scholarly journals Oncolytic vaccinia virus reinvigorates peritoneal immunity and cooperates with immune checkpoint inhibitor to suppress peritoneal carcinomatosis in colon cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e000857
Author(s):  
Yu Seong Lee ◽  
Won Suk Lee ◽  
Chang Woo Kim ◽  
Seung Joon Lee ◽  
Hannah Yang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
Vaccinia Virus ◽  
Peritoneal Carcinomatosis ◽  
Immune Checkpoint ◽  
Malignant Ascites ◽  
Peritoneal Tumor ◽  
Programmed Death ◽  
Ascites Formation ◽  
Anticancer Immunity

BackgroundPeritoneal carcinomatosis (PC) is a common and devastating manifestation of colon cancer and refractory to conventional anticancer therapeutics. During the peritoneal dissemination of colon cancer, peritoneal immunity is nullified by various mechanisms of immune evasion. Here, we employed the armed oncolytic vaccinia virus mJX-594 (JX) to rejuvenate the peritoneal antitumor immune responses in the treatment of PC.MethodsPC model of MC38 colon cancer was generated and intraperitoneally treated with JX and/or anti-programmed cell death protein 1 (PD-1) antibody. The peritoneal tumor burden, vascular leakage, and malignant ascites formation were then assessed. Tumors and peritoneal lavage cells were analyzed by flow cytometry, multiplex tissue imaging, and a NanoString assay.ResultsJX treatment effectively suppressed peritoneal cancer progression and malignant ascites formation. It also restored the peritoneal anticancer immunity by activating peritoneal dendritic cells (DCs) and CD8+ T cells. Moreover, JX selectively infected and killed peritoneal colon cancer cells and promoted the intratumoral infiltration of DCs and CD8+ T cells into peritoneal tumor nodules. JX reinvigorates anticancer immunity by reprogramming immune-related transcriptional signatures within the tumor microenvironment. Notably, JX cooperates with immune checkpoint inhibitors (ICIs), anti-programmed death-1, anti-programmed death-ligand 1, and anti-lymphocyte-activation gene-3 to elicit a stronger anticancer immunity that eliminates peritoneal metastases and malignant ascites of colon cancer compared with JX or ICI alone.ConclusionsIntraperitoneal immunotherapy with JX restores peritoneal anticancer immunity and potentiates immune checkpoint blockade to suppress PC and malignant ascites in colon cancer.

scholarly journals Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 738 ◽  
Author(s):  
Raju K. Vaddepally ◽  
Prakash Kharel ◽  
Ramesh Pandey ◽  
Rohan Garje ◽  
Abhinav B. Chandra
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Hematopoietic Cells ◽  
Fda Approval ◽  
Programmed Death ◽  
Cancerous Cells

Cancer is associated with higher morbidity and mortality and is the second leading cause of death in the US. Further, in some nations, cancer has overtaken heart disease as the leading cause of mortality. Identification of molecular mechanisms by which cancerous cells evade T cell-mediated cytotoxic damage has led to the modern era of immunotherapy in cancer treatment. Agents that release these immune brakes have shown activity to recover dysfunctional T cells and regress various cancer. Both cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Death-1 (PD-1) play their role as physiologic brakes on unrestrained cytotoxic T effector function. CTLA-4 (CD 152) is a B7/CD28 family; it mediates immunosuppression by indirectly diminishing signaling through the co-stimulatory receptor CD28. Ipilimumab is the first and only FDA-approved CTLA-4 inhibitor; PD-1 is an inhibitory transmembrane protein expressed on T cells, B cells, Natural Killer cells (NKs), and Myeloid-Derived Suppressor Cells (MDSCs). Programmed Death-Ligand 1 (PD-L1) is expressed on the surface of multiple tissue types, including many tumor cells and hematopoietic cells. PD-L2 is more restricted to hematopoietic cells. Blockade of the PD-1 /PDL-1 pathway can enhance anti-tumor T cell reactivity and promotes immune control over the cancerous cells. Since the FDA approval of ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody) in 2011, six more immune checkpoint inhibitors (ICIs) have been approved for cancer therapy. PD-1 inhibitors nivolumab, pembrolizumab, cemiplimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab are in the current list of the approved agents in addition to ipilimumab. In this review paper, we discuss the role of each immune checkpoint inhibitor (ICI), the landmark trials which led to their FDA approval, and the strength of the evidence per National Comprehensive Cancer Network (NCCN), which is broadly utilized by medical oncologists and hematologists in their daily practice.

scholarly journals Glial Cell Expression of PD-L1

2019 ◽  
Vol 20 (7) ◽  
pp. 1677 ◽  
Author(s):  
Priyanka Chauhan ◽  
James Lokensgard
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Pathogen Detection ◽  
Therapeutic Potential ◽  
Immune Checkpoint Blockade ◽  
Programmed Death ◽  
Cell Expression ◽  
Inflammatory Milieu ◽  
The Brain

The programmed death (PD)-1/PD-L1 pathway is a well-recognized negative immune checkpoint that results in functional inhibition of T-cells. Microglia, the brain-resident immune cells are vital for pathogen detection and initiation of neuroimmune responses. Moreover, microglial cells and astrocytes govern the activity of brain-infiltrating antiviral T-cells through upregulation of PD-L1 expression. While T-cell suppressive responses within brain are undoubtedly beneficial to the host, preventing cytotoxic damage to this vital organ, establishment of a prolonged anti-inflammatory milieu may simultaneously lead to deficiencies in viral clearance. An immune checkpoint blockade targeting the PD-1: PD-L1 (B7-H1; CD274) axis has revolutionized contemporary treatment for a variety of cancers. However, the therapeutic potential of PD1: PD-L1 blockade therapies targeting viral brain reservoirs remains to be determined. For these reasons, it is key to understand both the detrimental and protective functions of this signaling pathway within the brain. This review highlights how glial cells use PD-L1 expression to modulate T-cell effector function and limit detrimental bystander damage, while still retaining an effective defense of the brain.

scholarly journals 62 Identify immune cell types and biomarkers associated with immune-related adverse events using single cell RNA sequencing

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A67-A67
Author(s):  
Jiamin Chen ◽  
Lance Pflieger ◽  
Sue Grimes ◽  
Tyler Baker ◽  
Michael Brems ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
Immune System ◽  
Adverse Events ◽  
Single Cell ◽  
Immune Checkpoint ◽  
Inflammatory Responses ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Single Cell Rna Sequencing

BackgroundRecent advancements in immunotherapy are revolutionizing the landscape of clinical immuno-oncology and have significantly increased patient survival in a range of cancers. Notably, immune checkpoint blockade therapies have induced durable responses and provided tremendous clinical benefits to previously untreatable patients. However, unleashing immune system against cancer also disrupts the immunologic homeostasis and induce inflammatory responses, resulting immune-related adverse events. The precise mechanisms underlying immune-related adverse events (irAEs) remain unknown. Furthermore, it is unclear why immune checkpoint blockade therapies only induce irAEs in some patients but not the others. In this study, we systematically characterize the functional impacts of immune checkpoint blockade on the patient immune system at single-cell resolution.MethodsThe peripheral blood mononuclear cells (PBMCs) from seven cancer patients with melanoma, non-small cell lung cancer, or colon cancer (MSI-H) receiving immune checkpoint inhibitors (CPIs), i.e. anti–PD-1+anti-CTLA4 combo or anti-PD-1 single agent, were collected at three serial time points (T1, T2, and T3). During the immunotherapy, four patients developed irAEs, including colitis (2X), pneumonitis (1), hyper/hypothyroidism (1), while three patients showed no signs of irAEs. In total, we generated and characterized single cell gene expression profiles for more than 65,000 cells from 21 PBMC libraries. Furthermore, we simultaneously measured TCR and BCR from nine selected samples, thus generating a comprehensive profile of Immune repertoire upon CPIs.ResultsWe systematically characterized T cells, B cells, monocytes, NK cells, and platelets from PBMCs. Both checkpoint blockade and patient comorbidity affect PBMC populations. We found that irAEs are often associated with an acute increase in monocytes and decrease in T cells. After repeated CPI treatment, PBMC populations remained relatively stable. We characterized specific subsets within each cell type that are associated with CPI treatment as well as patient clinical conditions, and identified signature genes for each subset. For example, Mucosal-Associated Invariant CD8 T cells were strongly enriched in the PBMC population of the colon cancer patient. In the melanoma patient who received anti–PD-1+anti-CTLA4 combo but didn’t develop colitis, we found enriched NK cell subsets expressing chemokine such as XCL1 and CCL4. Furthermore, we found prominent T cell clonal expansion in this patient compared to the two melanoma patients who developed colitis. The administration of steroids after irAEs led to massive anti-inflammatory responses in PMBCs, often characterized by the prominent expression of AREG.ConclusionsOur study characterized the functional impact of CPIs on patient PBMCs. Our data demonstrated that single cell RNA sequencing provides a powerful tool to dissect and identify clinically actionable biomarkers for response prediction and side effects alleviation in patients receiving immunotherapy in the era of precision medicine.Ethics ApprovalThis study was approved by the Institutional Review Board (#1050678) at Intermountain Healthcare (Salt Lake City, UT USA)

scholarly journals The Impact of Tregs on the Anticancer Immunity and the Efficacy of Immune Checkpoint Inhibitor Therapies

2021 ◽  
Vol 12 ◽  
Author(s):  
Jose M. González-Navajas ◽  
Dengxia Denise Fan ◽  
Shuang Yang ◽  
Fengyuan Mandy Yang ◽  
Beatriz Lozano-Ruiz ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Effector T Cells ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Tumor Environment ◽  
The Impact ◽  
Anticancer Immunity

Although cancers arise from genetic mutations enabling cells to proliferate uncontrollably, they cannot thrive without failure of the anticancer immunity due in a large part to the tumor environment's influence on effector and regulatory T cells. The field of immune checkpoint inhibitor (ICI) therapy for cancer was born out of the fact that tumor environments paralyze the immune cells that are supposed to clear them by activating the immune checkpoint molecules such as PD-1. While various subsets of effector T cells work collaboratively to eliminate cancers, Tregs enriched in the tumor environment can suppress not only the native anticancer immunity but also diminish the efficacy of ICI therapies. Because of their essential role in suppressing autoimmunity, various attempts to specifically deplete tumor-associated Tregs are currently underway to boost the efficacy of ICI therapies without causing systemic autoimmune responses. A better understanding the roles of Tregs in the anti-cancer immunity and ICI therapies should provide more specific targets to deplete intratumoral Tregs. Here, we review the current understanding on how Tregs inhibit the anti-cancer immunity and ICI therapies as well as the advances in the targeted depletion of intratumoral Tregs.

Catumaxomab therapy in peritoneal carcinomatosis from colon cancer: Clinical benefit in comparison to systemic chemotherapy alone and cytoreductive surgery/hyperthermic chemoperfusion.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 488-488 ◽  
Author(s):  
M. A. Ströhlein ◽  
M. M. Heiss
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Side Effects ◽  
Intestinal Obstruction ◽  
Peritoneal Carcinomatosis ◽  
Cytoreductive Surgery ◽  
Systemic Chemotherapy ◽  
Early Stage ◽  
Malignant Ascites ◽  
Therapy Strategies

488 Background: There is still no effective treatment for the majority of patients suffering from peritoneal carcinomatosis (PC) of colon cancer. Palliative chemotherapy (CHEM) had limited efficacy. Cytoreductive surgery and hyperthermic chemoperfusion (HIPEC) showed promising results, but was manageable in early stage PC patients only. Catumaxomab therapy (CATU) offers a new option for intraperitoneal treatment in all stages of PC. Aim of the study was to evaluate CATU therapy in comparison to HIPEC and systemic therapy. Methods: Between 2005 and 2008, 76 patients suffering from PC of colon cancer were included and treated with systemic chemotherapy alone (35), HIPEC +/- systemic chemotherapy (21) and CATU +/- chemotherapy (22). All patients were assessed for therapy-related severe side effects, incidence of intestinal obstruction-ileus and ascites and for overall survival. Results: Grade IV side effects were observed in 9.1% of CATU patients, 14.3% after HIPEC and 5.7% after CHEM. Ascites was found in not a single patient after CATU vs. one patient after HIPEC (4.5%) and 7 patients after chemotherapy (20%, p<0.03). Intestinal obstruction was found in 22.7% of patients after CATU vs. 14.3% after HIPEC and in 42.9% of patients after chemotherapy (p<0.04). In comparison to systemic chemotherapy, overall survival was significantly increased after CATU (15.2 months, p=0.03) and HIPEC (20.1 months, p=0.02; median follow-up 17 months). Conclusions: Catumaxomab therapy of patients with PC from colon cancer was associated with a preventive effect for accumulation of malignant ascites and intestinal obstruction. Patients receiving CATU or HIPEC therapy concepts showed a survival benefit compared to systemic chemotherapy alone. Therapy strategies containing intraperitoneal catumaxomab treatment may be beneficial in patients with PC from colon cancer, even in advanced PC disease, when HIPEC was not feasible. [Table: see text]

scholarly journals Granzyme B PET Imaging of Immune Checkpoint Inhibitor Combinations in Colon Cancer Phenotypes

2020 ◽  
Vol 22 (5) ◽  
pp. 1392-1402
Author(s):  
J. L. Goggi ◽  
Y. X. Tan ◽  
S. V. Hartimath ◽  
B. Jieu ◽  
Y. Y. Hwang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
Pet Imaging ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Granzyme B ◽  
Cell Populations ◽  
Combination Therapies ◽  
Cancer Phenotypes

Abstract Purpose Immune checkpoint inhibitor (ICI) monotherapy and combination regimens are being actively pursued as strategies to improve durable response rates in cancer patients. However, the biology surrounding combination therapies is not well understood and may increase the likelihood of immune-mediated adverse events. Accurate stratification of ICI response by non-invasive PET imaging may help ensure safe therapy management across a wide number of cancer phenotypes. Procedures We have assessed the ability of a fluorine-labelled peptide, [18F]AlF-mNOTA-GZP, targeting granzyme B, to stratify ICI response in two syngeneic models of colon cancer, CT26 and MC38. In vivo tumour uptake of [18F]AlF-mNOTA-GZP following ICI monotherapy, or in combination with PD-1 was characterised and correlated with changes in tumour-associated immune cell populations. Results [18F]AlF-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells; however, overall uptake and response to monotherapy or combination therapies was very different in the CT26 and MC38 tumours, likely due to the immunostimulatory environment imbued by the MSI-high phenotype in MC38 tumours. Conclusions [18F]AlF-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations and is able to stratify tumour response to a range of ICIs administered as monotherapies or in combination. However, tracer uptake can be significantly affected by preexisting phenotypic abnormalities potentially confusing data interpretation.

scholarly journals Immune checkpoint inhibitor-associated celiac disease

2020 ◽  
Vol 8 (1) ◽  
pp. e000958 ◽  
Author(s):  
Yousef Badran ◽  
Angela Shih ◽  
Donna Leet ◽  
Meghan J Mooradian ◽  
Alexandra Coromilas ◽  
...  
Keyword(s):  
T Cells ◽  
Celiac Disease ◽  
T Cell ◽  
Lamina Propria ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Programmed Death

BackgroundRare cases of immune checkpoint inhibitor (ICI)-associated celiac disease (ICI-CeD) have been reported, suggesting that disruption of tolerance mechanisms by ICIs can unmask celiac disease (CeD). This study aims to characterize the clinicopathological and immunophenotypic features of ICI-CeD in comparison to ICI-associated duodenitis (ICI-Duo) and usual CeD.MethodsA medical and pathological records search between 2015 and 2019 identified eight cases of ICI-CeD, confirmed by tTG-IgA. Nine cases of ICI-Duo, 28 cases of moderate CeD, as well as 5 normal controls were used as comparison groups. Clinical information was collected from the electronic medical records. Immunohistochemistry for CD3, CD8, T-cell receptor gamma/delta (γδ), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) were performed, with quantification of intraepithelial lymphocyte (IEL) subsets in three well-oriented villi. CD68, PD-L1, and PD-1 were assessed as a percentage of lamina propria surface area infiltrated by positive cells. Statistical significance was calculated by the Student’s t-test and Fisher’s exact test.ResultsThe eight patients with ICI-CeD (F:M=1:3) and nine patients with ICI-Duo (F:M=5:4) presented similarly with diarrhea (13/17) and abdominal pain (11/17) after a median of 1.6 months on ICI therapy. In patients with ICI-CeD, tTG-IgA ranged from 104 to >300 IU/mL. Histological findings in ICI-CeD and ICI-Duo were similar and included expansion of the lamina propria, active neutrophilic duodenitis, variably increased IELs, and villous blunting. Immunohistochemistry showed that the average number of IELs per 100 enterocytes is comparable between ICI-CeD and ICI-Duo, with increased CD3+ CD8+ T cells compared with normal duodenum but decreased γδ T cells compared with CeD. Average PD-L1 percentage was 9% in ICI-CeD and 18% in ICI-Duo, in comparison to <1% in CeD and normal duodenum; average PD-1 percentage was very low to absent in all cases (<3%). On follow-up, five patients with ICI-CeD improved on a gluten-free diet (GFD) as the sole therapeutic intervention (with down-trending tTG-IgA) while the other three required immunosuppression. All patients who developed ICI-Duo received immunosuppression with variable improvement in symptoms.ConclusionsICI-CeD resembles ICI-Duo clinically and histologically but shares the serological features and response to gluten withdrawal with classic CeD. Immunophenotyping of IELs in ICI-CeD and ICI-Duo also shows similar CD3, CD8, γδ T cell subsets, and PD-L1 populations, all of which differed quantitatively from usual CeD. We conclude that ICI-CeD is biologically similar to ICI-Duo and is likely a variant of ICI-Duo, but treatment strategies differ, with ICI-CeD often improving with GFD alone, whereas ICI-Duo requires systemic immunosuppression.

Association between effector-type regulatory T cells and immune checkpoint expression on CD8+ T cells in malignant ascites from epithelial ovarian cancer

2022 ◽  
Author(s):  
Sho Sato ◽  
Hirokazu Matsushita ◽  
Daisuke Shintani ◽  
Nao Fujieda ◽  
Akira Yabuno ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Epithelial Ovarian Cancer ◽  
Immune Checkpoint ◽  
Malignant Ascites ◽  
Serous Carcinoma ◽  
Median Frequency ◽  
Color Flow ◽  
Inhibitory Networks

Abstract Background Regulatory T cells (Tregs) play an important role in the antitumor immune response in epithelial ovarian cancer (EOC). To understand the immune-inhibitory networks of EOC, we addressed the association between Tregs and immune checkpoint expression on T cells in the tumor microenvironment of EOC Methods A total of 41 patients with stage IIIC and IV EOC were included in the analysis. We harvested cells from malignant ascites and investigated them using multi-color flow cytometry. We categorized the Tregs into 3 groups: effector-type Tregs, naïve Tregs and non-Tregs, based on the expression patterns of CD45RA and Foxp3 in CD4+ T cells. Furthermore, the relationships between the expression of various immune checkpoint molecules, such as PD-1, on CD8+T cells and each of the Treg subtypes was also evaluated. Results The median frequency of naïve Tregs, effector-type Tregs and non-Tregs were 0.2% (0-0.8), 2.0% (0-11.4) and 1.5% (0.1-6.3) in CD4+ T cells of malignant ascites from EOC patients, respectively. A high frequency of effector-type Tregs was associated with high-grade serous carcinoma compared with the other histotypes. Patients with higher proportions of effector-type Tregs showed a trend towards increased progression-free survival. We also demonstrated a correlation between a higher proportion of effector-type Tregs and increased PD-1 expression on CD8+ T cells. In addition, C-C chemokine receptor 4 expression was also observed in effector-type Tregs. Conclusion These data suggest that multiple immune-inhibitory networks exist in malignant ascites from EOC patients, suggesting an approach towards combinational immunotherapies for advanced EOC patients.

scholarly journals Immune Checkpoint Ligand Reverse Signaling: Looking Back to Go Forward in Cancer Therapy

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 624 ◽  
Author(s):  
Daniele Lecis ◽  
Sabina Sangaletti ◽  
Mario P. Colombo ◽  
Claudia Chiodoni
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Clinical Response ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Immune Functions ◽  
Regulatory Pathways ◽  
Reverse Signaling ◽  
Programmed Death

The so-called immune checkpoints are pathways that regulate the timing and intensity of the immune response to avoid an excessive reaction and to protect the host from autoimmunity. Immune checkpoint inhibitors (ICIs) are designed to target the negative regulatory pathways of T cells, and they have been shown to restore anti-tumor immune functions and achieve considerable clinical results. Indeed, several clinical trials have reported durable clinical response in different tumor types, such as melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). Nonetheless, after the initial enthusiasm, it is now evident that the majority of patients do not benefit from ICIs, due to innate or acquired tumor resistance. It is therefore mandatory to find ways to identify those patients who will respond and to find ways to induce response in those who at present do not benefit from ICIs. In this regard, the expression of programmed death ligand 1 (PD-L1) on neoplastic cells was the first, and most obvious, biomarker exploited to predict the activity of anti-programmed death 1 (PD-1) and/or anti-PD-L1 antibodies. As expected, a correlation was confirmed between the levels of PD-L1 and the efficacy of anti-PD-1 therapy in melanoma, NSCLC and RCC. However, further results from clinical trials showed that some patients display a clinical response regardless of tumor cell PD-L1 expression levels, while others do not benefit from ICI treatment despite the expression of PD-L1 on neoplastic elements. These findings strongly support the notion that other factors may be relevant for the efficacy of ICI-based treatment regimens. Furthermore, although the current dogma indicates that the PD-1/PD-L1 axis exerts its regulatory effects via the signal transduced in PD-1-expressing T cells, recent evidence suggests that a reverse signaling may also exist downstream of PD-L1 in both tumor and immune cells. The reverse signaling of PD-L1, but also of other immune checkpoints, might contribute to the pro-tumoral/immune suppressive environment associated with tumor development and progression. Clarifying this aspect could facilitate the prediction of patients’ clinical outcomes, which are so far unpredictable and result in response, resistance or even hyper-progressive disease in some cases.

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