tbuckley/cabot-search huggingface dataset:
Novel engineered regulatory macrophages combined with ICIs for post-transplant recurrence after liver transplantation for HCC.
Authors: Yongwei Hu, Mingshen Zhang, Kaiming He, Lei Lv, Haoyuan Yu, Siqi Li, Wei Liu, Hua Li, Shuhong Yi, Yang Yang, Linsen Ye
Journal: Journal of Clinical Oncology (2024)

e14582 Background: Liver transplantation is the most effective treatment for early-stage hepatocellular carcinoma (HCC), but post-transplant recurrence limits the efficacy of surgery and affects the patient prognosis. Most of the current attempts to apply immune checkpoint inhibitors (ICIs) to posttransplant recurrence have resulted in either acute allograft rejection or tumor progression, which may be related to the disruption of the immune balance that maintains immune tolerance and enhances immune activation. Methods: Therefore, we constructed an engineered regulatory macrophages (Mregs) with anti-tumor capacity in the transplant setting using reprogrammed liposomes to precisely regulate the immune microenvironment of post-transplant recurrence, in order to create suitable conditions for the safe use of ICIs. Results: Experimentally, Mregs were shown to prolonged allograft survival without promoting tumor development. Through fusing with the Mregs membrane, reprogrammed liposomes insert an anti-CD47 lipid shell onto the surface, enhancing phagocytosis against tumor. The drug-loaded inner core entered into the cytoplasm to reprogram Mregs. Tomivosertib downregulated the expression of PD-L1 and attenuated the immunosuppressive effect. Pexidartinib inhibited the polarization of the M2 pathway and upregulated the expression of CD80, CD86, and MHC II, enhancing the ability of antigen presentation. Combination with anti-PD-L1 antibodies can enhance anti-tumor effect without accelerating allograft rejection. Both in vivo and in vitro results demonstrate that engineered Mregs provide conditions for the safe use of anti-PD-L1 antibodies in the context of transplantation. Conclusions: Engineered Mregs combined with ICIs enhances immunotherapeutic efficacy and provides a viable therapeutic approach for posttransplant recurrence after liver transplantation for HCC.
Intracellular retention of TCRαβ/CD3 and CD7 to generate novel allogeneic CAR-T cells targeting CD7 for treating T-cell malignancies.
Authors: Jun Li, Kaichun Liu, Jianmin Fu, Shanshan Chen, Yinhang Zhang, Guanggui Xu
Journal: Journal of Clinical Oncology (2024)

e14531 Background: The treatment for patients with T-ALL/LBL who relapse after hematopoietic stem cell transplantation (HSCT) are currently restricted. CD7 is highly expressed on the surface of T-ALL/LBL T cells and CAR-T cell therapy provides a promising avenue towards remission. However, CD7-targeting immunotherapies may be compromised by T-cell fratricide. Furthermore, in addition to the long production time, high cost, and high risk of production failure, the biggest challenges of autologous CAR-T cell therapy are how to isolate a sufficient number of healthy T cells from malignant T cells. Thus, allogeneic CAR-T cells can overcome these hurdles. Methods: A novel non-gene-editing allogeneic CAR-T platform was developed on the base of intracellular retention of membrane proteins, and named ThisCART (TCR and/or HLA-I intracellular sequestered). CD7-directed ThisCART cells are readily produced with a single lentiviral vector, encoding both a CD7-targeting CAR, an anti-CD7and anti-CD3 single chain antibody with the KDEL peptide fused to its C-termini. The surface expression of CAR, TCRαβ/CD3 and CD7 was measured by flow cytometer. Specific tumor cytotoxicity was evaluated both in vitro and in vivo. Furthermore, the safety of donor derived ThisCART cells were tested in a xenogeneic GvHD model. Results: The manufacturing platform of CD7 ThisCART was able to achieve over 130-folds of ex vivo CAR-T expansion in all batches, with the purity of products (CAR-positive/CD7-negative/TCRαβ-negative) above 99%. In preclinical models, CD7 ThisCART did not induce GvHD, and exhibited superior antitumor function compared to Control T. CD7 ThisCART cells were readily produced to a quantity and quality supporting clinical investigation. Conclusions: CD7 ThisCART cells based on intracellular retention of TCRαβ/CD3 complex and CD7 demonstrated superior CD7-dependent cytotoxicity and no xenogeneic GvHD in murine models. With streamlined single-vector-based production and potent cytotoxicity and favored preclinical safety profile, CD7 ThisCART warrant clinical investigation.
The effect of resting dendritic cells on overall survival in the hepatocellular carcinoma tumor microenvironment.
Authors: Paul Hanona, Neil Jairath, Mark Farha, Lavanya Yohanathan, Daniel Ezekwudo, Ishmael A. Jaiyesimi
Journal: Journal of Clinical Oncology (2024)

e14559 Background: Hepatocellular carcinoma (HCC) continues to have a poor prognosis even in the advent of new immunotherapy regimens. An area of growing interest in HCC is its tumor immune microenvironment. Classifying the immune microenvironment based on available genomics can lead to insights on prognosis and treatment, especially regarding the role of immunotherapy. Methods: RNA sequencing data was extracted from The Cancer Genome Atlas (TCGA), specifically from the hepatocellular carcinoma section (n = 366). CIBERSORT was utilized to organize the immune cell fractions present for each patient sample. Radiant by Shiny was used to perform a linear regression elucidating the relationship between overall survival and several other variables including: age, gender, tumor stage, race, ethnicity, B-cells naïve, B-cells memory, plasma cells, CD8 T-cells, CD4 T-cells, T-cells follicular, T-cells regulatory, natural killer activated and resting cells, monocytes, macrophages (M0, M1, M2), dendritic cells activated and resting, mast cells activated and resting, eosinophils, and neutrophils. Subgroup analyses were also performed via radiant regarding gender, race, and resting dendritic counts. Results: Resting dendritic cells were independently prognostic of overall survival on multivariable analysis (p = 0.041). The coefficient of correlation was +164.53 showing a positive association between the number of resting dendritic cells and the overall survival. Subgroup analysis showed no difference in resting dendritic counts between males and females (p = 0.526). Also, there was no difference seen in resting dendritic counts between populations of Asians and African Americans (p = 0.873), Asians and Whites (p = 0.223), and between Whites and African Americans (p = 0.811). Conclusions: Patients with a higher number of resting dendritic cells in their tumor immune microenvironment had a better overall survival. There was no difference between males and females in the resting dendritic counts. Likewise, there was no difference in the resting dendritic counts between Asian, African American, and white populations. Resting dendritic cells have been shown to be enriched in hepatocellular carcinomas with a low tumor mutational burden. This is a paradigm that should be explored further in the context of immunotherapy. Resting dendritic cells are also in a state of plasticity as they go from resting to active. Future genomic analysis of the tumor microenvironment regarding this plasticity could also lead to enhancing treatment options.
Racial/ethnic disparities in healthcare utilization, post-operative outcomes, and overall survival for IDH-wildtype glioblastoma stratifying by <i>MGMT</i> promoter methylation status.
Authors: Ping Zhu, Clark C Chen
Journal: Journal of Clinical Oncology (2024)

2081 Background: Glioblastoma is the most common malignant primary brain tumor and molecular profiles such as IDH1/2 and MGMT promoter methylation status have significant influence on survival outcomes. There is no "real-world" study has investigated the racial/ethnic disparities in healthcare utilization and outcomes for IDH-wildtype glioblastoma patients with MGMT promoter methylation status. Methods: A total of 21971 IDH-wildtype glioblastoma patients ( MGMT promoter-methylated: 41.5%, 9110/21971) were derived from the National Cancer Database (NCDB, 2018-2021). Race/Ethnicity was grouped into Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Asian/Pacific Islander (API), American Indian/Alaska Native (AIAN), Hispanic, and Others. Overall survival (OS) was set as primary outcome. Healthcare utilization and post-operative outcomes are secondary endpoints. Multivariable logistic regression models, Kaplan-Meier methods, and Cox proportional hazards models were performed for post-operative outcomes, healthcare utilization, and overall survival. Results: Compared to NHW, AIAN were 78% more likely to have MGMT promoter methylation after adjusting age and gender (aOR=1.78, p=0.030). API and Hispanic were significantly less likely to undergo GTR over STR comparing to NHW. The odds of receiving chemotherapy and RT for race/ethnicity minorities patients were significantly lower than NHW (Chemotherapy: NHB: aOR=0.79, AIAN: aOR=0.57, Hispanic: aOR=0.83; RT: NHB: aOR=0.88, Hispanic: aOR=0.80). The median OSs by race/ethnicity (NHW, NHB, API, AIAN, Hispanic, and Others, respectively) were: 11.5, 12.3, 14.5, 9.2, 13.6, and 15.6, months ( MGMT promoter-unmethylated, p&lt;0.001), 15.9, 18.8, 23.7, 14.8, 19.6, and 15.5, months ( MGMT promoter-methylated, p&lt;0.001). After adjusting the covariates, NHB, API, and Hispanic experienced significantly lower risk of death comparing to NHW (aHR=0.82, 0.66, and 0.75, all p&lt;0.001). Similar results were validated in stratification analysis by MGMT promoter methylation status, except MGMT promoter-unmethylated AIAN experienced 70% higher risk of death than NHW (aHR=1.70, p=0.021). Conclusions: Our findings suggests that racial/ethnic disparities exist in healthcare utilization, postoperative outcomes, and overall survival in IDH-wildtype glioblastoma population.
Correlation of distinct circulating cytokine/chemokine profiles with clinical benefits of Pexa-Vec (thymidine kinase-deactivated vaccinia virus plus GM-CSF) and cemiplimab (REGN2810; anti-PD-1) in metastatic or unresectable renal cell carcinoma (mRCC).
Authors: Jaime R. Merchan, Woo Kyun Bae, Chan Kim, Sung Yong Oh, Hyo Jin Lee, Kwonoh Park, Nataliya Mar, Russell Kent Pachynski, Seung-Hoon Beom, Lucia Carranza, Seunghyun Ma, Melissa Divya Mathias, Frank A. Seebach, Sun Young Rha
Journal: Journal of Clinical Oncology (2024)

e14539 Background: This study explores the transformation of 'cold' tumour microenvironments into 'hot' ones in mRCC, focusing on the potential of Oncolytic Viruses (OVs) for personalized immunotherapy. Recognizing the variability in patient responses, the research underscores the necessity for reliable biomarkers. The objective is to examine the correlation between plasma cytokine/chemokine levels and the efficacy of Pexa-Vec and cemiplimab, proposing that these biomarkers could predict treatment outcomes and contribute to more personalized cancer treatment protocols. Methods: In this study, mRCC patients from the REN026 trial were categorized into three treatment groups: Pexa-Vec (Intratumoral and intravenous) and cemiplimab combination therapy (N=65), intravenous Pexa-Vec and cemiplimab combination therapy (N=54), and cemiplimab monotherapy (N=14). Blood samples were collected at baseline, during treatment, and at end of treatment (EOT) for analysis. Subsequently, the plasma samples underwent analysis using the Human Cytokine 96-Plex Discovery Assay through the Luminex 200 system. The statistical approach included the Mann–Whitney U-test or Wilcoxon signed-rank test, along with a Cox proportional hazards model. The False Discovery Rate (FDR) method was employed to control type I error. Results: During the follow-up period from June 2018 to February 2023, key outcomes were observed as follows (Table): In the Pexa-Vec and cemiplimab cohort, a lower baseline of MCP-3 or an increased rate of change in post-treatment levels of IFNβ, Eotaxin, IL-1α, and sFasL were associated with improved Progression-Free Survival (PFS). Specifically, a low baseline of MCP-3 or an increased level of Eotaxin and sFasL post-treatment correlated with enhanced Overall Survival (OS). In the intravenous Pexa-Vec and cemiplimab group, a rise in post-treatment levels of IFNβ, Eotaxin, IL-17F, and sFasL were indicative of better PFS, with elevated Eotaxin also suggesting improved OS. Within the cemiplimab monotherapy group, an increase in post-treatment IP-10 was linked to favourable PFS. Conclusions: Our findings suggest the potential utility of plasma cytokine and chemokine profiles in clinical benefits of mRCC patient to the combination of Pexa-Vec and cemiplimab, thereby aiding in future personalized treatment approaches.
Pelareorep driven blood TIL expansion in patients with pancreatic, breast and colon cancer.
Authors: Richard Trauger, Houra Loghmani, Amy Kupic, Thomas Charles Heineman
Journal: Journal of Clinical Oncology (2024)

e14625 Background: Tumor infiltrating lymphocytes (TILs) represent a major immunological tumor control mechanism that is associated with better prognosis in cancer. One emerging cancer treatment approach to leverage the therapeutic potential of TILs is the expansion and adoptive cell transfer of autologous TILs, commonly referred to as autologous adoptive therapy (ACT). ACT clinical studies have shown encouraging results. While the majority of these trials have targeted melanoma, impressive clinical benefit has also been observed in cervical cancer, with preliminary efficacy in colorectal cancer (CRC), cholangiocarcinoma, non-small cell lung cancer, and breast cancer. Pelareorep (pela) is a live, replication competent reovirus (T3D) that selectively replicates in cancer cells and represents a new class of immunotherapy currently being explored in multiple clinical settings. To examine the effect of pela therapy on TIL expansion we applied T cell receptor sequencing of matched tumor tissue and whole blood pre- and post-treatment in a subset of breast, pancreatic, and (CRC) subjects receiving chemotherapy and atezolizumab, an anti-PD-L1 therapy, and intravenous treatment with pela. Methods: Identification of TIL clones was performed by immunosequencing of the CDR3 regions of human T-cell receptor-β (TCRβ) chains (ImmunoSEQ Assay, Adaptive Biotechnologies). DNA was isolated from tissue and blood at baseline and from blood collected post-treatment. TCRβ CDR3 regions were amplified by a multiplex, bias-controlled PCR with primers targeting the V and J genes of T cells as well as primers targeting housekeeping genes to quantitate the total nucleated cells in each sample. PCR products were sequenced on an Illumina NextSeq. Results: Pela treatment was observed to increase the expansion of pre-existing and new TIL clones in the blood in from all tumor samples after one cycle of treatment. We also observed that pre-existing TIL clonal expansion in the blood seemed to correlate with reductions in tumor volume in pancreatic cancer and to a lesser extent in CRC patients who received multiple cycles of therapy. Interestingly, unlike atezolizumab, pela’s clinical activity was lost when combined with avelumab, a PD-LI inhibitor capable of binding Fc receptors and inducing ADCC. The addition of avelumab eliminated pre-existing TIL expansion in the blood highlighting the importance of TIL expansion following pela therapy. Conclusions: These findings, while preliminary, suggest that the clinical benefits observed following pela immunotherapy may be mechanistically analogous to ACT. Accordingly, pela therapy may offer a means to directly expand TILs without the need for tumor resection, ex vivo TIL expansion, T cell ablation and IL-2 therapy. Clinical trial information: Eudra-CT: 2020-003996-16 .
The role of obesity on outcomes of adoptive cellular therapy in solid tumors.
Authors: Derrick Law Tao, Mirella Nardo, Cheuk Hong Leung, Heather Y. Lin, Lei Kang, Hung Le, Ecaterina Elena Dumbrava, David S. Hong
Journal: Journal of Clinical Oncology (2024)

2544 Background: Anti-tumor response and toxicity outcomes with adoptive cell therapy (ACT) have been heterogeneous in solid tumors, and it is still unclear how host factors such as obesity may contribute to efficacy and immune-related safety events. Methods: We conducted a retrospective study including 95 consecutive advanced solid tumor patients who received ACT on protocol in the Department of Investigational Cancer Therapeutics between August 2017 and June 2023. We analyzed baseline clinical characteristics, immune-related safety events, response to ACT, and survival outcomes between obese and non-obese patients. Overweight was defined as body mass index (BMI) 25-29.99 kg/m 2 and obesity was defined as BMI ≥ 30 kg/m 2 at the time of treatment. Fisher’s exact test was used to compare the proportions of categorical variables between two groups. Pairwise comparison with Bonferroni correction was performed if necessary. T-test was used to compare the mean of continuous variables between two groups. The distributions of overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method. Log-rank test was used to compare the distributions of OS and PFS by baseline characteristics. Hazard ratio was estimated in Cox proportional hazard regression model. A two-sided p-value &lt; 0.05 was considered statistically significant. Results: The median age at treatment was 60.9 (range 20.5 – 84). Thirty-nine patients (41.1%) had a BMI (kg/m 2 ) defined as normal weight, 26 (27.4%) as overweight, 27 (28.4%) as obese, and 3 (3.2%) as underweight. Eighty-four (88.4%) were Caucasian; 54 (56.8%) were female. The most prevalent cancers were gastrointestinal (21.1%), gynecologic (15.8%), sarcoma (11.6%), mesothelioma (10.5%), breast (8.4%). The median follow-up was 39.9 months, with a median PFS of 2.8 months (95% CI: 2.3, 3.5) and a median OS of 8.4 months (95% CI: 6.4, 11.0). The risk of death among the obese patients was 0.56 (95% CI: 0.31, 0.99) times the risk of death among normal weight patients (p = 0.045). No weight difference was found between responder and non-responder. While BMI was not associated with the development of cytokine release syndrome (CRS), the patients with normal weight had a higher proportion of immune effector cell-associated neurotoxicity syndrome (ICANS) than the obese patients (23.1% vs 0%, p = 0.049). Conclusions: Obesity was associated with improved survival and decreased ICANS rates following ACT. Our findings may suggest a differential interaction between obesity, different immunotherapeutic modalities, and hematologic vs nonhematologic cancers.
Integrative multimodality spatial biomarker analysis for tailoring checkpoint inhibitor therapies in non-small cell lung cancer.
Authors: Corinne Ramos, Corinne Ramos, Victor Senechal, Richard Ruez, Sandra Delebecq
Journal: Journal of Clinical Oncology (2024)

e14664 Background: Checkpoint inhibitor therapy has become a cornerstone in the treatment of non-small cell lung cancer (NSCLC). However, the response to checkpoint inhibitors varies widely among patients, with some experiencing significant benefits and others facing adverse reactions without therapeutic gain. The ability to accurately predict which patients will benefit from checkpoint inhibitor therapies is essential for enhancing treatment efficacy and minimizing side effects. In this context, the identification and analysis of predictive biomarkers, including the expression of immune checkpoint proteins such as PD-L1 and TIGIT, and the comprehensive profiling of cytokines in the tumor microenvironment, are of paramount importance. Methods: A multimodal strategy was employed to identify predictive biomarkers for checkpoint inhibitor therapy in non-small cell lung cancer (NSCLC). This approach integrated metabolic, transcriptomic, and proteomic data to achieve a thorough insight into the biomarkers likely to influence patient responses. The diverse data sets were fused through advanced machine learning techniques, creating a holistic dataset. Analysis of this integrated dataset facilitated the discovery of multimodal biomarker signatures, offering the potential to predict which NSCLC patients would positively respond to checkpoint inhibitor treatments. Results: Initial observations revealed considerable variability in the expression of PD-L1 and TIGIT alongside other immune checkpoint molecules, across different regions of the tumor microenvironment in non-small cell lung cancer (NSCLC). Multimodal biomarker signatures, encompassing distinct expressions of immune checkpoint inhibitors, cytokine levels, and the presence of immune cells, showed a strong correlation with patient outcomes following treatment with immune checkpoint inhibitors. Conclusions: Our research highlights the significant promise of using a multimodal stratification method to unravel the complexities of non-small cell lung cancer (NSCLC) and to predict patient responses to immune checkpoint inhibitors. Through the integration of metabolomic, transcriptomic, and proteomic data, we discovered distinctive biomarker signatures that were highly predictive of responses to these immunotherapies.
Risk factors for thrombotic events among patients taking immune checkpoint inhibitors: A systematic review and meta-analysis.
Authors: Junmin Song, Ana Yasmin Caceres Lessa, Pei-Lun Lee, Ishmum Chowdhury, Yu Chang, Yu-Cheng Chang, Rachel Schwartz, Kuan-Yu Chi, Abhishek Kumar
Journal: Journal of Clinical Oncology (2024)

e14610 Background: Cancer is well known to be a hypercoagulable state, and several studies suggest that targeted therapies, including immune checkpoint inhibitors (ICIs), may also cause thrombotic events. Despite the identification of multiple risk factors associated with ICI administration, no studies have definitively clarified these factors. This study aims to comprehensively investigate the risk factors of thrombotic events upon ICI use. Methods: We conducted a systematic review and meta-analysis. Search terms included immune checkpoint inhibitors (PD-1, PD-L1, and CTLA-4 inhibitors) and thrombotic events (venous, arterial thrombosis, and immune-related adverse events). The primary endpoint was calculating each risk factor's aggregated odds ratio (OR) for any kind of thrombotic event, including venous and arterial thrombosis. The secondary endpoint was to combine the hazard ratio (HR) for each risk factor on thrombosis formation. Results: Out of 8718 studies found, a total of 13 studies with 10608 patients were included. Most patients had non-small cell lung cancer (37.2%) or melanoma (24.8%) and had advanced disease (stage IV being 84.9%). All possible risk factors included in the studies were extracted, and their OR and HR were aggregated. Notably, previous history of thrombus (OR: 3.01; 95% CI: 1.53-5.92), history of COPD (OR: 1.87; 95% CI: 1.00-3.51), smoking history (OR: 1.69; 95% CI: 1.15-2.48), and BMI higher than 30 (OR: 1.68, 1.37-2.07) were associated with a higher risk of thrombotic events. In multivariate analysis, poor performance status of ECOG PS ≥ 2 (HR: 1.55, 95% CI: 1.02-2.36, I 2 : 35%) and Khorana risk score ≥ 2 (HR: 1.5, 95% CI: 1.23-1.84, I 2 : 0%) showed higher thrombotic risk. Conclusions: Similar to the known risk factors for thrombosis, previous history of thrombus, smoking history, and obesity are predictors of future thrombus in patients on ICI treatment. Further studies are needed to know if arterial and venous events happen at different rates and/or are associated with different risk factors. [Table: see text]