tbuckley/cabot-search huggingface dataset:
Circulating metabolic profiling as a biomarker for immune checkpoint blockade efficacy.
Authors: Erick Figueiredo Saldanha, Sally C. M. Lau, Robert C. Laister, Ben X Wang, Susanne Penny, Devanand Pinto, Adrian G. Sacher, Samuel Saibil
Journal: Journal of Clinical Oncology (2024)

2564 Background: Immune checkpoint blockade (ICB) has changed the treatment landscape of non-small cell lung cancer (NSCLC). Despite being the mainstay of treatment for advanced NSCLC, the development of resistance to ICB is common. Hence, identifying biomarkers that can be used to select patients (pts) who will benefit from ICB is crucial. Here, we interrogate the circulating metabolome to identify the metabolic parameters associated with ICB effectiveness. Methods: This single-center retrospective analysis used a mass-spectrometry (MS) targeted metabolomics approach to assess the relative abundance of 115 metabolites in baseline (pre-ICB) plasma of 55 pts with advanced NSCLC. Pts treated with ICB at the Princess Margaret Cancer Centre from 2018-2020 were included. Electronic medical records were reviewed to collect clinicopathological and treatment data. All pts had tumour next-generation sequencing (NGS) by a targeted gene panel. Descriptive statistics were used to summarize the patient characteristics, treatment modalities, and outcomes. Time-to-event outcomes were analyzed using the Kaplan-Meier method. Progression-free survival (rwPFS) and overall survival (rwOS) were defined as the time from the first treatment dose to radiographic or clinical progression or death from any cause and time from the first dose of treatment to death from any cause, respectively. The response rate was assessed using RECIST 1.1. Statistical significance was determined as a p-value &lt;0.05. Results: Amongst the 55 pts profiled, 42 (76.3%) had adenocarcinoma. The most common molecular alterations included KRAS (n=15), BRAF non-V600 (n=5), and METex14 (n=3). The median PD-L1 score was 65% (IQR 22.5 – 59%). All pts were treated with a single-agent PD-1 inhibitor, and 67.2% of pts received ICB as the first line of treatment. Metabolomic analysis of the pre-ICB initiation plasma samples identified 8 metabolites whose relative abundance significantly differed between responding (CR/PR) and non-responding pts (SD/PD). Amongst these metabolites was the endogenous danger signal Glucosylceramide (d 18:1/24:0), whose abundance was increased in the plasma of the responding pts. When we stratified pts by circulating levels of glucosylceramide, we found a statistically significant higher rwPFS (8.5 vs. 1.6 months, p=0.0001) and rwOS (13.5 vs. 6.1 months, p=0.0001) in pts who had high baseline plasma levels of Glucosylceramide (d 18:1/24:0) (top 50%) versus those with lower levels (bottom 50%). Conclusions: Utilizing a targeted metabolomics approach, we identified the metabolite and endogenous danger signal glucosylceramide (d 18:1/24:0) as a potential metabolic biomarker of response to ICB therapy. Future work will aim to validate this finding in a larger cohort and to understand the biological mechanism underpinning this correlation.
Example of a simple and scalable manufacturing process for immunomodulatory alpha neutrophils, a specifically designed immuno-cell therapy with direct and indirect anti-cancer activity for solid tumour indications.
Authors: Durva Patel, Samuel Florence, Aoife McGinley, Jakub Lich, Urvi Thacker, Alex Blyth, Andrew Willis, Alfonso Quintas-Cardama, Oxana Polyakova
Journal: Journal of Clinical Oncology (2024)

e14512 Background: Recent findings have demonstrated neutrophils play a key role in tumour control and in facilitating successful responses to cancer immunotherapy. At LIfT Biosciences we have developed the first-in-class, allogeneic, off-the-shelf, stem cell-derived immuno-cell therapy with anti-cancer neutrophil properties. Immunomodulatory Alpha Neutrophils (IMANs) exert their anti-cancer activity via multiple direct and indirect mechanisms, ensuring direct antigen-independent tumour cell killing, as well as impacting anti-cancer function of other direct acting cells such as NK and gamma delta T cells, and further immunomodulation of the environment to boost adaptive immune responses ensuring maximal T cell activity can be achieved. IMANs have the potential to provide major clinical benefits in the treatment of multiple solid tumours. Methods: We present a patent-pending, GMP-compliant manufacturing process starting with CD34+ cells isolated from mobilized peripheral blood of healthy donors. Extensive characterisation of starting material in combination with in-process and raw material controls results in a simple, consistent, scalable manufacturing process using known and established manufacturing platforms. IMANs are granulopoietic myeloid progenitors derived from the expansion of CD34+ cells followed by differentiation in proprietary media compositions, composed of critical priming agents which are known to promote anti-cancer neutrophil phenotype and function. Neutrophil functional heterogeneity is becoming increasingly appreciated and we have designed our manufacturing process to produce activated, committed, persistent IMANs with multimodal mechanisms of action. IMANs are composed of distinct neutrophil progenitor populations. IMANs are cytotoxic towards numerous solid tumour cell lines, expressing tumour-ablating Neutrophil elastase. Furthermore, IMANs exert immunomodulatory properties through cytokine and chemokine secretion, and expression of ligands for T and NK cell co-stimulatory receptors. Results: The manufacturing process has been optimised with vast expansion capacity, showing up to 1000-fold increase from starting cell populations and efficient cryopreservation with exceptional post-thaw recovery. Conclusions: Cryopreserved IMANs offer a cost-effective and globally accessible cell therapy with the potential for long term clinical benefit.
PD-1 inhibitor combined with ablation in liver metastasis: A retrospective, multicenter study.
Authors: Dengyao Liu, Tao Huang, Zhanguo Sun, Pan Hu, Tao Zhu, Dongcun Huang, Bingchen Xu, Dechao Jiao, Fujun Zhang, Letao Lin
Journal: Journal of Clinical Oncology (2024)

e14644 Background: This study aimed to retrospectively evaluate the efficacy of ablation combined with programmed cell death protein 1 (PD-1) inhibitor versus PD-1 inhibitor monotherapy in patients with liver metastasis. Methods: We retrospectively enrolled patients with liver metastasis who received PD-1 inhibitor therapy with or without ablation at three medical institutions between January 2017 and September 2022. Progression-free survival (PFS) and 1-year survival rates were compared after propensity score matching. Additionally, intrahepatic and extrahepatic lesion progression and treatment-related adverse events were recorded during follow-up. Finally, prognostic factors for the combined therapy group were analyzed. Results: We included 172 patients and classified them into the combined therapy and PD-1 inhibitor monotherapy (n = 86 each) groups. Patients in the combined therapy group had better median PFS and 1-year survival rates than those in the PD-1 inhibitor monotherapy group. Combined therapy was an independent prognostic factor for PFS in the univariate and multivariate analyses. New lesions constituted the main pattern of progression, with combined therapy showing significantly lower intrahepatic progression, but similar extrahepatic progression rates. Adverse events associated with PD-1 inhibitors were comparable between the two groups. Additionally, 8 (9.3%) patients experienced ablation-related complications. However, neither univariate, nor multivariate analyses revealed the predictive factors for PFS in the combined therapy group. Conclusions: Ablation combined with a PD-1 inhibitor was superior to PD-1 inhibitor monotherapy in improving the survival of patients with liver metastasis.
Next generation CD44v6-specific CAR-NK cells for the treatment of solid tumors.
Authors: Gabriele Pecher, Alexander Sebastian Franzén, Abdelhadi Boulifa, Clarissa Radecke, Sebastian Stintzing, Martin Raftery
Journal: Journal of Clinical Oncology (2024)

e14518 Background: There is a medical need to develop new and effective therapies against solid tumors. CD44v6, an adhesion molecule that is implicated in tumorigenesis and metastases, was identified as a suitable target in solid tumors such as triple negative breast cancer (TNBC) or glioblastoma. Methods: We have developed a next-generation CAR targeting CD44v6 that incorporates IL-15 superagonist and checkpoint inhibitor molecules to overcome the immunosuppressive microenvironment (TME). NK cells were used due to their potential for allogeneic usage. Results: CD44v6 CAR-NK cells demonstrated effective cytotoxicity against TNBC and glioblastoma in 3D spheroid models. The IL-15 superagonist was specifically released upon recognition of CD44v6 on TNBC and contributed to the cytotoxic attack. Competitive inhibition of PD1 neutralized inhibition by PD1 ligands. We have validated iPSC-derived CD44v6 CAR-NK cells. Conclusions: Next generation CD44v6 CAR-NK cells are resistant to TME immunosuppression and offer a new therapeutic option for the treatment of solid tumors.
Analysis of proteomics based on LC-MS detection on the efficacy of immunocombined therapy for hepatocellular carcinoma.
Authors: Nanya Wang, Yueqi Yan, Shibo Wang, Bo Liu, Yu Li, Ying Wang
Journal: Journal of Clinical Oncology (2024)

e14549 Background: Combined immunotherapy has become the preferred treatment for HCC. However, it faces challenges: possible serious adverse reactions, the low objective response rate, and the median overall survival is about 20 months, which is far from meeting the clinical treatment needs. There is still a lack of effective predictive biomarkers in clinical practice to screen the dominant population of combined immunotherapy. The purpose of this study is to use LC-MS to screen and identify differential metabolites between patients with different efficacy to help screen the dominant population of clinical immunotherapy. Methods: 38 HCC patients were included who were treated in the Tumor Center of the First Hospital of Jilin University from June 2020 to March 2022 and received combined immunotherapy. Sample collection and follow· -up, and collect basic clinical data. The enrolled patients underwent enhanced CT examination every 3 treatment cycles, and the efficacy of the patients was evaluated according to the solid tumor efficacy evaluation standard 1.1 (RECIST V1.1). The serum of patients before treatment was detected by LC-MS, and the difference of mass spectrometry data between patients with different curative effects was compared, and the differential metabolites were explored by proteomics analysis. Results: The best of response was partial response in 7 patients (22.6 %), stable disease in 6 patients, and progressive disease in 18 patients (58.1 %). Based on LC-MS proteomics analysis, differential metabolites between patients with different therapeutic effects were screened and identified, namely Q9Y275, Q56UQ5, P13611, and P30530 (P &lt; 0.05). The relative abundance of Q9Y275, Q56UQ5, P13611 and P30530 in the disease control rate group was higher than that in the PD group. Conclusions: Based on LC-MS proteomics analysis, four types of differential metabolites between different populations of PLC patients receiving combined immunotherapy were screened and identified, namely Q9Y275, Q56UQ5, P13611 and P30530.
Influence of gender on acute kidney injury among patients undergoing chimeric antigen receptor T-cell (CAR-T cell) therapy: Insights from National Inpatient Sample.
Authors: Joud Zakhour, Abdul Rahman Akkawi, Anas Alqam, Wissam Karam, Raj N Shah, Bassam Ibrahim Mattar
Journal: Journal of Clinical Oncology (2024)

e14524 Background: Chimeric antigen receptor T-cell (CAR-T Cell) immunotherapy has shown promising results in patients with B-cell leukemia and lymphoma and multiple myeloma. The side effect profile is still being studied and acute kidney injury (AKI) following treatment has been a commonly reported outcome in the context of cytokine release syndrome. In most cases, the kidney injury is reversible with adequate hydration and treatment of the underlying cytokine release syndrome when needed. This study aimed to investigate the outcomes of gender in patients undergoing CAR-T cell therapy along with the protective variables and independent predictors of AKI in this patient population. Methods: This was a retrospective analysis of data the National Inpatient Sample (NIS) between January 2019 and December 2020 to identify patients who underwent CAR-T cell therapy. We stratified the data based on gender and studied the incidence of AKI in patient admitted to the hospital primarily for CAR-T cell treatment. The primary endpoint was in-hospital mortality, AKI, average age, length of stay (LOS), and total charge by hospital. Additionally, we explored independent predictors and protective variables for AKI in patients receiving the treatment. Results: A total of 4010 patients underwent CAR-T Cell therapy from January 2019 to December 2020. Among these patients, females comprised 41.1% (n=1650). The mean age at the time of CAR-T cell treatment for males was 57.5 and for females 56.9. The inpatient mortality rates for both groups were 3% (p=0.97). The total incidence of AKI in patients undergoing CAR-T cell therapy was 14.9%, with rates of 19% in males and 9% in females (p&lt;0.01). LOS for males and females was 19 days, and 20 days respectively (p=0.4). Average total hospital charge for males was 958,345 and 1,017,685 for females (p=0.3642). Interestingly, there was no difference between genders in relation to the incidence of cytokine release syndrome (p=0.3). Notably, CKD, obesity, liver disease, and electrolyte imbalances were independent predictors of AKI with an adjusted odds ratio of 4.26 (p&lt;0.01; 95% confidence interval [CI]: 1.7-10.6), 2.7 (p=0.015; 95% CI: 1.2-6.06), 2.7 (p=0.045; 95% CI: 1.02-7.23), 2.5 (p&lt;0.01; 95% CI: 1.67-3.81). Importantly, gender was a protective variable for females when it came to AKI after CAR-T cell therapy with an adjusted odds ratio of 0.38 (p&lt;0.01; 95% CI: 0.23-0.63). Conclusions: AKI has been documented as a common side effect in patients undergoing CAR-T cell therapy. In most cases the kidney injury is reversible with adequate hydration and CRS treatment when necessary. Our study highlights CKD, obesity, liver disease, and electrolyte imbalance as independent predictors of AKI after CAR-T cell therapy and female gender as a predictive variable against developing AKI.
Dual-agent immunotherapy for prevention of melanoma brain metastases: A real-world analysis of 8686 patients.
Authors: Alireza Mansouri, Debarati Bhanja, Hannah E. Wilding, Nicholas Mikolajewicz, Ahmad Ozair, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2024)

2022 Background: Melanoma brain metastases (MBM) are a common endpoint among patients with advanced melanoma and prognosis is poor. Strategies for MBM prevention can prolong life and reduce morbidity. Dual agent immunotherapy (dIT) has been paradigm-changing in management malignant melanoma management. Recent clinical trials have supported the role of dIT for upfront management of small, asymptomatic MBM. Yet, its potential role in extending brain metastasis-free survival (BMFS) and decreasing MBM incidence overall has not been explored. The objective was to compare MBM incidence, median overall survival (OS), and BMFS in melanoma patients treated with dIT versus single immunotherapy (sIT). Methods: A real-world deidentified database collating clinical information from 92 organizations (TriNetX, Inc.) was queried. Melanoma patients without brain metastases prior to immunotherapy were stratified by treatment (anti-CTLA4 [sIT] and combination anti-CTLA4/ anti-PD1 [dIT]) and propensity-score matched. MBM incidence was measured within 5 years post-IT initiation. A complementary single-institution retrospective cohort study analyzed melanoma patients treated from 2012-2019. Median OS and BMFS were compared via log-rank tests and multivariate Cox proportional-hazards models. A competing risk analysis was performed to measure the cumulative incidences of MBM and death without MBM. Results: TriNetX identified 8,686 melanoma patients who received immunotherapy (4,585 dIT; 4,101 sIT). MBM incidence was 13.4%, and 19.3%, for the dIT and sIT cohorts, respectively (p &lt; 0.0001). DIT was associated with a lower likelihood of developing MBM compared to sIT (RR [95%CI], 0.69 [0.62-0.77]). After propensity-score matching on demographics and comorbidities, MBM incidence was similarly 13.3% and 18.5% for the dIT and sIT cohorts, respectively. On single-institution analysis, 130 melanoma patients were included (87 dIT; 43 sIT with anti-CTLA4). In patients with stage IV disease, median OS was 1.70 and 3.66 years for the sIT and dIT cohorts, respectively (p=0.6). Median BMFS was 1.56 and 2.36 years in the sIT and dIT cohorts respectively (p=0.76). On multivariable Cox proportional hazard regression analysis, NRAS mutation was significantly correlated with a worse prognosis for BMFS. Conclusions: These data highlight the impact of combination anti-CTL4/ anti-PD1 immunotherapy in decreasing MBM incidence. The potential primary prophylactic role of dIT in MBM warrants prospective exploration, including mechanistic understanding.
Effect of RIPK3 on non-canonical PANoptosis to suppress anti-tumor immunity in lung cancer.
Authors: Hua Zhong, Yv Yang, Yue Wang, Erpeng Wu
Journal: Journal of Clinical Oncology (2024)

e14565 Background: Hypoxia and glucose deprivation are common features of solid malignancies and considered the causes of tumor necrosis, while the molecular mechanisms of tumor cell death and its impact on tumor progression are not yet clear. PANoptosis is a newly recognized programmed cell death pathway, characterized by the simultaneous activation of necroptosis, apoptosis and pyroptosis. The canonical PANoptosis is controlled by an ASC-dependent multimeric protein complex named the PANoptosome. Methods: Using immunoblot and immunofluorescent analysis, we described the RIPK3 expression patterns and detected the programmed cell death markers in lung cancer tissues. We built a RIPK3 2 ×Fv -Flag-expressing PKLC cell line and identified the key molecules involved in tumor cell death by using MS analysis of RIPK3-immunoprecipitate. These molecules were confirmed by CRISPR-Cas9 mediated gene knockout. Then we analyzed the secretome by 4D-diaXLMS of cell death conditioned medium and identified a variety of DAMPs and cytokines released by PANoptotic tumor cells. Last, the differences of tumor growth and the immune microenvironment between wild-type and Ripk3 KO PKLC-CDX were compared. Results: Hypoxia and glucose deprivation could induce over expression of RIPK3 and mediated PANoptosis of tumor cells. The oligomerized RIPK3 rapidly recruits MLKL and mediates MLKL phosphorylation to induce necroptosis. Further aggregated RIPK3 can recruit RIPK1 and assembles with FADD and Caspase-8, causing Caspase-8 auto-cleavage. Active Caspase-8 can directly cleave caspase-3 and GSDMD to induce apoptosis and pyroptosis. The PANoptosis we described is initiated by RIPK3 and independent of ASC, which we termed non-canonical PANoptosis. We also found that Caspase-3, as an executor of apoptosis, is able to cleave RIPK3, RIPK1 and truncated GSDMD, negatively regulating PANoptotic cell death. Finally, we identified a variety of DAMPs released by PANoptotic tumor cells, which facilitate neutrophil differentiation and activation, promoting tumor progression by suppressing anti-tumor immunity. Conclusions: Hypoxia and glucose deprivation induce non-canonical PANoptosis that is initiated by RIPK3 and independent of ASC. The PANoptotic tumor cells suppress anti-tumor immunity through releasing DAMPs and cytokines to mediate neutrophil differentiation and activation, which promote lung cancer progression.
Phase I trial of talimogene laherparepvec for the treatment of peritoneal surface malignancies (TEMPO).
Authors: John H. Stewart, Melissa Lowe, Andrew G Chapple, Donna Niedzwiecki, Ashley Moyer, Emily Bolch, Shannon Diane MacLaughlan, Edward A. Levine, Omeed Moaven, Niharika Nettu, John H Strickler, Dan G. Blazer
Journal: Journal of Clinical Oncology (2024)

2668 Background: Peritoneal surface malignancies (PSM) constitute a group of difficult-to-treat metastatic diseases that respond poorly to standard chemotherapy. Talimogene Laherparepvec (T-VEC), the first FDA-approved oncolytic virus (OV), demonstrates potential in treating various malignancies by effectively initiating crucial immune responses. Yet, the utility of intraperitoneal (ip) T-VEC for unresectable PSM is still unexplored. Methods: TEMPO (NCT03663712) was a nonrandomized, open-label, multicenter phase I trial involving 18 patients with unresectable PSM originating from the appendix (n=14), ovary (n=3), or small bowel (n=1). The trial aimed to determine the recommended Phase 2 dose (RP2D) and maximum tolerated dose (MTD) of ip T-VEC, as well as to evaluate its safety and tolerability. An exploratory endpoint was the Restricted Mean Survival Time (RMST), the estimated non-parametric mean survival time up until the longest patient follow-up time (i.e. maximum of the longest follow-up, and generally an underestimate of the actual mean survival time especially in small samples). Patients received an initial dose of 4x10 6 plaque-forming units (pfu) of ip T-VEC, followed by their assigned dose every two weeks for up to four additional doses, using a standard ‘3+3’ dose escalation scheme. The doses tested were 4x10 6 , 4x10 7 , and 4x10 8 pfu of ip T-VEC. Safety assessments were conducted regularly. Results: The RP2D is 4x10 8 pfu of T-VEC. The trial reported no dose-limiting toxicities, thus the MTD was not reached. Treatment-Related Adverse Events (TRAEs) were recorded and categorized by the maximum dose received (Table).One patient treated with 4x10 6 pfu had grade 3 abdominal pain and another grade 3 fatigue. No severe TRAEs occurred with 4x10 7 pfu. One patient showed a grade 3 neutrophil count decrease at 4x10 8 pfu. The RMST, calculated with a truncation time of 5.5 months, varied across the doses. Patients receiving 4x10 6 pfu had an RMST of 3.1 (95% CI= 1.550-4.733) months, while those treated with 4x10 7 and 4x10 8 pfu had RMSTs of 4.2 (95% CI= 2.492-5.884) and 4.6 (95% CI= 3.551-5.722) months, respectively. Conclusions: We conclude that ip T-VEC is safe in patients with unresectable PSM. TEMPO successfully identified 4x10 8 pfu as the RP2D for TVEC. Notably, the RMST increased with increasing doses of TL. These results are promising, considering the limited benefit of conventional chemotherapy in treating PSM. This study positions T-VEC as a promising candidate for combination immunotherapies for PSM that amplifies the bystander immune response induced by OVs. Clinical trial information: NCT03663712 . [Table: see text]