These cells also exhibited increased mitochondrial mass, particularly within proinflammatory T cell subsets implicated in disease. Together, these findings suggest that T cell-derived TNF-α drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.

P1, N=64, Recruiting, Corvus Pharmaceuticals, Inc. | Not yet recruiting --> Recruiting

P1, N=0, Withdrawn, Ornovi, Inc. | N=128 --> 0 | Trial completion date: Jun 2024 --> Feb 2024 | Not yet recruiting --> Withdrawn | Trial primary completion date: Jun 2024 --> Feb 2024

P1, N=64, Not yet recruiting, Corvus Pharmaceuticals, Inc.

P1, N=151, Active, not recruiting, Corvus Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

Conclusions Our findings reveal a novel immune regulatory mechanism by which the ITK inhibitor soquelitinib induced normal CD4+ Th1 cells and CD8+ TEMRA cells and reduced CD4+ Treg cells in the tumor microenvironment in responding patients. These findings demonstrate the potential of soquelitinib as a novel immunotherapy for the treatment of T-cell lymphomas and solid tumors.

ITK inhibition directly reinvigorate exhausted CTL in vitro as it enhanced cytokine production, decreased inhibitory receptor expression, and downregulated the transcription factor TOX. Our study demonstrates that intermittent ITK inhibition can be used to directly ameliorate CTL exhaustion and enhance immunotherapies even in solid tumors that are ICB resistant.

Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Finally, the relapsed lymphoma cells showed in vitro resistance to standard BTK inhibitors but sensitivity to vecabrutinib, active against mutated BTK, and to PIM1 inhibitor. In summary, we provide in-depth molecular characterization of a case representing leukemic form of DLBCL and discuss mechanisms that may have contributed to lymphoma progression and development of drug resistance.

73 patients had only one BTKi (ibrutinib (IBR), 64; acalabrutinib (ACA), 9). 12 pts had multiple BTKis, 8 with two drugs with IBR first followed by ACA (Nf3, 37.5%), vecabrutinib (Nf1, 12.5%), and PIR (Nf4, 50.0%); and 4 with three or more drugs... Our retrospective report summarizes mutations detected during BTKi treatment and shows that BTK L528W can occur during both covalent and non-covalent BTK inhibitor therapy. Four of six patients who progressed on PIR had T474 mutations. In addition, our results may suggest that activating mutations in RAS/RAF/MAPK pathway are related to BTKi resistance.

No abstract available

BSJ-05-037 displayed enhanced anti-proliferative effects relative to its parent inhibitor BMS-509744, blocked the activation of NF-kB/GATA-3 signaling, and increased the sensitivity of T cell lymphoma cells to cytotoxic chemotherapy both in vitro and in vivo. In summary, targeted degradation of ITK is a novel approach to modulate TCR signal strength that could have broad application for the investigation and treatment of T cell-mediated diseases.

Ibrutinib mediated reversal of CTL exhaustion was BTK independent. To conclude, our study demonstrates that ITK inhibition can be used to directly ameliorate CTLs exhaustion and overcomes immune checkpoint blockade resistance in solid tumors.

A nomogram was finally constructed with good discrimination and calibration. cr-TILCD8TSig is a useful tool to independently predict prognosis, chemotherapy response, and immunotherapy outcomes in patients with breast cancer.

Levels of several exhaustion makers were down-regulated by treatment with CPI-818, suggesting that inhibition of ITK by CPI-818 produces favorable changes in the tumor microenvironment. Our findings provide insights into the effects of selective ITK blockade on tumor immunity and its potential role in immunotherapy.

To determine the role of ITK in CD28-218 phosphorylation: 1) PSCA-specific CAR-T cells were treated with ITK inhibitors 10 μM (BMS-509744 or Ibrutinib) for 24h and 2) ITK-deficient Jurkat cells expressing a PSCA-specific CAR were cocultured with HPAC cells for 0 or 10 min...In vivo, this mutation completely abrogated the therapeutic effect of CAR-T cells in a pancreatic cancer model. In conclusion, these results indicate that ITK is required for CD28-Y218 phosphorylation, a signaling event that plays an important role in CAR-T cell function, with direct impact on IL-2 secretion and antitumor efficacy.

Through the R package pRRophetic, drug sensitivity tests showed that the low-risk score group would benefit more from sunitinib and less from pazopanib, sorafenib, temsirolimus, gemcitabine and doxorubicin than the high-risk score group. We performed the relevant basic assay validation for CPT1B, and the proliferation ability of RCC cells was inhibited after the knockdown of protein expression of CPT1B. In conclusion, we established a four-gene model that can predict outcomes of RCC with potential applications in diagnosis and treatment.

The VEGF inhibitors pazopanib and lenvatinib were tested in the model and were validated by a 3D invasion assay, which demonstrated that changes induced by the carcinogen in spheroids were consistent with a malignant phenotype. In summary, we successfully established a 3D spheroid model of oral carcinogenesis for biomarker discovery and drug testing. This model is a validated preclinical model for OSCC development and would be suitable for testing a range of chemotherapeutic agents.

SLP76 deficiency should be added to the growing list of monogenetic diseases that predispose affected individuals to acquire severe and uncontrolled EBV infections and to develop substantial complications. This case further links mutations in the SLP76 gene to a significant human immunodeficiency and extends its clinical phenotype.

Other TKs are consistently expressed and active in PTCLs, such as PDGFRA, and members of the T-cell receptor signaling family, such as SYK. Notably, as in the case of ALK, STAT proteins have emerged as key downstream factors for most of the involved TK.

Finally, we demonstrated that LINC02154 and our constructed risk signature could predict outcomes and have potential clinical value.

Moreover, pazopanib was able to significantly decrease the VEGF expression in pATC cells (p < 0.05). To conclude, in this study, we demonstrate the antineoplastic activity of the antiangiogenic inhibitor, pazopanib, in human pATC in vitro.

First we screened the AG gene set from GeneCard website, and then performed angiogenesis-related scores (AGS) per cell from single cell sequencing dataset GSE168652, followed by performing weighted gene co-expression network analysis (WGCNA) for cervical cancer patients according to angiogenesis phenotype...Patients in the low-AGS group were more sensitive to AMG.706, Bosutinib, and Lenalidomide while Imatinib, Pazopanib, and Sorafenib were more recommended to patients in the high-AGS group...Meanwhile, the results showed that TXNDC12 promoted the migration of cervical cancer cells and the tubule-forming ability of endothelial cells. In conclusion, our model based on genes with AG features can effectively assess the prognosis of cervical cancer, and can also provide reference for clinicians to choose immune-related treatments.

The patient was later diagnosed with bilateral lung metastases. He was treated with pazopanib, radiation therapy, and cystoprostatectomy and is symptom-free on a 15-month follow-up.

Furthermore, unselective JAK kinase inhibitors (ruxolitinib) inhibited both, TCL progression and granulocyte activation in various PTCL mouse models. Our results support the important role of granulocyte-driven inflammation, cytokine-induced granulocyte/CD4+ TCL interactions and the requirement of an intact JAK/STAT signaling pathway for PTCL-TFH development, and support broad JAK kinase inhibition as an effective treatment strategy in early disease stages.

Oral administration of ASK120067 led to significant tumor regression in B-cell lymphoma and T-cell leukemia xenograft models by weakening Bruton's tyrosine kinase and interleukin-2-inducible T cell kinase signaling, respectively. Taken together, our studies demonstrated that ASK120067 exerted preclinical anti-tumor activities against B-/T-cell malignancy by targeting BTK/ITK.

Finally, we proposed five KG-guided repurposable drug molecules (imatinib, regorafenib, pazopanib, teniposide, and dexrazoxane) for TNBC through network pharmacology and molecular docking analyses. These drug molecules also showed significant binding performance with some cancer-related PTM-sites (phosphorylation, succinylation, and ubiquitination) of top-ranked four key proteins (EGFR, AURKB, BIRC5, and TOP2A). Therefore, the findings of this computational study may play a vital role in early diagnosis and therapies against TNBC by wet-lab validation.

P1, N=62, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2022 --> Oct 2023 | Trial primary completion date: Oct 2022 --> Oct 2023

Administration of pazopanib (10 mg·kg·d, i.p., for 10 days) exerted significant anti-inflammatory and neuronal protective effects, and improved motor abilities impaired by LPS in the mice. Together, we discover a promising candidate compound for anti-neuroinflammation and provide a potential repositioning of pazopanib in the treatment of PD.

A strong expression of PD-L1 was an independent factor of poor prognosis on survival. These results deserve to be confirmed on prospective studies, in order to specify the place of this biomarker to guide the therapeutic strategy in the mutated EGFR CBNPC.

In multivariate analysis the presence of brain metastases and albuminemia <35g/L are predictive of a poorer SG but not the PDL1 status. Conclusion An expression of PDL1 ≥1% seems to be associated with an early increase in the first 6 months of treatment by ITK in the 1st line in the EGFRM CBNPC, but without impact on the SG.

The accuracy, areas under the curve, specificity, sensitivity, positive predictive value, and negative predictive value of the logistic regression model were 0.80, 0.86, 0.89, 0.74, 0.90, and 0.71, respectively. TP53 gene mutations are correlated with radiomic features in lung cancer, which may have application value for TP53 therapy in the future.

This study revealed the effects of CRLs on BCa and further established CRLs model, which can be used in clinic for predicting prognosis, immunological response and treatment sensitivity inpatient with BCa.

In addition, patients with high ENO2 expression showed lower sensitivity to common chemotherapy drugs for ccRCC, including axitinib, cisplatin, gemcitabine, pazopanib, sunitinib, and temsirolimus. Overall, these results suggest that ENO2 is a potential prognosis biomarker of ccRCC and could affect the malignant biological behavior of cancer cells, highlighting its value as a potential therapeutic target.

SA-GA-OCT@PC-mediated combination therapy with PD-L1 blockade agents dramatically suppressed tumor growth and inhibited tumor relapse in B16F10 melanoma mouse models. Overall, the combination of the SA-modified nanocomplex platform and PD-L1 blockade offers a treatment opportunity for IBR in solid tumors, providing novel insights for tumor immunotherapy.

Of note, PI3K inhibition reveals the strongest anti-migratory effect in Daoy cells. Thus, our in vitro observations provide new insights into different strategies of blocking Rac1 and inhibiting migration in medulloblastoma employing clinically available agents paving the way for confirmatory studies in in vivo models.

Furthermore, patients in the high-risk group are more sensitive to targeted therapy or chemotherapy, including bosutinib, elesclomol, lenalidomide, midostaurin, pazopanib and sunitinib, while the low-risk group is more likely to benefit from immunotherapy. Finally, in vitro study confirmed the oncogenic significance of ATG14 in both HCT116 and SW480 cells, whose overexpression increased CRC cell proliferation, colony formation, and migration. In conclusion, we developed a novel mitophagy-related gene signature that can be utilized not only as an independent predictive biomarker but also as a tool for tailoring personalizing treatment for CRC patients, and we confirmed ATG14 as a novel oncogene in CRC.

To characterize acalabrutinib effects on T cell numbers and function in patients with CLL, we analyzed serial samples from 12 acalabrutinib-treated CLL patients at baseline, after 1 week, and after 1, 3, 6, and 12 months of continuous acalabrutinib treatment (with monthly Obinutuzumab added during months 3-9) in an ongoing Phase 2 trial (NCT04505254). Collectively, the reduction in T cells and T helper cell subset numbers, along with changes in surface activation markers, and reduced cytokine and Ki-67 expression suggest that an activated pre-treatment T helper cell compartment normalizes during continuous acalabrutinib therapy. These findings are reminiscent of the T cell data from patients receiving ibrutinib therapy, suggesting that off-target effects of the BTK inhibitor may not dictate T helper cell changes, and these may rather be due to activation by the CLL clone, which diminishes as the underlying disease responds to treatment.

This real-world experience shows overall good tolerability of ACA after prior IBR therapy in pts with CLL. We observed a lower incidence of Afib (17% vs. 10%) and HTN (10% vs.

Here,we generated and comprehensively characterized BTK and PLCG2 mutations conferring resistance to ibrutinib and five different non-covalent BTKi namely pirtobrutinib (LOXO-305), vecabrutinib (SNS-062), nemtabrutinib (ARQ-531), fenebrutinib (GDC-0853), and RN-486. We also found that cells harboring these novel BTK mutations showed differential sensitivity to the covalent vs. non-covalent BTKi. We further demonstrate the potential of venetoclax as follow up treatment upon resistance to non-covalent BTKi.

We conclude that IFITM3 is essential for antigen receptor and oncogenic signaling not only in B cells but also in T cells. These findings identify a novel component of TCR signaling and suggest a shared mechanism for lymphocyte dependency on IFITM3 through scaffolding the lipid PIP3, a mechanism which can be leveraged to amplify oncogenic signaling in T cell malignancies.