tbuckley/cabot-search huggingface dataset:
Effect of novel autologous immune training platform on end-stage patients with cancer.
Authors: John F Pulford, James A. Lederer, E Murzin, D Younger, Jeffrey C. Goh, Ganessan Kitchenadasse, Victoria Atkinson, Warren Lance Joubert, Vineet Kwatra, Meena Okera, Sarwan K. Bishnoi, Sharron Gargosky, Frank Borriello, Rohit Joshi
Journal: Journal of Clinical Oncology (2024)

2546 Background: SUPLEXA therapeutic cells are the initial autologous and non-engineered candidate to emerge from the novel ENLIST cells training platform. Manufacturing is robust, reproducible and with an acceptable cost of goods. The method requires 35 days to produce multiple doses. Multiple mechanisms of SUPLEXA therapeutic cells have been delineated and all appear to complement that of immune checkpoint inhibitors (ICIs) with SUPLEXA cells serving to enhance the number of primed anti-tumor host T cells while ICIs serve to increase the durability of primed T cells by blocking their premature down-regulation. Methods: A 35 patient Phase 1 single-agent study survey study is currently ongoing in Australia to test the safety and clinical activity of SUPLEXA cells in end-stage patients with various tumor types. No chemo preconditioning or concomitant cytokine treatment was employed. CYTOF analysis of longitudinal peripheral blood is used to monitor changes to the host immune system. Results: To date, SUPLEXA therapeutic cells have demonstrated safety and significant clinical benefit with an observed CR, PR, and many durable SD in approximately half the patients. Several solid tumor patients remain on study beyond 1 year and doing well. Longitudinal analysis of PBMCs from SUPLEXA cell treated cancer patients demonstrated durable changes in the composition of myeloid immune cell subsets in SUPLEXA treated patients, impacting the anti-tumor bias of the host immune system. Specifically, we identified a dramatic decrease in the number of peripheral myeloid derived suppressor cells (MDSCs), within 3 weeks of SUPLEXA treatment. In patients with CR and PR, we also identified stable increases in activated classical CD14+ blood monocytes. Conclusions: SUPLEXA therapeutic cells are a highly differentiated approach to cellular therapy. The first-in-human experience demonstrated a pristine safety profile and strong clinical benefit as a single-agent. The pharmacodynamic decrease of in the number of MDSCs, known to suppress the anti-tumor immune response and limit immune checkpoint inhibitors (ICIs) efficacy, supports the further clinical testing to test the hypothesis that the multiple mechanisms of SUPLEXA cells will enhance the clinical activity of ICIs. Clinical trial information: NCT05237206 .
ITHindex: An integrated tool for quantifying intra-tumor heterogeneity using omics data in cancers.
Authors: Yutao Liu, Yuan Jiang, Wenchuan Xie, Jing Zhao, Guoqiang Wang, Shangli Cai, Yongqin Wen
Journal: Journal of Clinical Oncology (2024)

e14689 Background: Intra-tumor heterogeneity (ITH) is a hallmark of cancer and plays a significant role in tumor evolution, treatment response, and the development of drug resistance. However, there is currently no standardized metric for assessing ITH in clinical practice. Several recent studies have proposed different algorithms of ITH based on multi-omics data. In this study, we have developed a web-based tool for analyzing tumor heterogeneity using diverse omics data and investigated the correlation between different ITH algorithms using TCGA data. Methods: We collected previously published ITH algorithms based on single-/multi-region genomic, transcriptomic, and proteomic data. We integrated these algorithms into a web server called ITHindex, which utilizes Shiny framework. TCGA data was employed for a comprehensive comparison of five ITH algorithms including MATH, CNH, DEPTH2, Shannon index and DITHER. Results: ITHindex (https://xwen.shinyapps.io/ithindex/) is an open-access online tool that encompasses a total of eight algorithms. Based on the type of input data, these algorithms can be categorized into SNV, cancer cell fraction (CCF), copy number variations segment, bulk or single-cell RNAseq, and multi-region mass spectrometry of protein. According to the calculation principles, these algorithms include those based on Shannon entropy, MAD, tumor clonality, ratio, and distance. To demonstrate the practicality of ITHindex, we employed TCGA data to calculate ITH values using five algorithms. The analysis unveiled that the distribution of the same algorithm differs across various tumor types. When considering the same type of input data, different algorithms exhibited a strong correlation. Furthermore, with the exception of MATH, the other ITH values displayed a negative correlation with overall survival. Conclusions: ITHindex is a user-friendly web-based tool that quantifies intra-tumor heterogeneity, empowering researchers to investigate the role of ITH in oncologic biology.
A novel liquid biopsy assay with an 88% detection rate of genomic alterations across CNS tumors.
Authors: Matthew Gordon Varga, Christian Klosowski, Xavier Bower, David Tsao, Gary A. Palmer, Santosh Kesari
Journal: Journal of Clinical Oncology (2024)

2077 Background: Diagnosis and treatment decisions for CNS tumors rely upon imaging with subsequent histological and genomic analyses of tissue to identify appropriate courses of therapy. Genomic profiling of tumor tissue for informative alterations is used to guide treatment, however contemporaneous tissue can sometimes be unavailable, inconclusive or overlook possible actionable alterations given the high amount of spatial heterogeneity in certain tumor types such as glioblastomas GBMs. Liquid biopsies may pose a possible solution, as they are readily accessible and provide a holistic snapshot of the tumoral genomic landscape. However, detection of ctDNAs from CNS tumors is impeded by its inherently low shedding biology and poor permeability across the BBB resulting in low plasma variant allele fractions (VAFs), with alteration detection rates ranging 27-55%. Thus, current assays do not yet have the sensitivity to be clinically useful in aiding decision making for CNS tumors. Methods: 62 cases of primary CNS tumors were submitted commercially for assessment with Northstar Select, a tumor-naive, plasma-based ctDNA liquid biopsy assay. Cases were obtained from a single clinic dating from January-December 2023. Results: See table. Conclusions: There remains an unmet clinical need for a highly sensitive liquid biopsy assay for use in determining the genomic landscape of CNS tumors to aid in clinical decision making. Current assays do not have a low enough limit of detection (LoD) to accurately detect ctDNAs at low VAFs. Herein, we demonstrate that Northstar Select has a detection rate of 88.7% in all cases and 91.4% in GBMs, nearly doubling current rates. This is due to the assay’s uniquely low LoD of 0.13-0.16% VAF, which is below the 0.17% median VAF demonstrated across CNS tumors in this study, allowing for more low-abundance alterations to be detected. Given the increased total variant detection rate, nearly 50% of which were actionable when alterations were detected, these data support the clinical utility of Northstar Select to inform clinical decisions either as a complement to imaging and tissue analyses or independently when tissue biopsies are infeasible. These data further suggest that the clinical utility of Northstar Select may be expanded into metastatic brain disease and other low ctDNA shedding tumors. [Table: see text]
Relationship of angiotensin II receptor blocker (ARB) to the effectiveness of immune checkpoint blockade (ICB) in non-small-cell lung cancer (NSCLC) and inhibition of angiotensin II/AGTR1 signaling in fibroblasts to reduce collagen deposition in the tumor microenvironment (TME).
Authors: Kai Yang, Jiahui Chu, Jie Mei, Yongmei Yin
Journal: Journal of Clinical Oncology (2024)

e14618 Background: Immune checkpoint blockade (ICB) has achieved remarkable success. However, not all patients with advanced tumors respond to ICB. Remodeling of the tumor microenvironment (TME) has emerged as a strategy to facilitate the development of cancer therapies. As the most notable features of TME, immune cells and collagens play a significant role in influencing anti-tumor immunity, with collagen deposition is the most significant physical barrier that hinders immune cell infiltration. Cancer patients are often prescribed multiple medications to address pre-existing comorbidities or side effects from anti-tumor therapy. Given the high prevalence of concurrent medications and the potential for interactions between them and ICB, we identified that the angiotensin II receptor 1 (AGTR1) was positively expressed in CAFs and AGTR1 inhibitor angiotensin receptor blocker (ARB) suppressed the expression of type I collagen and promote immune infiltration. Methods: Retrospective clinical study: An in-house cohort was a multi-center cohort and included 270 patients with non-small-cell lung cancer (NSCLC) receiving ICB therapy from 2020 to 2021 from The Affiliated Wuxi People's Hospital of Nanjing Medical University and The First Affiliated Hospital of Nanjing Medical University. Meta-analysis: 4 studies involving 1,268 participants in total and an in-house cohort with 270 participants were included. We performed an additional meta-analysis on the association between the use of ARBs in cancer patients receiving ICB therapy. Animal models: Xenograft tumor models were randomly divided into two groups, including control and Losartan-treated groups, and mouse cancer models were randomly divided into three groups at the first round and four groups at the second round. Three groups included control, Losartan-treated, and Losartan-treated &amp; CD8-deleted groups, and four groups included control, Losartan-treated, anti-PD-1-treated, and Losartan &amp; anti-PD-1-treated groups. Results: Patients with NSCLC who received ARBs showed improved overall survival and response to immunotherapy compared to those who did not receive ARBs. Losartan, a representative drug of the ARB class, significantly increased collagen deposition in mice tumors, elevated levels of immune cell infiltration, and sensitized anti-PD-1 therapy. Conclusions: We reported that Losartan shaped an inflamed TME by inhibiting collagen I expression of CAFs and enhanced anti-PD-1 immunotherapy in the mouse tumor model. We recommend that ARB should be selected as much as possible for patients receiving ICB therapy and requiring antihypertensive treatment.
Possibilities of long-term atezolizumab immunotherapy in patients with metastatic urothelial cancer.
Authors: Sergey Kamishov, Mirzagaleb Tillyashaykhov, Elena Boyko, Shakhnoza Khamoydinovna Niyozova, Kamila Izrailbekova, Meri Lipartiya, Odiljon Kobilov, Dilshod Rafiev
Journal: Journal of Clinical Oncology (2024)

e14628 Background: Results from various studies have indicated that atezolizumab can be an effective and well-tolerated treatment option for patients with advanced and metastatic urothelial cancer. However, the landscape of oncological practices in Uzbekistan reflects a scarcity of experience and data concerning the utilization of atezolizumab in the treatment of patients afflicted with urothelial cancer. This research endeavors to bridge this gap by contributing. Methods: In our retrospective study, a total of 44 patients were selected, with a mean age of 64.5±7.6 years, diagnosed with stage IV urothelial cancer and the presence of distant metastases in the lungs, bones, and liver. There were 28 (63.6%) males and 16 (36.4%) females. Group 1 included 18 (40.9%) patients with elevated PD-L1 levels SP142 – IC 2/3, receiving atezolizumab at 1200 mg intravenously (IV) on day 1 of each 21-day cycle + cisplatin at a dose of 70 mg/m 2 body surface area (BSA), IV, on day 1 of each cycle, and gemcitabine at a dose of 1000 mg/m 2 BSA, IV, on days 1 and 8 of each cycle. Group 2 included 26 (59.1%) patients receiving standard chemotherapy (cisplatin + gemcitabine) in the same regimens. Immunohistochemical analysis was performed using the Ventana Bench Mark Ultra automated stainer with Ventana PD-L1 SP142 monoclonal antibodies. Results: The research was conducted from September 2019 to May 2023, and the administered treatment was the first line for these patients. Treatment was administered until disease progression was registered or until the development of unacceptable toxicity. Grade I toxicity was not observed in both groups. Grade II toxicity in Group 1 was noted in 3 (16.7%), and in Group 2 - in 4 (15.4%). Grade III toxicity was identified in 9 patients (50.0%) in Group 1 and 14 patients (53.8%) in Group 2. Grade IV toxicity was encountered in 6 patients (33.3%) in Group 1 and 8 patients (30.8%) in Group 2. Hematological toxicity, regardless of atezolizumab use, predominated among the III and IV degrees of toxicity. The median overall survival in Group 1 was 14.8 months (95% CI: 12.8-16.2), while in Group 2, it was 11.9 months (95% CI: 9.3-13.5). Progression-free survival in Group 1 was 6.8 months (95% CI: 5.1-7.4), and in Group 2, it was 4.3 months (95% CI: 3.8-5.7). The objective response rate in Group 1 was 44.5%, and in Group 2, it was 38.5%. Conclusions: Atezolizumab, used in combination with standard platinum-based chemotherapy in the first line, improves treatment outcomes for metastatic urothelial cancer by increasing overall survival and progression-free survival without causing an increase in the toxicity of the administered therapy.
Effect of SLAMF8 on the phagocytosis of tumor-associated macrophages in colorectal cancer.
Authors: Qun Zhang, Zhihao Liu, Xingzhi Han, Xiaoping Qian
Journal: Journal of Clinical Oncology (2024)

e14571 Background: Phagocytosis plays an essential role in innate immunity and is key in bridging innate immunity and adaptive immunity. Phagocytosis checkpoints promote tumor immune escape by inhibiting phagocytosis by tumor-associated macrophages (TAMs). SLAMF8, which is mainly expressed on the surface of TAMs, may be involved in regulating the tumor immune microenvironment. However, its regulation of the phagocytosis of TAMs remains unclear. The present study aims to investigate the effect of SLAMF8 on the phagocytosis of TAMs and to provide a new target for tumor immunotherapy. Methods: The dataset including 458 colorectal cancer (CRC) tissues from the TCGA database was used to analyze the correlation between the expression of SLAMF8 and several classical phagocytosis checkpoint molecules, and the above correlation was further verified by the RNA-sequencing data of 20 CRC tissues in our center. In vitro, the effects of SLAMF8 expression level on tumor cell proliferation and macrophage phagocytosis were also evaluated. RNA sequencing was used to analyze the effect of SLAMF8 on the expression of genes related to promoting macrophage phagocytosis. The effect of SLAMF8 on the expression levels of proteins related to FcR-mediated phagocytosis was detected by flow cytometry. Results: The results from the TCGA dataset and our validation dataset both showed that the SLAMF8 expression was significantly positively correlated with the expression levels of classical phagocytosis checkpoint molecules such as SIGLEC11, SIGLEC10, SIGLEC9, CD274and LILRB1. In vitro, functional tests showed that the phagocytosis of CT26 CRC cells by macrophages was significantly enhanced after SLAMF8 knockdown. RNA sequencing results suggested that the expression levels of molecules related to FcR-mediated phagocytosis were significantly upregulated after the decreased expression of SLAMF8.Flow cytometry analysis confirmed that SLAMF8 inhibited the expression levels of FcR-mediated phagocytosis related proteins such as CD16/32, CD64, and CD11b. Conclusions: SLAMF8 may release the “don’t-eat me” signal to inhibit FcR-mediated phagocytosis of tumor cells by macrophage. Further studies are needed to investigate the underlying mechanism of SLAMF8 on the regulation of macrophage phagocytosis and to test its possibility as a new immunotherapy target.
The clinical application of circulating tumor cells (CTCs) for immunotherapy in advanced pancreatic cancer.
Authors: Jianhua Chen, Li‘Na Zhang, Junjian Li, Jing Wang, Ping Lin, Hongxia Wang
Journal: Journal of Clinical Oncology (2024)

e14541 Background: Circulating tumor cell (CTCs) has the potential utility for screening, prognostic and predictive assessment, and offers the potential for personalized management. This trial aimed to evaluate the prognostic and predictive impact of programmed cell death ligand 1 (PD-L1) positive CTCs in patients with pancreatic ductal adenocarcinoma (PDAC). Methods: Twenty-three heavily treated advanced PDAC patients were randomized to receive camrelizumab combined with apatinib or capecitabine, or placebo plus capecitabine until disease progression or unacceptable toxicity, and peripheral blood CTCs samples were collected at baseline and after treatment. Forty-nine CTCs samples from 23 recruited advanced PDAC patients were detected by subtraction enrichment and immunostaining-FISH (SE-iFISH). PD-L1 expression level also was evaluated in tumor tissue samples by Immunohistochemistry (IHC). Investigator-assessed 6-month overall survival (OS) rate and 3-month progression-free survival (PFS) rate was evaluated. Results: The positive detection rate of CTCs in 23 PDAC patients was 95.7%. The cell sub-types of sizes of CTC analysis showed that 58.6% CTCs was the small CTCs (Diameter &lt; 5μm). CTCs karyotypes analysis exhibited that triploid small CTCs were the main karyotype (41.2%) in small CTC, and pentaploid large CTCs was the major karyotype (74.7%) in large CTCs. PD-L1 + CTCs were detected in 43.5% of PDAC patients. Tissue PD-L1 positive detection rate was 50% (CPS &gt; 1%) in available tissue samples(n=10). The presence of PD-L1 + CTCs cohort exhibited a significant increase in 6-month OS rate (80% versus 38.5%, P &lt; 0.05) and 3-month PFS rate (70% versus 23.1%, P &lt; 0.05) compared to PD-L1 - CTCs cohort. Compared with the PD-L1 - CTCs patients, the combination therapy camrelizumab markedly improved the 6-month OS rates (75% versus 50%) and 3-month PFS rate (62.5% versus 25%) in PD-L1 + CTC patients. Conclusions: PD-L1 + CTCs could be considered as a favorable prognostic marker in advanced PDAC. These results suggest that PD-L1 + CTCs might be used as a predictor of the efficacy of cancer immunotherapy in advanced PDAC, and provide a new monitoring method for the precise treatment of advanced PDAC. The expanding sample size test is now ongoing. Clinical trial information: ChiCTR1900024095 .
Characteristics of hospital admission during checkpoint-inhibition therapy.
Authors: Tabea Constanze Fröhlich, Jonas Paul Wiegmann, Nora Möhn, Susann Mahjoub, Laura Duzzi, Emily Narte, Johanna Aurich, Dominik Berliner, Thomas Wirth, Heiko Golpon, Imke von Wasielewski, Florian Heidel, Thomas Skripuletz, Ralf Gutzmer, Gernot Beutel, Philipp Ivanyi
Journal: Journal of Clinical Oncology (2024)

e14510 Background: Immune checkpoint inhibitors (ICI) have enriched the therapeutic armamentarium in outpatient oncology care; however, data on necessity of hospitalizations associated with immune-related adverse event (irAEs) are scarce. Here, we retrospectively characterize hospitalizations of patients (pts) undergoing ICI. Methods: Between 12/2019 and 06/2022, 237 pts were included. Clinical data and characteristics of ICI were collected during a 6-month observation period after the initiation of therapy. Descriptive Statistics and Kaplan-Meier statistics were administered. Results: 30 out of 237 pts were hospitalized (HA+). Most common underlying tumor entities in the overall cohort were malignant melanoma (59.5%), renal cell carcinoma (13.1%), and non-small cell lung carcinoma (12.7%). Hospitalized pts exhibited an increased rate of pulmonary and cerebral metastases. We observed a significantly higher hospitalization rate during dual ICI with Nivolumab and Ipilimumab. The predominant irAEs for hospitalization were colitis (26.7), followed by hypophysitis (13.3%), leading to a median hospitalization of 7 days (range 1-34). Most pts were treated on the general ward (76.7%). Interdisciplinary consultations were frequent, especially to gastroenterology (46.7%) and neurology (26.7%). Although a trend towards an overall survival in the HA+ subgroup was identified, no statistically significant difference was found among the subgroups. Conclusions: The hospitalization rate of 12.6% is comparable to the literature. There was a disproportionate admission of patients with immune-related colitis and hypophysitis compared to the prevalence described under ICI. We observed a high need for interdisciplinary consults in line with the heterogeneity of immune-mediated side effects. When compared to non-hospitalized pts, there was no survival disadvantage in the cohort of hospitalized patients.
Transforming tumor immune microenvironments with a novel systemic enveloped oncolytic virotherapy targeting all tumor sites.
Authors: Duong Nguyen, Yunyi Kang, Karolin Streule, Stephanie Songco, Lina Schulte, Laura Edith Schneider, Selamawit Worku Alemu, Trevor Smith, Ashley Alamillo, Ana Sy-Quia, Forrest Neuharth, Ivelina Minev, Jacob Stewart, Matthew Seikkula, Boris Minev, Thomas Herrmann, Antonio F. Santidrian
Journal: Journal of Clinical Oncology (2024)

2559 Background: Systemic oncolytic virotherapy offers a promising solution for treating both local and metastatic diseases. However, the rapid inactivation of virotherapeutics by the immune system has resulted in disappointing clinical efficacy. To address this challenge, we have built a new program (ImmunoNova) to develop a cellular-based technology that protects oncolytic virotherapy, allowing for successful targeting of the therapy to tumor sites and effectively overcoming clinical challenges. This approach involves utilizing a newly selected and engineered, tumor-selective strain of vaccinia virus (RT-01). This strain produces high levels of extracellular enveloped virions (EEVs) that contain a second human cell-derived membrane, providing augmented protection against elimination by the immune system when administered systemically. The process requires specific manufacturing methods to preserve this crucial second human cellular membrane. Methods: The resistance of the manufactured enveloped RT-01 (envRT-01) virus against human humoral immunity and its rapid spread were assessed ex-vivo using a plaque assay. EnvRT-01 was administered in various xenograft and syngeneic models to evaluate its specificity in targeting tumors and its therapeutic efficacy, either alone or in combination with cell therapies. The amplification of virus-encoded RFP was monitored using an imaging system. Additionally, flow cytometry and immunohistochemistry (IHC) were employed to analyze immune infiltration in both treated and untreated tumors. Results: EnvRT-01 particles exhibited an approximately 80% survival rate in the presence of active complement. In animal studies, a single systemic dose of envRT-01 selectively targeted three distinct human cancer indications (lung, melanoma, head &amp; neck), leading to the suppression of tumor growth in all three cases. Similarly, in an immunocompetent syngeneic lung tumor model, envRT-01 effectively targeted and reduced multiple murine lung tumors with just a low single dose of treatment. EnvRT-01 was capable of targeting and expressing viral-encoded proteins in all tumor sites and drastically modifying the tumor immune microenvironment, favoring an anti-tumor immune phenotype and facilitating other cell therapies such as innate-based cell therapies. Conclusions: The development of this innovative enveloped oncolytic virotherapeutic, coupled with advancements in its manufacturing methods, opens up new possibilities in the realm of cancer therapy. It addresses the limitations posed by untargetable and untreatable metastatic diseases, presenting a transformative solution with broad implications for the field.