These results suggested that POM-1 had synergistic effect with radiotherapy by enhancing cell apoptosis through Bax/Bcl-2 signal pathway in ESCC. The combination of POM-1 and radiotherapy is expected to enhance the anti-tumor effect in ESCC.
HLA-DQ is an HLA class II molecule expressed on APCs. Patients were enrolled May 2020 to Feb 2022 and treated with standard dosing of G/nP (d1, 8, 15) and either TTX-030 40mg/kg followed by 20mg/kg every two weeks (n = 31) or TTX-030 every 2 weeks and budigalimab (anti-PD1 Ab) 500mg every 4 weeks (n = 28). TTX-030 combinations show promising clinical activity in 1L PDAC with HLA-DQhigh having marked benefit. A randomized phase 2 study (NCT06119217) is underway to further evaluate TTX-030 combination treatment based on HLA-DQ status in metastatic PDAC.
Live cell imaging demonstrated PBMC-mediated cytotoxicity against 1B3-transfected tumor cells. These data demonstrate for the first time that miR-193a-3p induces long-term immunity against tumor development via modulation of the tumor microenvironment and induction of immunogenic cell death.
In cynomolgus monkeys, systemically dosed AB598 results in effective enzymatic inhibition in tissues, full peripheral and tissue target engagement, and a reduction in cell surface CD39 both in tissues and in the periphery. Taken together, these data support a promising therapeutic strategy of harnessing the eATP generated by standard-of-care chemotherapies to prime the tumor microenvironment for a productive anti-tumor immune response.
P2, N=16, Terminated, Coherus Biosciences, Inc. | Completed --> Terminated; The study was terminated for strategic reasons, not due to any safety concerns.
ARL67156 activates NK cells through the vav1-Syk signaling pathway to enhance their cytotoxicity against gastric cancer cells, which may serve as a new strategy for NK cell immunotherapy for gastric cancer.
Clinically, high VISTA expression is associated with poor prognosis in patients with NSCLC. Altogether, our data provide deep insight into acquired resistance to RT from an immune perspective and present rational combination strategies.
Assessment of exploratory biomarkers is also planned. A Safety Review Committee will conduct evaluations on an ongoing basis and two interim analyses will be performed.
over 1 year ago
Clinical • P2 data • PD(L)-1 Biomarker • IO biomarker
The expression of CD39 on CD8 T cells in the CK region was higher in cancer tissue than in paracancerous tissue (p = 0.011), and high CD39-expressing CD8 T cells in the CK region (HR, 2.587; p = 0.033) and high CD39-expressing CD8 T cells in the CK region (HR, 3.090; p = 0.008) were independent risk factors for prognosis in ESCC patients; the expression of ENTPD1 was upregulated in ESCC tissues compared to normal tissues (adjusted p < 0.001; log fold change = 1.99), and its expression was significantly positively correlated with the expression of PDCD1, CTLA4, and HAVCR2. High CD39-expressing CD8 T cells can be used as a new molecular marker for the diagnosis and prognosis of ESCC, and the restoration of partially exhausted CD8 T cells by inhibiting CD39 may be a new strategy for treating ESCC.
over 1 year ago
Journal • PD(L)-1 Biomarker • IO biomarker
|
CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
Importantly, inhibition of CD39 augmented in vivo anti-lymphoma effects by therapeutic antibodies including rituximab and daratumumab. Furthermore, the addition of a CD39 inhibitor to anti-CD20 and anti-CD47 combination therapy significantly improved survival in a disseminated model of aggressive B-cell lymphoma, supporting the benefit of dual targeting CD39-mediated eATP hydrolysis and CD47-mediated "don't eat me" signal. Together, preventing eATP degradation may be a potential approach to unleash macrophage-mediated anti-lymphoma immunity.
Furthermore, we found that S3I-201 displayed prominent anti-tumor efficacy in C3H/He OSCC mouse model via inhibiting CD39/CD73-adenosine signal pathway and decreasing MDSCs. These results suggest that STAT3 signal can induce the differentiation of monocytes into MDSCs in tumor microenvironment depending on CD39/CD73-adenosine signal pathway and STAT3 blockade is a promising therapeutic strategy for OSCC.
CD73 expression on human and mouse PDAC tumor cells also protected against DNA damage induced by gemcitabine and irradiation. Moreover, cGAS expression in mouse KPC tumor cells was required for anti-tumor activity of the CD73 inhibitor AB680 in vivo. Our study, thus, illuminates molecular mechanisms whereby CD73 and CD39 seemingly cooperate to promote PDAC progression.
In addition, a significant synergistic effect is observed between CD39i and cisplatin, but the CD39i + anti-PD-L1 (or anti-PD1) strategy does not show any synergistic effects in the BC model. Our results confirm that CD39 is a potential target for the immune therapy of BC.
Targeting the Ado pathway has recently been reported to improve Durvalumab (D) efficacy in early-stage NSCLC patients, through the use of Oleclumab, an anti-CD73 mAb...Finally, in vivo, in a mouse tumor model engrafted in huCD39KI mice, moIPH5201 improved the anti-tumor efficacy of gemcitabine and anti-PD-L1 combination. Conclusions IPH5201 was shown to block CD39 enzymatic activity, to lower Ado and increase ATP levels in the TME and finally to improve anti-tumor efficacy in preclinical models. Altogether, the expression profile of CD39 in early stage NSCLC and preclinical combination data support the clinical evaluation of IPH5201 in combination with D and CT in early stage NSCLC patients.
Radiation and CD39 inhibition-induced ICD of glioma stem cells as a vaccine enhance CAR-T expansion in peripheral blood, multifunctionality in the TME, and antitumor effect in a glioma model. The multispecificity of CAR-T cells, targeting CAR and tumor antigens, vastly enhances the function of conventional CAR-T cells, stimulates a native immune response, and overcomes obstacles of specific antigen loss or low expression of target cells in antitumor therapy.
2 years ago
Journal • CAR T-Cell Therapy • IO biomarker
|
IRF1 (Interferon Regulatory Factor 1) • STAT1 (Signal Transducer And Activator Of Transcription 1) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1) • NLRP3 (NLR Family Pyrin Domain Containing 3)
Results Real-time measurement of ATP showed the ability of oxaliplatin to induce ATP release in MC38 tumor cells in vitro . Relative percentages of the immune cells in the lymph nodes were unaffected, suggesting internalization or downregulation, not cellular depletion, as the mechanism for the decrease in cell-surface CD39. Conclusions Our results indicate the superb ability of AB598 to inhibit enzymatic activity and tumor growth in vivo and provide a rationale for the combination of CD39 inhibition with ICD-inducing chemotherapy in the clinic.
Additionally, numerous exhaustion markers such as LAG3, TIGIT, and CTLA4 were decreased on tumor in comparison to peripheral blood (p < 0.01). These results demonstrate the complex nature of immune signaling in GBM tumor microenvironment that our team continues to investigate.
2 years ago
PD(L)-1 Biomarker • IO biomarker
|
LAG3 (Lymphocyte Activating 3) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
CD39 inhibition might contribute to the effects of the powerful anticancer drug ceritinib. Ceritinib is a novel CD39 inhibitor with high metabolic stability and optimized physicochemical properties; according to our knowledge, it is the first brain-permeant CD39 inhibitor. Our discovery will provide the basis (i) to develop more potent and balanced dual CD39/ALK inhibitors, and (ii) to optimize the ceritinib scaffold towards interaction with CD39 to obtain potent and selective drug-like CD39 inhibitors for future in vivo studies.
Restraining the function of NAMPT resulted in the functional improvement of effector CD8+ T cells by decreasing extracellular adenosine levels and inducing apoptosis of GC cells simultaneously. Therefore, this study demonstrates that NAMPT can be an effective target for gastric cancer immunotherapy.
The designed POL can effectively inhibit the growth of in situ, lung metastasis and postoperative recurrence melanoma model and form long-term immune memory. With the powerful clinical transformation potential of nanoliposome platforms, this new synergistic strategy is expected to enhance anticancer effects safely and effectively.
Accordingly, CD39 enzymatic inhibition enhances SS cells viability and IL-2 production upon activation. These results strongly suggest a special caution for SS treatment with therapeutic inhibitors of CD39.