Safety profile of INT230-6, a novel intratumoral (IT) formulation, during injections into a variety of refractory deep and superficial tumors with evidence of tumor regression and immune activation.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2602-2602
Author(s):  
Anthony B. El-Khoueiry ◽  
Jacob Stephen Thomas ◽  
Diana L. Hanna ◽  
Lillian L. Siu ◽  
Nilofer Saba Azad ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Tumor Regression ◽  
Systemic Exposure ◽  
Systemic Absorption ◽  
Frequent Adverse Event ◽  
Load Increase ◽  
Cancer Types ◽  
And Diffusion ◽  
Clinical Trial Information

2602 Background: INT230-6 is comprised of cisplatin (CIS), vinblastine (VIN) and an amphiphilic penetration enhancer which facilitates dispersion throughout tumors and diffusion into cancer cells. In preclinical experiments, INT230-6 led to necrosis and recruitment of immune cells with high rates of complete responses of injected and bystander tumors. This abstract highlights the safety and early pharmacodynamic activity of this approach. Methods: Patients with solid tumors that progressed on all standard treatments were enrolled. Dose escalation occurred by increasing number of tumors injected, loading per tumor, and total dose. INT230-6 was injected once every 2 weeks in multiple lesions for 5 sessions. Patients were monitored for safety and tolerability weekly. Pharmacokinetic(Pk) samples and peripheral blood were collected for flow cytometry and circulating cytokines. Pre and on study biopsies are ongoing. Results: 28 patients (14 unique cancer types) receiving a median of 3 prior treatments were enrolled. Doses from 0.3 ml up to-80 ml of INT230-6 were given into single lesions with some patients receiving a total of 120 mL ( = 9.7mg VIN exceeding the IV VIN dose) without significant systemic absorption or typical cytotoxic adverse events. Pk analysis suggests that systemic exposure of VIN or CIS is ~10% of injected. No DLT’s or drug-related SAE’s reported. The most frequent adverse event was grade 1 or 2 pain at injected site. Superficial tumors showed signs of response including flattening, areas of necrosis and ulceration. Tumor reduction, apparent in in both injected and bystander tumors, may indicate an abscopal effect. An increase > 30% in CD8 T-cells was seen in the blood of 3/9 evaluable patients. Conclusions: INT230-6 was safe and well tolerated in > 100 injections (28 patients) with encouraging activity and pharmacodynamic effects in advanced refractory tumors. Additional analysis of immune cells from on study biopsies will be presented. A new cohort will evaluate combination with an anti-PD1 antibody to understand if local tumor destruction can increase systemic antigen load, increase immune cell recognition and initiate a systemic immune response. Clinical trial information: NCT 03058289.

scholarly journals Paving the Way for Immunotherapy in Pediatric Acute Myeloid Leukemia: Current Knowledge and the Way Forward

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4364
Author(s):  
Joost B. Koedijk ◽  
Inge van der Werf ◽  
Friso G. Calkoen ◽  
Stefan Nierkens ◽  
Gertjan J. L. Kaspers ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Patient Care ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Current Treatment ◽  
Treatment Regimens ◽  
Cancer Types ◽  
Pediatric Aml ◽  
The Way

Immunotherapeutic agents may be an attractive option to further improve outcomes and to reduce treatment-related toxicity for pediatric AML. While improvements in outcome have been observed with immunotherapy in many cancer types, immunotherapy development and implementation into patient care for both adult and pediatric AML has been hampered by an incomplete understanding of the bone marrow environment and a paucity of tumor-specific antigens. Since only a minority of patients respond in most immunotherapy trials across different cancer types, it will be crucial to understand which children with AML are likely to respond to or may benefit from immunotherapies. Immune cell profiling efforts hold promise to answer this question, as illustrated by the development of predictive scores in solid cancers. Such information on the number and phenotype of immune cells during current treatment regimens will be pivotal to generate hypotheses on how and when to intervene with immunotherapy in pediatric AML. In this review, we discuss the current understanding of the number and phenotype of immune cells in the bone marrow in pediatric AML, ongoing immunotherapy trials and how comprehensive immune profiling efforts may pave the way for successful clinical trials (and, ultimately, implementation into patient care).

A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): Interim safety, efficacy, and pharmacokinetic findings in advanced cancers.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 12-12 ◽  
Author(s):  
James J. Harding ◽  
Amita Patnaik ◽  
Victor Moreno ◽  
Mark Stein ◽  
Anna M. Jankowska ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Dose Escalation ◽  
Immune Cells ◽  
Tumor Regression ◽  
Target Engagement ◽  
Open Label ◽  
Open Label Phase ◽  
Related Reaction ◽  
Clinical Trial Information

12 Background: Combined targeting of both the TIM-3 and PD-L1 immune checkpoint pathways may improve efficacy. LY3321367 mAb targets TIM-3 on immune cells and LY3300054 mAb targets PD-L1 on tumor cells and tumor-infiltrating immune cells. This analysis presents safety, efficacy, pharmacokinetic (PK) and pharmacodynamics/soluble target engagement (TE) results from LY3321367 (anti-TIM-3) monotherapy and in combination with LY3300054 (anti-PD-L1) in patients (pts) with advanced cancer. Methods: This ongoing, open-label phase 1a/1b, dose escalation and expansion study enrolled pts with histologically confirmed advanced relapsed/refractory solid tumors. Pts received IV infusions of 3mg-1200mg LY3321367 Q2W monotherapy (Arm A) or 70mg-1200mg LY3321367 + 200mg-700mg LY3300054 Q2W combination therapy (Arm B). Primary objectives assessed safety and tolerability and determined the RP2D. PK, soluble target TE, anti-drug antibodies (ADAs), and clinical efficacy (RECIST v1.1) were also evaluated. Results: At data cutoff (3 August 2018), LY3321367 monotherapy was administered to 23 pts (Arm A); 18 pts received LY3321367 combination therapy (Arm B) as phase 1a dose escalation (3 mths median follow-up). Treatment-related AEs observed in Arms A and B were mild (Gr ≤2), except for 1 pt with Gr 3 anemia in Arm B (200 mg LY3321367 + 700 mg LY3300054). No dose limiting toxicities, dose limiting-equivalent toxicities, treatment-related SAEs, or deaths were observed in Arm A or B. For LY3321367, 68.2% (Arm A) and 88.2% (Arm B) of pts were positive for treatment-emergent ADAs. Despite ADAs, no effect on PK was noted; ADA titers were low, except for 1 pt with an infusion-related reaction. LY3321367 t1/2 was ~22 days. Full TE was maintained 2 wks after 1200 mg dose; 600 mg Q2W maintained TE at steady-state. In Arm A, 2 pts had > 20% tumor regression, 1 of which was later confirmed as a PR in a post-PD-1 SCLC pt. Conclusions: LY3321367 is well tolerated as a monotherapy and in combination with LY3300054. The RP2D for LY3321367 combination therapy is 1200 mg IV infusions Q2W for cycles 1-2; 600 mg infusions Q2W starting at cycle 3 onward. Clinical trial information: NCT03099109.

scholarly journals Large scale analysis of smoking-induced changes in the tumor immune microenvironment

2020 ◽  
Author(s):  
Arghavan Alisoltani ◽  
Xinru Qiu ◽  
Lukasz Jaroszewski ◽  
Mayya Sedova ◽  
Zhanwen Li ◽  
...  
Keyword(s):  
Immune Cells ◽  
Large Scale ◽  
Immune Cell ◽  
Survival Outcomes ◽  
Host Immune System ◽  
Large Scale Analysis ◽  
Tumor Immune Microenvironment ◽  
Cancer Types ◽  
Never Smokers ◽  
Induced Changes

AbstractTobacco smoke is a known carcinogen, mostly due to its genotoxicity, but its effects on the host immune system are also playing an important role. Here, we leveraged recent results on the immune landscape of cancer based on The Cancer Genomic Atlas (TCGA) data analysis and compared the proportions of major classes of tumor-infiltrating immune cells (TIICs) between smokers and never smokers in ten TCGA cancer types. We show that statistically significant changes can be identified in all ten cancers, with increased plasma cell populations and the modified ratio of activated to resting TIICs being the most consistent features distinguishing smokers and never-smokers across different cancers, with both being correlated with survival outcomes. Analysis of existing single-cell RNA-seq data further showed that smoking differentially affects the gene expression profile of cancer patients based on the immune cell type. The smoking-induced changes in the patterns of immune cells and their correlations to survival outcomes are stronger in female smokers.

scholarly journals The Transmembrane Receptor TIRC7 Identifies a Distinct Subset of Immune Cells with Prognostic Implications in Cholangiocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6272
Author(s):  
Thomas Albrecht ◽  
Benjamin Goeppert ◽  
Fritz Brinkmann ◽  
Alphonse Charbel ◽  
Qiangnu Zhang ◽  
...  
Keyword(s):  
Cell Density ◽  
Immune Cells ◽  
Immune Cell ◽  
Signet Ring Cell ◽  
Cell Immune Response ◽  
Functional Studies ◽  
Dismal Prognosis ◽  
Signet Ring ◽  
Cancer Types ◽  
Ring Cell

Cholangiocarcinoma (CCA) is a heterogeneous malignancy with a dismal prognosis. Therapeutic options are largely limited to surgery and conventional chemotherapy offers limited benefit. As immunotherapy has proven highly effective in various cancer types, we have undertaken a quantitative immunohistopathological assessment of immune cells expressing the immunoinhibitory T cell immune response cDNA 7 receptor (TIRC7), an emerging immunoinhibitory receptor, in a cohort of 135 CCA patients. TIRC7+ immune cells were present in both the tumor epithelia and stroma in the majority of CCA cases with the highest levels found in intrahepatic CCA. While intraepithelial density of TIRC7+ immune cells was decreased compared to matched non-neoplastic bile ducts, stromal quantity was higher in the tumor samples. Tumors exhibiting signet ring cell or adenosquamous morphology were exclusively associated with an intraepithelial TIRC7+ phenotype. Survival analysis showed intraepithelial TIRC7+ immune cell density to be a highly significant favorable prognosticator in intrahepatic but not proximal or distal CCA. Furthermore, intraepithelial TIRC7+ immune cell density correlated with the number of intraepithelial CD8+ immune cells and with the total number of CD4+ immune cells. Our results suggest the presence and prognostic relevance of TIRC7+ immune cells in CCA and warrant further functional studies on its pharmacological modulation.

scholarly journals CancerImmunityQTL: a database to systematically evaluate the impact of genetic variants on immune infiltration in human cancer

2020 ◽  
Vol 49 (D1) ◽  
pp. D1065-D1073
Author(s):  
Jianbo Tian ◽  
Yimin Cai ◽  
Yue Li ◽  
Zequn Lu ◽  
Jinyu Huang ◽  
...  
Keyword(s):  
Immune Cells ◽  
Genetic Variants ◽  
Immune Cell ◽  
Human Cancer ◽  
Tumor Development ◽  
Multiple Cancer ◽  
Immune Infiltration ◽  
Cancer Types ◽  
Cell Fractions ◽  
The Impact

Abstract Tumor-infiltrating immune cells as integral component of the tumor microenvironment are associated with tumor progress, prognosis and responses to immunotherapy. Genetic variants have been demonstrated to impact tumor-infiltrating, underscoring the heritable character of immune landscape. Therefore, identification of immunity quantitative trait loci (immunQTLs), which evaluate the effect of genetic variants on immune cells infiltration, might present a critical step toward fully understanding the contribution of genetic variants in tumor development. Although emerging studies have demonstrated the determinants of germline variants on immune infiltration, no database has yet been developed to systematically analyze immunQTLs across multiple cancer types. Using genotype data from TCGA database and immune cell fractions estimated by CIBERSORT, we developed a computational pipeline to identify immunQTLs in 33 cancer types. A total of 913 immunQTLs across different cancer types were identified. Among them, 5 immunQTLs are associated with patient overall survival. Furthermore, by integrating immunQTLs with GWAS data, we identified 527 immunQTLs overlapping with known GWAS linkage disequilibrium regions. Finally, we constructed a user-friendly database, CancerImmunityQTL (http://www.cancerimmunityqtl-hust.com/) for users to browse, search and download data of interest. This database provides an informative resource to understand the germline determinants of immune infiltration in human cancer and benefit from personalized cancer immunotherapy.

scholarly journals Novel Immune Infiltrating Cell Signature Based on Cell Pair Algorithm Is a Prognostic Marker in Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Hao Zhang ◽  
Zeyu Wang ◽  
Ziyu Dai ◽  
Wantao Wu ◽  
Hui Cao ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Immune Cells ◽  
Immune Cell ◽  
Immune Escape ◽  
High Sensitivity ◽  
Cellular Heterogeneity ◽  
Genomic Alteration ◽  
Cell Pair ◽  
Cancer Types ◽  
Pan Cancer

Tumor-infiltrating immune cells (TIICs) have become an important source of markers for predicting the clinical outcomes of cancer patients. However, measurements of cellular heterogeneity vary due to the frequently updated reference genomes and gene annotations. In this study, we systematically collected and evaluated the infiltration pattern of 65 immune cells. We constructed the Immune Cell Pair (ICP) score based on the cell pair algorithm in 3,715 samples and across 12 independent cancer types, among which, the ICP score from six cancer types was further validated in 2,228 GEO samples. An extensive tumorigenic and immunogenomic analysis was subsequently conducted. As a result, the ICP score showed a robust reliability and efficacy in predicting the survival of patients with gliomas, in pan-cancer samples, and six independent cancer types. Notably, the ICP score was correlated with the genomic alteration features in gliomas. Moreover, the ICP score exhibited a remarkable association with multiple immunomodulators that could potentially mediate immune escape. Finally, the ICP score predicted immunotherapeutic responses with a high sensitivity, allowing a useful tool for predicting the overall survival and guiding immunotherapy for cancer patients.

scholarly journals A Cancer-Specific Qualitative Method for Estimating the Proportion of Tumor-Infiltrating Immune Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Huiting Xiao ◽  
Jiashuai Zhang ◽  
Kai Wang ◽  
Kai Song ◽  
Hailong Zheng ◽  
...  
Keyword(s):  
Immune Cells ◽  
Qualitative Method ◽  
Immune Cell ◽  
Tumor Development ◽  
Rna Seq ◽  
Batch Effects ◽  
Relative Expression Orderings ◽  
Immune Contexture ◽  
Cancer Types ◽  
Novel Method

Tumor-infiltrating immune cells are important components in the tumor microenvironment (TME) and different types of these cells exert different effects on tumor development and progression; these effects depend upon the type of cancer involved. Several methods have been developed for estimating the proportion of immune cells using bulk transcriptome data. However, there is a distinct lack of methods that are capable of predicting the immune contexture in specific types of cancer. Furthermore, the existing methods are based on absolute gene expression and are susceptible to experimental batch effects, thus resulting in incomparability across different datasets. In this study, we considered two common neoplasms as examples (colorectal cancer [CRC] and melanoma) and introduced the Tumor-infiltrating Immune Cell Proportion Estimator (TICPE), a cancer-specific qualitative method for estimating the proportion of tumor-infiltrating immune cells. The TICPE was based on the relative expression orderings (REOs) of gene pairs within a sample and is notably insensitive to batch effects. Performance evaluation using public expression data with mRNA mixtures, single-cell RNA-Seq (scRNA-Seq) data, immunohistochemistry data, and simulated bulk RNA-seq samples, indicated that the TICPE can estimate the proportion of immune cells with levels of accuracy that are clearly superior to other methods. Furthermore, we showed that the TICPE could effectively detect prognostic signals in patients with tumors and changes in the fractions of immune cells during immunotherapy in melanoma. In conclusion, our work presented a unique novel method, TICPE, to estimate the proportion of immune cells in specific cancer types and explore the effect of the infiltration of immune cells on the efficacy of immunotherapy and the prognosis of cancer. The source code for TICPE is available at https://github.com/huitingxiao/TICPE.

scholarly journals Reprogramming Immune Cells for Enhanced Cancer Immunotherapy: Targets and Strategies

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Dong ◽  
Zhuo Wan ◽  
Xiaotong Gao ◽  
Guodong Yang ◽  
Li Liu
Keyword(s):  
Immune Cells ◽  
Causes Of Death ◽  
Immune Cell ◽  
Ex Vivo ◽  
Immune Surveillance ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
The Past ◽  
Cancer Types

Cancer is one of the leading causes of death and a major public health problem all over the world. Immunotherapy is becoming a revolutionary clinical management for various cancer types. Restoration of aberrant immune surveillance on cancers has achieved markable progress in the past years by either in vivo or ex vivo engineering of the immune cells. Here, we summarized the central roles of immune cells in tumor progression and regression, and the existing and emerging strategies for different immune cell-based immunotherapies. In addition, the current challenges and the potential solutions in translating the immunotherapies into the clinic are also discussed.

scholarly journals TIMER2.0 for analysis of tumor-infiltrating immune cells

2020 ◽  
Vol 48 (W1) ◽  
pp. W509-W514 ◽  
Author(s):  
Taiwen Li ◽  
Jingxin Fu ◽  
Zexian Zeng ◽  
David Cohen ◽  
Jing Li ◽  
...  
Keyword(s):  
Immune Cells ◽  
Large Scale ◽  
Immune Cell ◽  
The Cancer Genome Atlas ◽  
Multiple Cancer ◽  
Public Data ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Transcriptomic Changes ◽  
Web Platform

Abstract Tumor progression and the efficacy of immunotherapy are strongly influenced by the composition and abundance of immune cells in the tumor microenvironment. Due to the limitations of direct measurement methods, computational algorithms are often used to infer immune cell composition from bulk tumor transcriptome profiles. These estimated tumor immune infiltrate populations have been associated with genomic and transcriptomic changes in the tumors, providing insight into tumor–immune interactions. However, such investigations on large-scale public data remain challenging. To lower the barriers for the analysis of complex tumor–immune interactions, we significantly improved our previous web platform TIMER. Instead of just using one algorithm, TIMER2.0 (http://timer.cistrome.org/) provides more robust estimation of immune infiltration levels for The Cancer Genome Atlas (TCGA) or user-provided tumor profiles using six state-of-the-art algorithms. TIMER2.0 provides four modules for investigating the associations between immune infiltrates and genetic or clinical features, and four modules for exploring cancer-related associations in the TCGA cohorts. Each module can generate a functional heatmap table, enabling the user to easily identify significant associations in multiple cancer types simultaneously. Overall, the TIMER2.0 web server provides comprehensive analysis and visualization functions of tumor infiltrating immune cells.

scholarly journals Leveraging Patient‐Derived Models for Immunotherapy Research

2020 ◽  
pp. e344-e350
Author(s):  
Katerina Politi
Keyword(s):  
Cancer Immunotherapy ◽  
Cancer Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Experimental Models ◽  
Cancer Types ◽  
Cancer Immunotherapies ◽  
Immune Oncology

As cancer immunotherapies become mainstream for the treatment of many different cancer types and the numbers of new agents continue to increase, the need for experimental models is also rising. An approach to develop and study models for immune-oncology that has garnered intense interest in recent years is that of using patient-derived models. Patient-derived models can recapitulate many of the features and heterogeneity of the corresponding human tumors. Historically these models have been used to study cancer cell–intrinsic properties of tumors and drugs that target tumor cells directly. In recent years, increasing recognition of the role immune cells play in cancer and how these represent good therapeutic targets has led to efforts to optimize and use patient-derived models for cancer immunotherapy studies. Patient-derived models are now being used to study the properties of cancer cells that modulate their ability to respond to immune stimulation. Further efforts are underway to use and develop patient-derived models that incorporate human immune cells in vitro and in vivo (humanized mice) so that cancer cell–immune cell interactions can be studied in the context of cancer immunotherapies. As these models are further refined, leveraging patient-derived models for cancer immunotherapy research can provide insight into mechanisms of sensitivity and resistance to cancer immunotherapies, uncover new targets, reveal how specific agents work, and be used to evaluate the antitumor efficacy of therapeutic regimens.

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