scholarly journals Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Megan M. Tu ◽  
Hany A. Abdel-Hafiz ◽  
Robert T. Jones ◽  
Annie Jean ◽  
Katelyn J. Hoff ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Response ◽  
Multiple Cancer ◽  
Cell Recruitment ◽  
Multiple Tumor ◽  
Area Of Interest ◽  
Signaling Axis ◽  
Metastasis Models ◽  
Cancer Types ◽  
Tumor Types

AbstractImmunotherapies targeting the PD-1/PD-L1 axis are now a mainstay in the clinical management of multiple cancer types, however, many tumors still fail to respond. CCL2 is highly expressed in various cancer types and has been shown to be associated with poor prognosis. Inhibition or blockade of the CCL2/CCR2 signaling axis has thus been an area of interest for cancer therapy. Here we show across multiple murine tumor and metastasis models that CCR2 antagonism in combination with anti-PD-1 therapy leads to sensitization and enhanced tumor response over anti-PD-1 monotherapy. We show that enhanced treatment response correlates with enhanced CD8+ T cell recruitment and activation and a concomitant decrease in CD4+ regulatory T cell. These results provide strong preclinical rationale for further clinical exploration of combining CCR2 antagonism with PD-1/PD-L1-directed immunotherapies across multiple tumor types especially given the availability of small molecule CCR2 inhibitors and antibodies.

scholarly journals RNA Exosome Component EXOSC4 Amplified in Multiple Cancer Types Is Required for the Cancer Cell Survival

2022 ◽  
Vol 23 (1) ◽  
pp. 496
Author(s):  
Kenzui Taniue ◽  
Tanzina Tanu ◽  
Yuki Shimoura ◽  
Shuhei Mitsutomi ◽  
Han Han ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Viability ◽  
The Cancer Genome Atlas ◽  
Multiple Cancer ◽  
Pancreatic Cancer Cells ◽  
Cancer Cell Survival ◽  
Cellular Machinery ◽  
Cancer Types ◽  
Rna Exosome ◽  
Tumor Types

The RNA exosome is a multi-subunit ribonuclease complex that is evolutionally conserved and the major cellular machinery for the surveillance, processing, degradation, and turnover of diverse RNAs essential for cell viability. Here we performed integrated genomic and clinicopathological analyses of 27 RNA exosome components across 32 tumor types using The Cancer Genome Atlas PanCancer Atlas Studies’ datasets. We discovered that the EXOSC4 gene, which encodes a barrel component of the RNA exosome, was amplified across multiple cancer types. We further found that EXOSC4 alteration is associated with a poor prognosis of pancreatic cancer patients. Moreover, we demonstrated that EXOSC4 is required for the survival of pancreatic cancer cells. EXOSC4 also repressed BIK expression and destabilized SESN2 mRNA by promoting its degradation. Furthermore, knockdown of BIK and SESN2 could partially rescue pancreatic cells from the reduction in cell viability caused by EXOSC4 knockdown. Our study provides evidence for EXOSC4-mediated regulation of BIK and SESN2 mRNA in the survival of pancreatic tumor cells.

Distribution of ETV6-NTRK3 translocations across neoplasms identified from the Mitelman Database.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23141-e23141
Author(s):  
Juan Carlos Malpartida ◽  
Eric Vick ◽  
Noah Hunter Richardson ◽  
Kruti Patel ◽  
Matthew K Stein ◽  
...  
Keyword(s):  
Ductal Carcinoma ◽  
Tumor Type ◽  
Invasive Adenocarcinoma ◽  
Data Set ◽  
Oncogenic Potential ◽  
Multiple Tumor ◽  
Cancer Types ◽  
Mitelman Database ◽  
Tumor Types ◽  
Tumor Profiling

e23141 Background: Discovered as a novel aberration in congenital fibrosarcoma (CF), the ETV6-NTRK3 translocation (EN) confers oncogenic potential and is inhibited by crizotinib. The present study aims to survey the scope of neoplasms that harbor EN across tumor types. Methods: Utilizing the National Cancer Institute’s Mitelman Database (MD) of Chromosome Aberrations and Gene Fusions patients (pts) were identified with EN and categorized based on tumor type, subtype and incidence. Cancer pts who received tumor profiling with Caris were also surveyed for EN. Results: 47 pts with EN across 12 cancer types were extracted from the MD and had median age of 0.17 years (7 unreported); 38% male; 51% acquired malignancies, 49% congenital; 62% cases were pediatric, 23% adult and 15% unknown. 0/204 pts with Caris tumor profiling were found to have an EN. Cancers with the highest number of EN were: 15 (31.9% EN data set) congenital mesoblastic nephromas (CMN), 10 (21.3%) CF, 7 (14.9%) breast carcinoma (BC; 6 secretory ductal carcinoma (SD) and 1 invasive adenocarcinoma (IA)) and 3 (6.4%) colorectal carcinoma (CRC). EN were found in 8 other malignancies (Table 1). Cancer types with the highest incidence of EN+ cases in the MD were gastrointestinal stromal tumor (GIST; 100%), CMN (75%) and CF (23.3%). Conclusions: These results further our understanding of the distribution of ETV6-NTRK3 translocations in multiple tumor types across the age spectrum and suggest that pts with CMN, CF, BC and CRC requiring high order therapy should be considered for NTRK3-based treatment. [Table: see text]

scholarly journals Suppressing immunotherapy by organ-specific tumor microenvironments: what is in the brain?

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chenyu Zhang ◽  
Dihua Yu
Keyword(s):  
Immune Checkpoint Blockade ◽  
Multiple Cancer ◽  
Tissue Specific ◽  
Tumor Microenvironments ◽  
Specific Tumor ◽  
Organ Specific ◽  
Metastasis Models ◽  
Cancer Types ◽  
The Impact ◽  
The Brain

Abstract Recent breakthroughs in cancer immunotherapy have led to curative efficacy and significantly prolonged survival in a subset of patients of multiple cancer types; and immunotherapy has become the newest pillar of cancer treatment in addition to surgery, chemotherapy, radiotherapy and precision targeted therapies. In the metastatic disease setting, responses to immunotherapy are heterogeneous depending on the metastatic organ sites. The tissue-specific immuno-biology in the tumor microenvironments (TMEs) contributes to the differential therapeutic responses. Herein, we review the impact of tissue-specific tumor microenvironment on the efficacy of immunotherapy, with a focus on historically under-represented central nervous system (CNS) metastasis, which was excluded from most clinical trials. Retrospective examination of patient specimens and prospective clinical studies with immune checkpoint blockade (ICB) have established that brain can harbor an “active” immune microenvironment for effective immunotherapy. Regulation by the innate immune microglial cells and remodeling of the blood–brain barrier (BBB) may contribute to immunotherapeutic responses mediated by T lymphocytes. How to convert an “inactive” (cold) brain microenvironment into an “active” (hot) brain TME should be the focus of future efforts. Thus, procurement and complete examination of clinical specimens from brain metastases as well as development of appropriate preclinical brain metastasis models susceptible to external manipulation of the TME are critical steps towards that goal. A deeper understanding of the immuno-biology in distinct organ microenvironments will help to expand the benefits of immunotherapy to more needed patients.

Final results of a phase I study of oral belinostat (PXD101) in patients with solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3531-3531 ◽  
Author(s):  
W. K. Kelly ◽  
J. DeBono ◽  
G. Blumenschein ◽  
U. Lassen ◽  
J. Zain ◽  
...  
Keyword(s):  
Clinical Activity ◽  
Atypical Chest Pain ◽  
Dose Cohort ◽  
Multiple Tumor ◽  
Multiple Schedules ◽  
Deacetylase Inhibitor ◽  
Effect Of Food ◽  
Cancer Types ◽  
Elevated Creatinine ◽  
Tumor Types

3531 Background: Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. IV Bel is well-tolerated with clinical activity at 1 g/m2 daily x5, q3w. Methods: Patients (pts) were treated with multiple schedules (see table) to assess safety, pharmacokinetics (PK) and efficacy. PK was done on day (d) 1 (fasting) and d7 (non-fasting) along with serial ECGs. Results: 92 pts, median age 60 (range 32–89) have been included. Major cancer types included colorectal (22%), prostate (17%), bladder (11%). Most frequent related adverse events (AEs), any grade (gr), were fatigue (53%), nausea (49%), anorexia (36%), vomiting (27%), diarrhea (25%). Only related gr 3/4 AE noted by more than 1 pt was fatigue. Hematological tox included gr 2: anemia (6 pts), leucopenia (2 pts), and thrombocytopenia (1 pt). Two events of gr 2 QTc prolongation were reported. Recommended dose (RD) for continuous dosing was determined as 250 mg, QD or BID, based on dose limiting toxicity (DLT; gr 3 if not indicated) seen in 2 pts in cohort 2A: dehydration and fatigue. Based on overall tolerability and DLTs (cohort 2C fatigue; 3C gr 2 nausea/vomiting/diarrhea; 4C atypical chest pain, elevated creatinine; 2D atrial fibrillation, hypokalemia, fatigue) the RD for d1–14 dosing was determined as 750 mg QD, with option for intra-pt dose escalation if limited tox. For d1–5 dosing, evaluation of the highest dose-cohort is not finalized; 1 pt had gr 3 psychosis, but also experienced same event 16d after treatment stopped. Exposure of Bel in plasma correlates with dose; PK on d1/d7 indicate a possible effect of food. To date, 33 pts (41%) have SD; 5 pts ≥6 months (d on treatment: 710 adenoidcystic, +488 bladder, 485 renal, 196 rectal, 182 prostate), and 12 pts 3–6 months. Conclusions: Oral Bel can be delivered safely with multiple schedules. The safety profile and long stabilizations in multiple tumor types makes Bel an interesting option for further evaluation as a monotherapy and in combination with chemotherapy. [Table: see text] [Table: see text]

scholarly journals RIPK3 Suppresses the Progression of Spontaneous Intestinal Tumorigenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Qun Zhao ◽  
Jian Guo ◽  
Xinran Cheng ◽  
Yingying Liao ◽  
Yun Bi ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Histological Grade ◽  
Tumor Formation ◽  
Intestinal Tumorigenesis ◽  
Interacting Protein ◽  
Multiple Tumor ◽  
Stat3 Signaling ◽  
Signaling Axis ◽  
Clinical Correlate ◽  
Tumor Types

Receptor-interacting protein 3 (RIPK3), a member of the family of serine/threonine protein kinases, emerged as a critical regulator of necroptosis. Downregulated expression of RIPK3 is correlated with poor prognosis in multiple tumor types. Here, we show that RIPK3 is involved in the progression of spontaneous intestinal tumorigenesis. As a clinical correlate, reduced expression of RIPK3 is positively associated with histological grade, lymphatic metastasis and poor prognosis in CRC patients. RIPK3-deficient (Ripk3-/-) mice exhibit increased tumor formation in Apcmin/+ spontaneous intestinal tumorigenesis. Apcmin/+Ripk3-/- tumors promote hyperactivation of IL-6/STAT3 signaling, which exacerbates proliferation and inhibits apoptosis. Blocking IL-6 signaling suppressed tumor formation and reduced STAT3 activation in Apcmin/+Ripk3-/- mice. Thus, our results reveal that RIPK3 is a tumor suppressor in spontaneous intestinal tumorigenesis, and implicate targeting the IL-6/STAT3 signaling axis as a potential therapeutic strategy for intestinal tumor patients with reduced RIPK3.

CTNI-55. THE CDK4/6 INHIBITOR ABEMACICLIB IN PATIENTS WITH RECURRENT MENINGIOMA AND OTHER PRIMARY CNS TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi72-vi73
Author(s):  
Elizabeth Coffee ◽  
Katherine Panageas ◽  
Robert Young ◽  
Tara Morrison ◽  
Ahmad Daher ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Single Agent ◽  
Pituitary Tumors ◽  
Molecular Characteristics ◽  
Multiple Cancer ◽  
Who Grade ◽  
Multiple Tumor ◽  
Primary Brain Tumors ◽  
Basket Trial ◽  
Tumor Types

Abstract BACKGROUND Medical therapies for recurrent brain tumors are limited. Abemaciclib is a small molecule CDK4/6 inhibitor that has demonstrated antitumor activity in multiple cancer types and crosses the blood-brain barrier. METHODS We conducted a phase II trial of single-agent abemaciclib in patients with recurrent primary brain tumors utilizing a novel CNS basket trial design with multiple tumor types accrued to separate cohorts including patients with recurrent IDH-wildtype gliomas (Cohort A), any recurrent gliomas requiring cytoreductive surgery (Cohort B), and any other recurrent primary brain tumors (Cohort C) including IDH-mutant gliomas, meningiomas, and other tumor types. In all patients, abemaciclib was administered orally at 200mg twice daily for each 28-day cycle. In cohort B abemaciclib was administered 4-7 days prior to surgery then resumed after recovery. Neuroimaging disease assessments were performed every two cycles. Cohorts were individually assessed for efficacy, tumoral molecular characteristics, and exploratory biomarker analyses. Next generation sequencing was performed on patients who had prior surgery. RESULTS To date, a total of 61 patients have enrolled and initiated treatment with abemaciclib. Cohort A enrolled 9 patients with IDH-wildtype WHO grade II and III astrocytomas. Cohort B enrolled 10 patients with astrocytomas of varying IDH-status. Cohort C is a diverse group of 42 patients including 22 treatment-refractory meningiomas, 10 IDH-mutant gliomas (5 astrocytomas, 5 oligodendrogliomas), 3 ependymomas, 3 primary CNS lymphomas, 2 pituitary tumors, 1 glioneuronal rosette forming tumor, and 1 diffuse midline glioma. A total of 7 grade 3 toxicities occurred in 6 patients: fatigue (3), neutropenia (2), colitis (1) and seizure (1); no grade 4 toxicities occurred. CONCLUSIONS We present the results of a novel CNS basket trial looking at the efficacy of abemaciclib across multiple recurrent primary brain tumors. Efficacy results will be presented, highlighting an update on promising results in the 22 patients with recurrent meningiomas.

WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Ensong Guo ◽  
Rourou Xiao ◽  
Yifan Wu ◽  
Funian Lu ◽  
Chen Liu ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Interferon Response ◽  
Dependent Manner ◽  
Multiple Cancer ◽  
Multiple Tumor ◽  
Cancer Types

Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell–dependent manner. A WEE1 inhibition–induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.

Phenotypic Differences of CD103+ Tissue-Resident Memory T Cells Associated with Various Cancers

Pathobiology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Hye Seon Park ◽  
Yeonjin Jeon ◽  
Hyun Lee ◽  
Heejae Lee ◽  
Young-Ae Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Importance ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Clinicopathologic Characteristics ◽  
Phenotypic Differences ◽  
Cancer Types ◽  
Tumor Types ◽  
Resident Memory T Cells

<b><i>Background/Aims:</i></b> The presence and clinical importance of tissue-resident memory T (T<sub>RM</sub>) cells have been recently described in association with various cancer types. However, the frequency and the traditional naïve–effector–memory phenotypic characteristics of T<sub>RM</sub> cells are largely unknown. <b><i>Methods:</i></b> We analyzed single-cell populations of colorectal cancer (CC, <i>n</i> = 18), stomach cancer (SC, <i>n</i> = 13), renal cell carcinoma (RCC, <i>n</i> = 19), and breast cancer (BC, <i>n</i> = 16) by dissociation of tumor tissue with collagenase/hyaluronidase. We investigated populations of naïve, effector, and memory T and T<sub>RM</sub> cells by flow cytometry. <b><i>Results:</i></b> Among CD8<sup>−</sup> cells, CC was associated with a significantly higher proportion of CD103<sup>+</sup> T cells than other tumor types (<i>p</i> &#x3c; 0.001). Among CD8<sup>+</sup> cells, CC and SC were associated with higher CD103<sup>+</sup> T-cell proportions than RCC and BC (<i>p</i> &#x3c; 0.001). Significantly more CD8<sup>+</sup> than CD8<sup>−</sup> cells expressed CD103 (<i>p</i> &#x3c; 0.001). In association with SC, RCC, and BC, CD8<sup>+</sup> T cells had a similar T-cell phenotype composition pattern: fewer effector T cells and more memory-type T cells among CD103<sup>+</sup> cells compared with CD103<sup>−</sup> cells (<i>p</i> &#x3c; 0.05). Tumors with higher proportion of CD103<sup>+</sup> cells had no specific clinicopathologic characteristics than those with lower proportion of CD103<sup>+</sup> cells. <b><i>Conclusion:</i></b> T<sub>RM</sub> cell abundance and phenotypes varied among CC, SC, RCC, and BC. Further studies regarding the functional differences of T<sub>RM</sub> associated with various tumors are warranted.

Cytotoxic T-lymphocyte-associated Protein 4 and Cancer Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-7-SCI-7
Author(s):  
James Allison
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Therapy ◽  
Mouse Models ◽  
Late Stage ◽  
Cd4 T Cells ◽  
Controlled Trial ◽  
Immune Checkpoints ◽  
Multiple Tumor ◽  
Tumor Types

Abstract The existence of multiple non-redundant l inhibitory pathways that limit T cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits CD28 mediated costimulation. Antibodies to CTLA-4 have proven effective against multiple tumor types in both pre-clinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long term (>4.5 years) survival benefit in about 23% of patients in a randomized, placebo-controlled trial in late stage melanoma. In 2011 it was approved by the FDA for treatment of late stage melanoma and is now a standard of care for that disease. A recent retrospective study of almost 5,000 patients showed an inflection point at about 2.5 years with essentially no deaths of about 20% of patients for 10 years following treatment. The mechanism(s) of action of anti-CTLA-4 are still being elucidated. We and others have shown that CLTA-4 limits T cell proliferation by a cell intrinsic mechanism. However, there is also evidence that anti-CTLA-4 has to engage the target on both effector (Teff) and regulatory (Treg) T cells. We have recently uncovered a mechanism whereby anti-CTLA-4 antibodies expand Treg in lymph nodes but cause their depletion in the tumor microenvironment. Thus anti-CTLA-4 exerts its anti-tumor effects by multiple mechanisms. We have also shown that CTLA-4 blockade results in a 2-5 fold increase in the frequency of CD4 T cells expression ICOS (inducible costimulator) in both tumor tissues and blood. This population contains that vast majority of tumor antigen specific cells that produce IFNg and TNFa. The appearance of the ICOS+ CD4 cells serves as a pharmacodynamic marker of a biological effect of anti-CTLA-4 activity. Using mouse models, we have shown that the ICOS/ICOSL pathway is critical for optimal anti-tumor activity of anti-CTLA-4. Furthermore, we have shown that agonist stimulation of ICOS coupled with CTLA-4 blockade results in enhanced anti-tumor efficacy in mouse models, suggest that ICOS is a compelling molecule to develop as a target for agonistic targeting of costimulatory checkpoints. PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T cell antigen receptor mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25% . A recent phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late stage melanoma patients. Our studies indicate that the mechanisms of anti-PD-1 mediated tumor immunity are distinct from those of anti-CTLA-4, at least as for the role of ICOS+ CD4 T cells. These studies and their implications for cancer therapy will be discussed. Disclosures Allison: Jounce Therapeutics: Consultancy, Equity Ownership, Patents & Royalties: Licensed patent.; Bristol Meyers-Squibb: Patents & Royalties: Licensed patent owned by the University of California. Previously received royalties.

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