving atezolizumab plus carboplatin-etoposide: stratification of outcome based on a composite score that combines gene expression profiling and immune characterization of microenvironment.
PURPOSE
Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need.
EXPERIMENTAL DESIGN
Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin-etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed.
RESULTS
42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups.
CONCLUSIONS
In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients.
Topics: Humans; Carboplatin; Lung Neoplasms; Male; Antibodies, Monoclonal, Humanized; Female; Small Cell Lung Carcinoma; Tumor Microenvironment; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Aged; Middle Aged; Gene Expression Profiling; Adult; Neoplasm Staging
PubMed: 38955418
DOI: 10.1136/jitc-2024-008974 -
Bioscience, Biotechnology, and... Jul 2024Poly-γ-glutamic acid (PGA) has been of interest as a sustainable biopolymer in industrial applications. PGA biosynthesis in Bacillus subtilis is catalyzed by a...
Poly-γ-glutamic acid (PGA) has been of interest as a sustainable biopolymer in industrial applications. PGA biosynthesis in Bacillus subtilis is catalyzed by a transmembrane protein complex comprising PgsB, PgsC, and PgsA. To determine the Pgs component responsible for PGA overproduction, we constructed recombinants in which the promoter of the host-derived pgs gene was replaced with another host-derived gene promoter. These recombinants were then transformed using high-copy-number plasmids with various pgs-gene combinations to enhance Pgs component in different ratios. Subsequently, PGA production was investigated in batch cultures with l-glutamate supplemented medium. The recombinant strain enhanced with pgsB alone significantly overproduced PGA (maximum production 35.8 gL-1) than either the pgsC- or pgsA-enhanced strain. The molecular weight of the PGA produced with pgsB-enhanced strain was also greater than the pgsC- or pgsA-enhanced strain (approximately 10-fold). Hence, PgsB enhancement alone contributes to PGA overproduction with increased molecular weight.
PubMed: 38955395
DOI: 10.1093/bbb/zbae093 -
Metallomics : Integrated Biometal... Jul 2024Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized...
Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized two new Ir(III) complexes, [Ir(L1)(bppy)2] (Br-Ir) and [Ir(L2)(bppy)2] (Cl-Ir), with 5,7-dibromo-2-methyl-8-hydroxyquinoline (HL-1) or 5,7-dichloro-2-methyl-8-hydroxyquinoline (HL-2) as the primary ligand. Complexes Br-Ir and Cl-Ir successfully inhibited antitumor activity in Hep-G2 cells. In addition, complexes Br-Ir and Cl-Ir were localized in the mitochondrial membrane and caused mitochondrial damage, autophagy, and cellular immunity in Hep-G2 cells. We tested the proteins related to mitochondrial and mitophagy by western blot analysis, which showed that they triggered mitophagy-mediated apoptotic cell death. Remarkably, complex Br-Ir showed high in vivo antitumor activity, and the tumor growth inhibition rate (IR) was 63.0% (p <0.05). In summary, our study on complex Br-Ir revealed promising results in in vitro and in vivo antitumor activity assays.
PubMed: 38955388
DOI: 10.1093/mtomcs/mfae032 -
BMJ Case Reports Jul 2024A woman in her 30s presented with a 12-month history of reduced mouth opening and swelling on the right side of her mandible. The swelling was non-tender and firm on...
A woman in her 30s presented with a 12-month history of reduced mouth opening and swelling on the right side of her mandible. The swelling was non-tender and firm on palpation. The swelling began to increase in size after the extraction of her carious wisdom tooth. Histopathological and serological examinations confirmed the diagnosis of IgG4-related disease, manifested as a mass in the mandible. The patient was prescribed oral corticosteroids at a tapering dosage over 8 weeks. After 3 months, there was an improvement in the patient's mouth opening and a reduction in the size of the swelling. The patient remains in follow-up care. Including IgG4-related disease in the list of potential diagnoses for oral soft tissue masses is crucial, given their positive response to medical treatment, highlighting the significance of an accurate diagnosis to prevent unnecessary surgery, with oral lesions potentially serving as early indicators before multiorgan complications arise.
Topics: Humans; Trismus; Female; Immunoglobulin G4-Related Disease; Adult; Diagnosis, Differential; Mandibular Diseases; Mandible; Immunoglobulin G
PubMed: 38955385
DOI: 10.1136/bcr-2024-260749 -
BMJ Case Reports Jul 2024Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive disease caused by mutation in proteoglycan 4 (PRG4) gene on chromosome...
Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive disease caused by mutation in proteoglycan 4 (PRG4) gene on chromosome 1q25-q31. We faced a dilemma and delay in diagnosis in two sisters. The elder sister had pericardial effusion with constrictive pericarditis, underwent pericardiectomy and received empirical treatment for suspected tuberculosis. After 2 years, she developed bilateral knee swelling with restriction of movement. At the same time, her younger sister also presented with bilateral knee swelling which aroused the suspicion of genetic disease. The whole-genome sequencing revealed homozygous PRG4 mutation suggestive of CACP syndrome.
Topics: Humans; Female; Coxa Vara; Proteoglycans; Hand Deformities, Congenital; Arthropathy, Neurogenic; Pericardial Effusion; Upper Extremity Deformities, Congenital; Pericarditis, Constrictive; Lower Extremity Deformities, Congenital; Pericardiectomy; Mutation; Diagnosis, Differential; Synovitis
PubMed: 38955384
DOI: 10.1136/bcr-2024-260146 -
International Journal of Gynecological... Jul 2024Molecular features are essential for estimating the risk of recurrence and impacting overall survival in patients with endometrial cancer. Additionally, the surgical...
OBJECTIVE
Molecular features are essential for estimating the risk of recurrence and impacting overall survival in patients with endometrial cancer. Additionally, the surgical procedure itself could be personalized based on the molecular characteristics of the tumor. This study aims to assess the feasibility of obtaining reliable molecular classification status from biopsy specimens collected during hysteroscopy to better modulate the appropriate surgical treatment.
METHODS
This monocentric, retrospective, observational study was conducted on 106 patients who underwent a biopsy procedure followed by radical surgery for endometrial cancer, with concurrent molecular investigation. The molecular classification was determined through immunohistochemical staining for p53 and mismatch repair proteins, along with gene sequencing for POLE.
RESULTS
Overall, 106 patients underwent molecular investigation, which was finally achieved on 99 patients (93.4%). Among these, the molecular analysis was conducted in 71 patients (67%) on the pre-operative endometrial biopsy and on the final uterine specimen in 28 patients (26.4%). Most of the endometrial biopsies were performed using Bettocchi hysteroscopy (66%). Molecular analysis was not possible in seven patients (6.6%), with six cases due to sample inadequacy and one case attributed to intra-mucosal carcinoma. The molecular results showed that the copy number low sub-group was the most common, and five cases of 'multiple classifiers' were observed in the low-risk category.
CONCLUSION
Our experience in obtaining molecular information from biopsy samples underscores the feasibility and efficacy of this technique, even in small tissue samples. This capability helps define the prognostic group of patients, facilitates timely decision-making, and develops a personalized strategy for each patient.
PubMed: 38955372
DOI: 10.1136/ijgc-2024-005478 -
Journal of Agricultural and Food... Jul 2024In recent years, there has been a growing interest in the pure casein fraction of milk protein, particularly β-casein due to its physicochemical properties as well as... (Review)
Review
In recent years, there has been a growing interest in the pure casein fraction of milk protein, particularly β-casein due to its physicochemical properties as well as its bio- and techno-functional properties. The utilization of self-assembled β-caseins from bovine origin as nanocarriers for the delivery of nutraceutical compounds or drugs has increased dramatically. Concerning β-caseins from other milk sources, the use of hypoallergenic donkey β-caseins as a potential delivery vehicle for nutraceutical hydrophobic compounds is beginning to generate interest. The present review deals with casein micelles models, bovine and donkey β-casein molecular structures, as well as their physical-chemical properties that account for their exploitation in nutraceutics and pharmaceutics. This review work suggests the possibility of developing delivery systems for hydrophobic bioactive compounds using β-casein purified from hypoallergenic donkey milk, highlighting the potential of this protein as an innovative and promising vehicle for enhancing the enrichment and bioavailability of various bioactive substances in food products.
PubMed: 38955361
DOI: 10.1021/acs.jafc.4c02052 -
International Journal of Hyperthermia :... 2024Cryoablation (Cryo) is a minimally invasive treatment for tumors. Cryo can activate the body's immune response, although it is typically weak. The immune response...
BACKGROUND
Cryoablation (Cryo) is a minimally invasive treatment for tumors. Cryo can activate the body's immune response, although it is typically weak. The immune response induced by Cryo in hepatocellular carcinoma (HCC) is poorly understood. PD-1 and CTLA-4 monoclonal antibodies are immune checkpoint inhibitors used in immunotherapy for tumors. The combined use of these antibodies with Cryo may enhance the immune effect.
METHODS
A Balb/c mouse model of HCC was established and treated with Cryo, immune checkpoint blockade (ICB), or Cryo + ICB (combination therapy). The growth trend of right untreated tumors and survival time of mice were determined. The expression of apoptosis-related proteins was detected by Western blot (WB) assay. The percentages of immune cells and immunosuppressive cells were analyzed by flow cytometry. The numbers of infiltrating T lymphocytes were checked by immunohistochemistry, and the levels of T-cell-associated cytokines were detected by Quantitative real-time Polymerase Chain Reaction (qRT-PCR) assays and Enzyme-Linked Immunosorbent Assays (ELISA) assays.
RESULTS
Cryo + ICB inhibited the growth of right untreated tumors, promoted tumor cell apoptosis, and prolonged the survival time of mice. Local T-cell infiltration in right tumor tissues increased after the combination therapy, while the number of immunosuppressive cells was significantly reduced. In addition, the combination therapy may induce the production of multiple Th1-type cytokines but reduce the production of Th2-type cytokines.
CONCLUSIONS
Cryo can activate CD8 and CD4 T-cell immune responses. Cryo + ICB can relieve the immunosuppressive tumor microenvironment and shift the Th1/Th2 balance toward Th1 dominance, further enhancing the Cryo-induced T-cell immune response and resulting in a stronger antitumor immune response.
Topics: Animals; Carcinoma, Hepatocellular; Mice; Liver Neoplasms; Cryosurgery; Mice, Inbred BALB C; Immune Checkpoint Inhibitors; Disease Models, Animal; Cell Line, Tumor
PubMed: 38955354
DOI: 10.1080/02656736.2024.2373319