bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune checkpoint inhibitor (ICI) rechallenge after immune-related adverse events (irAE) requiring hospitalization: A single-center 10-year experience.
Authors: Wu Chia-Yun , Zubiri Leyre , Rouhani Sherin Juliet , Merkin Ross D. , Holt Allison , Falade Ayo Samuel , Grealish Kelley , Hathaway Nora , Reynolds Kerry Lynn 
Published: June 2024

e14609 Background: ICI rechallenge after irAE has become a significant clinical dilemma, with irAE recurrence rates of 30-40% after rechallenge. Here we examine factors influencing ICI rechallenge rates across a 10-year period at the Massachusetts General Hospital (MGH), where the Severe Immunotherapy Complications service is available to provide multidisciplinary irAE expertise. Methods: We included patients admitted to MGH for an irAE from August 2011 to July 2023. We collected baseline demographics, ICI regimens, and irAE features. The choice of ICI used at rechallenge was grouped into 3 categories: 1) restarting an ICI within the same class, 2) switching classes (CTLA-4 to PD-(L)1 or vice versa), or 3) de-escalating from combination to monotherapy. Chi-square and Mann-Whitney U tests were applied to descriptive statistics. Results: Among 5882 patients treated with ICI, 671 (11.4%) patients were admitted for irAE. The median age was 67.6 (IQR, 59-74.9) years and 58% were male. Initial ICI regimens consisted of anti-PD-(L)1 (64.8%), anti-CTLA4 (10.9%), and ICI combinations (24.3%). 174 of 671 patients (25.9%) were rechallenged after an irAE requiring hospitalization. Rechallenge was common after rheumatologic, endocrine, dermatologic irAE and GI irAE, but rare after cardiac, neurologic, or pulmonary irAE (Table 1). The median time to rechallenge was 25 days (IQR 18-91) after endocrine irAE and 72 days (IQR 40-209) after non-endocrine irAE (p<0.001). Rechallenge was more common in melanoma (35%, p<0.001), and less common in lung (13.6%, p<0.001) and GU cancers (10%, p=0.003). Rechallenge rates were significantly higher in patients initially on combination therapy (39.6%) versus PD-(L)1 monotherapy (15.5%), p<0.001. Of those rechallenged, 43.2% initially on combination therapy were de-escalated to monotherapy and 53% were restarted within the same class. Amongst the PD-(L)1 monotherapy group, 88.4% were restarted within the same class and 11.6% switched classes. Conclusions: Here we examine practice patterns at a large academic center, where 25.9% of patients with irAE requiring hospitalization were rechallenged. Rechallenge was more prevalent in patients with melanoma or on ICI combination therapy, whereas it was less frequent following cardiac, neurologic, or pulmonary irAE. Under adequate risk-benefit evaluation, close monitoring, and multidisciplinary care, ICI rechallenge can be considered. [Table: see text]
Impact of the tumor proportion score (TPS) and the combined positive score (CPS) on the use of immunotherapy in patients with metastatic non-small cell lung cancer.
Authors: Kanan Duaa , Kanan Tarek , Celik Serkan , Hacıhasanoğlu Ezgi , Oven Basak Bala 
Published: June 2024

e14611 Background: Expression of programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) has often been measured by the Tumor Proportion Score (TPS) (1). Recently, the Combined Positive Score (CPS), which evaluates PD-L1 expression in tumor and inflammatory cells and applies to other types of cancer including gastric and head and neck cancers, was found to be equally predictive of the response to immunotherapy in NSCLC (1). In this study, we aimed to conduct a single center retrospective analysis to evaluate the clinical use and impact of using TPS and CPS data in patients with metastatic NSCLC. Methods: Patients with NSCLC who had TPS and CPS scores and received PD-1/PD-L1 inhibitors between 2021-2022 as a monotherapy or in combination with chemotherapy were included. Patients’ data was retrieved from the electronic medical record data and analysis included histopathological data, lung cancer surgical history, presence of EGFR mutation, ALK mutation, Ki67, use of adjuvant chemotherapy, type of immunotherapy used, and development of immune checkpoint inhibitor- related toxicity and treatment as applicable. TPS and CPS positivity was defined as >1 % and >1 respectively. Statistical methods employed included descriptive approaches such as calculated means as well as the Kaplan-Meier estimate. Results: 40 patients with NSCLC were included. Patients’ age ranged from 19 to 82 years old with an average age of 64.3 years old. Most patients had adenocarcinoma (65 %) and were at stage IV (72.5 %). TPS positivity was identified in 29 patients (72.5 %) and CPS positivity was identified in 35 patients (87.5 %). Patients received immunotherapy mostly as first or second line of treatment (90 %). Immune checkpoint inhibitors received by patients were pembrolizumab (50 %), nivolumab (35 %), atezolizumab (12.5 %), and durvalumab (2.5 %). The median overall survival was 16, 12, and 17 months in the <1 %, 1-49 % and > 49 % TPS groups respectively (p= 0.354); while the median overall survival was 11, 16 and 17 months in the <1, 1-49, and > 49 CPS groups respectively (p= 0.417). It is critical to highlight that there were 7 patients (17.5 %) with TPS of zero who had CPS positivity (score range: 1-10). Most of these patients had adenocarcinoma (71.4 %), received pembrolizumab or atezolizumab (85.7 %) and had a median survival of 16 months. Conclusions: The Combined Positive Score (CPS) has proven to be an effective method in evaluating the level of expression of PD-L1 in NSCLC (1,2). Similar to TPS, CPS provides critical information that can be applied to guide the use of immunotherapy, and which can greatly impact patients with NSCLC. 1. De Marchi et al., 2021. 2. Ulas et al., 2023.
Toxicity of weight-based vs. flat dosing for immune checkpoint inhibitors in patients with low weight: Retrospective analysis from a tertiary care center.
Authors: Hamad Hussein , Kyasaram Ravi Kumar , Mangla Ankit 
Published: June 2024

e14616 Background: Immune checkpoint inhibitors (ICI) have come to the forefront of cancer therapy. Barring Ipilimumab, all other ICIs are dosed at flat doses for ease of administration. Pharmacokinetic studies have shown a wide range of peak and trough concentrations for flat doses. However, for underweight patients (<50 Kg), when one looks at weight-based dosing, it may seem that flat dose may deliver excessive amounts of the drug within a short period of time, which in turn may cause an immune-related adverse event (irAE). We conducted a retrospective study comparing the toxicities and outcomes of weight based and flat doses in underweight patients treated with ICI. Methods: This is a retrospective study of patients receiving ICI for any cancer-related indication. Patients receiving chemotherapy with pembrolizumab, nivolumab and/or ipilimumab were included. Patients on other ICI were excluded. All grade toxicities were recorded, and Odds ratio (OR) was calculated using the Z-test. Results: 313 patients were included where 255 (81.5%) were females, median age 66 years (range 19-93), and 225 (72%) were White. Lung cancer was the most common histology (n-170, 54%) followed by H&N (n-34, 11%) and GI cancers (n- 27, 9%). The median weight was 47 Kgs (range: 31-50). 252 patients (80.5%) received flat dose ICI and 61 patients (19.5%) received weight-based ICI, most of whom (n-45, 74%) received prior to 2018. Median ICI cycles was 4 (2-9) vs. 5 (3-10). Single agent PDL-1 inhibitor was prescribed to 205 patients (65%) of which 120 received pembrolizumab (59%) and 85 received nivolumab (41%), and 89 patients (28%) received ICI in combination with chemo or targeted therapy. 94 patients (30%) experienced all grade toxicities. Thyroid dysfunction (n-47, 15%) and colitis (n-24, 8%) were the most common. There was a non-significant trend towards lower toxicity in weight-based dosing: 13 (21.3%) vs. 81 (32.1%), OR =0.57, 95% CI (0.29 - 1.11) p =0.10, and a trend toward less hospitalization or need for treatment for iRAE: 8 (13.1%) vs. 55 (21.8%), OR =0.54, 95% CI (0.24 - 1.20) p=0.13. Significantly higher toxicity was recorded when chemotherapy-ICI or TT-ICI combinations: 56 (24.8%) vs. 38 (43.7%) OR = 0.42, 95% CI (0.25 - 0.71) p= 0.001. There was no difference in death or needing hospice care rates: 43 (70.5%) vs 169 (67.1%), OR= 1.17 (95% CI, 0.64 - 2.16) p= 0.61. Conclusions: Compared to standard flat dosing, weight-based dosing of ICI was associated with a trend towards lower iRAE in patients < 50 Kgs without a difference in survival. These results urge the oncology community to consider the potential financial toxicity savings if weight-based dosing of ICI is adopted more broadly in underweight patients without negatively impacting outcomes, large scale and prospective studies are needed to support this hypothesis.
Long-term pooled safety analysis of tislelizumab as monotherapy or in combination with chemotherapy in patients with advanced cancers.
Authors: Zhou Caicun , Meyer Tim , Huang Rose , Yuan Yuan , Schnell Patrick , Wu John , Kadva Alysha , Mehmeti Jola , Ajani Jaffer A. 
Published: June 2024

e14617 Background: The PD-1 inhibitor tislelizumab (TIS) has demonstrated efficacy and tolerability in patients (pts) with advanced cancers. To evaluate long-term safety of TIS as monotherapy (mono) or in combination (combo) with chemotherapy in pts with advanced gastrointestinal (GI) and lung cancers, data were pooled from 8 pivotal phase III studies conducted between 2017 and 2023. Methods: 2636 adult pts with GI (n=1415) or lung (n=1221) cancers and an ECOG PS of 0-1, who received ≥1 dose of study drug, were included. Endpoints included immune-mediated adverse events (imAEs) by tumor type, treatment (Tx) duration, and race. Early and delayed imAEs, defined as occurring within 1 year (yr) and >1 yr after starting TIS, respectively, were also evaluated. Results: Median (range) Tx duration in the GI and lung cancer studies was 4.9 (0.1-50.4) and 6.2 (0.2-44.9) months, respectively, with 20.9% and 29.6% of pts, respectively, having ≥1 yr exposure. Most pts were Asian (GI mono: 76.4%; GI combo: 74.9%; lung mono: 79.2%; lung combo: 100%). ImAEs occurred in 32.5% of pts in the GI mono and combo studies (Table); most were low grade, with grade ≥3 imAEs reported in 6.2% (mono) and 8.2% (combo) of pts. Incidence of imAEs in the mono and combo lung studies, respectively, was 34.3% and 43.7% (grade ≥3: 6.4% and 9.6%). ImAE incidence was comparable between Asian and White race subgroups, respectively, in the GI mono (33.6% vs 29.5%), GI combo (34.9% vs 23.9%), and lung mono (35.5% vs 32.3%) studies. Most imAEs occurred within 1 yr of starting TIS in the GI (mono: 32.0%; combo: 32.4%) and lung (mono: 34.1%; combo: 42.2%) studies. Delayed imAEs occurred less often than early imAEs; of pts still on Tx or in study follow-up 1 yr after initial Tx, 54/757 (7.1%) in GI studies and 86/804 (10.7%) in lung studies experienced a delayed imAE. Frequently reported imAEs were consistent, regardless of time of onset (early vs delayed). Conclusions: This long-term, retrospective, pooled analysis supports TIS as a tolerable Tx for pts with advanced GI and lung cancers. Delayed imAEs were relatively infrequent and were consistent with the established safety profile of TIS. Clinical trial information: NCT03412773 ; NCT03430843 ; NCT03358875 ; NCT03663205 ; NCT03777657 ; NCT03783442 ; NCT03594747 ; NCT04005716 . [Table: see text]
Combination treatment effect of an immunotherapeutic agent with microtubule inhibitors.
Authors: Perrin Hee Benjamin Thor , Kazarian Edgar K. , Karp Jacob A. , Hamel Ernest , Madiraju Charitha 
Published: June 2024

e14619 Background: The microtubule (MT) is a polymer formed by self-assembly of αβ-tubulin heterodimers. MT inhibitors either stabilize or destabilize microtubule assembly and halt cell proliferation during the mitotic phase of the cell cycle. However, due to non-specificity, high resistance, and adverse reactions observed with MT-targeting drugs, various approaches to novel combination chemotherapies are being used in the clinic. The specific goal of this study is to investigate the ability of an immunotherapeutic agent to alter the activity of MT-targeting chemotherapeutics when used in a combination treatment approach. Methods: The combination treatment effect of the immunotherapeutic agent with microtubule inhibitors was investigated using two methods: 1) Tubulin polymerization studies using purified tubulin and microtubule inhibitors, paclitaxel (a microtubule stabilizing agent) and dolastatin 10 (a microtubule destabilizing agent), studied alone or in combination with the immunotherapeutic agent. (2) Co-culture system expressing the stably expressing Nuclear Factor of Activated T cells (NFAT)- Renilla luciferase (NFAT- Rluc) reporter gene to study anti-tumor immune response of MT inhibitors alone or in combination with the immunotherapeutic agent. Results: Spectrophotometric-based tubulin polymerization studies demonstrated that the immunotherapeutic agent (0.01 - 0.1 mg/mL) altered tubulin polymerization when studied in combination with either paclitaxel (10 µM) or dolastatin 10 (0.5 mM). Luminescence-based reporter gene expression studies in a co-culture system, consisting of CD3− antigen presenting Chinese hamster ovary and CD3+ effector Jurkat T cells, demonstrated the combination treatment effectively induced NFAT- Rluc activity when compared to the controls, the immunotherapeutic agent alone or to the MT-inhibitor alone. Statistical analysis was done using one-way analysis of variance (ANOVA). A significant difference ( p < 0.05) in mean IC50 values (expressed as ng/mL ± SEM, N=4) was observed between the immunotherapeutic plus dolastatin 10 versus the immunotherapeutic agent alone, and a 6.5-fold decrease (85% reduction) in the IC50 value was observed for induction of NFAT- Rluc activity in the presence of immunotherapeutic plus dolastatin 10 versus the immunotherapeutic alone. There was a notable decrease (1.9-fold or 46% reduction) in the IC50 value observed for induction of NFAT- Rluc activity in the presence of the immunotherapeutic plus paclitaxel versus the immunotherapeutic alone. Conclusions: These results suggest a boost in T-cell stimulation by the immunotherapeutic agent in the presence of MT inhibitors. The implications of enhanced T-cell activation on antitumor immunity and modulation of tubulin polymerization by a combination treatment of the immunotherapeutic agent and microtubule inhibitors are currently under investigation.
Pelareorep driven blood TIL expansion in patients with pancreatic, breast and colon cancer.
Authors: Trauger Richard , Loghmani Houra , Kupic Amy , Heineman Thomas Charles 
Published: June 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 .
Interplay of cachexia progression on the efficacy and toxicity of immune checkpoint inhibitors in patients with esophageal squamous cell cancer (ESCC): A longitudinal perspective.
Authors: Li Haoqian , Li Butuo , Zhang Huan , Wang Chunni , Fan Bingjie , Wang Linlin 
Published: June 2024

e14629 Background: Immune checkpoint inhibitors (ICIs) have significantly improved the survival of patients with advanced esophageal squamous cell cancer (ESCC), however, the benefit of ICIs was limited to a few patients. It is vital to comprehend the factors influencing the response in order to identify patients who might benefit from ICIs. Cachexia, an intricate multifaceted syndrome characterized by the loss of skeletal muscle and substantial weight reduction, might impact on the immune response and efficacy of ICIs in cancer patients. The purpose of this study is to explore the impact of longitudinal dynamics of cachexia on the efficacy and adverse effect of ICIs for advanced ESCC patients. Methods: Advanced ESCC patients received at least two cycles of ICIs were enrolled from 2017 to 2021. The baseline and longitudinal changes of cachexia during ICI treatment were collected. Based on the longitudinal weight changes during ICI treatment, patients exhibiting cachexia at baseline were categorized into "reversible cachexia" and "irreversible cachexia" group, and patients without cachexia at baseline were also divided into "latent cachexia" and "cachexia-free" group. Kaplan-Meier curves and Cox regression analysis were performed to explore the impact of cachexia on the efficacy ICIs for ESCC patients. And chi-square test was used to evaluate the correlation between cachexia and immune-related adverse effects (irAEs). Results: A total of 278 individuals who had either received or were presently undergoing ICI treatment were enrolled, with the median progression free survival (PFS) of 5.8 months and overall survival (OS) of 8.3 months. Patients with cachexia before treatment had notably poorer outcomes, with median PFS of 7.9 vs 5.3 months (P=0.001), median time to progression (TTP) of 10.9 vs 6.1 months (P<0.001), and median OS of 14.3 vs 9.2 months (P=0.001). In terms of the longitudinal dynamics of cachexia, significantly inferior outcomes were observed for patients in irreversible cachexia compared to reversible cachexia, with the PFS of 4.4 months and 9 months (P<0.001), the TTP of 4.9 months and 9 months (P=0.006), and the OS of 7.8 months and 15 months, respectively (P=0.003). Although patients in latent cachexia group had inferior survival compared to cachexia-free group, no statistical difference was observed, with the PFS of 10.0 and 7.9 months and OS of 13.9 and 16.2 months. Besides, neither baseline nor longitudinal changes of cachexia was associated with irAEs for ESCC patients. Conclusions: This study indicated the impact of baseline and longitudinal cachexia on the efficacy of ICIs for advanced ESCC patients with ICIs. Dynamic monitoring and management of cachexia was recommended during the ICI treatment of ESCC patients.
Pathological evaluation of tumor immune microenvironment before first-line anti-PD1 plus anti-angiogenic therapy in patients with unresectable hepatocellular carcinoma (HCC): Towards a prediction for treatment efficacy.
Authors: Chen Jun , Zhou Mingzhen , He Xintao , Pu Xiaohong , Wu Hongyan , Chen Sidong , Wang Yang , Jiao Lei , Liu Baorui , Shen Jie 
Published: June 2024

e14662 Background: Immune checkpoint inhibitor (ICI) combined with anti-angiogenic therapy is the standard first-line treatment for unresectable HCC patients. However, most patients do not derive durable benefit and will progress faster. Simultaneously, sufficient clinically validated biomarkers to stratify patients are lacking in HCC. Recent studies have shed a light on the strong connection between immunotherapy efficacy and tumor immune microenvironment (TIME) in HCC. Thus, this study aims to investigate TIME features before treatment to develop a potential way for survival prediction which may optimize risk stratification. Methods: A total of 84 unresectable HCC patients who received first-line ICI plus anti-angiogenic therapy at Nanjing Drum Tower Hospital were included. 4 multiplex immunohistochemistry (mIHC) panels containing 18 biomarkers were developed to thoroughly evaluate immune cells in TIME before therapy, such as cytotoxic T cells, tissue-resident memory T cells, macrophages and neutrophils. TIME features were then extracted from raw image by digital pathology, including cell subpopulation abundance and spatial profiling. We identified a list of TIME features associated with objective response rate (ORR), progression free survival (PFS) and overall survival (OS), and developed a TIME-based risk score (TIS) in our cohort using machine-learning. Results: After data cleaning, a total of 78 patients with complete clinical information and TIME features were included and split into training and validation sets. A higher positive rate of CD103+ cells and CD8+ cells were observed in responder, while patients with higher CD66b+ positive rate showed shorter PFS and OS. In terms of spatial profiling, tumor cells accompanied with more CD8+ cells were associated with longer PFS and OS, while longer distance from CD14+ cells and CD66b+ cells to tumor cells favored longer PFS and OS. Regarding PFS prediction, our machine-learning model TIS included both immune cell abundance and spatial features. Stratifying patients in the low- and high-risk groups using TIS revealed prolonged PFS (p<0.0001, HR: 0.24, 95%CI [0.13-0.45]) and OS (p = 0.00057, HR: 0.27, 95%CI [0.12-0.60]) in TIS low-risk group. Moreover, ORR in TIS low-risk group was 52.9% (17/34) and 15.9% (7/44) in TIS high-risk group. Univariable and multivariable analysis demonstrated that TIS was an independent predictor for ORR (p = 0.0017), PFS (p = 0.00065) and OS (p = 0.00042). Independent validation is still awaited. Conclusions: This study demonstrates that our machine-learning based risk score can improve treatment response and survival prediction using TIME features, which provides the potential to optimize risk stratification before first-line treatment for unresectable HCC patients.