bluuebunny/crossref_metadata_2025_split huggingface dataset:
COVID-19 induced remission of biliary and renal cell carcinomas.
Authors: Tan Jocelyn L 
Published: June 2023

e14598 Background: Clear cell renal carcinoma and cholangiocarcinoma are resistant to standard therapy. Complete remissions are rare. SARS-CoV-2 (COVID-19) boosts anti-viral immune responses but effects on cancers are unknown. Case reports of hematologic cancer remissions after COVID infection are emerging. Anti PD1/PD-L1 antibody therapy have prolonged remission in 20% of solid tumor patients. mRNA COVID-19 vaccines and COVID-19 active infections create anti-viral immune responses - increased IgG titers, SARS-CoV-2-specific antibodies, and boost T-cell response. Anti PD-1/PD-L1 antibodies immune responses, are presumed independent of the immune response to COVID vaccination/infection. Two previous case reports of hematologic remission were seen after COVID infection. (Hodgkins, multiple myeloma). There are no cases of solid cancer remission after COVID-19 exposure. Methods: Three patients with solid cancers and complete/near complete radiographic remissions after COVID-19 exposure. Two on low carbohydrate diets. History, dietary course and clinical outcomes are presented. Results: Case 1: 58 year old male diagnosed with stage IV clear cell renal carcinoma (lung nodules, mediastinal nodes). After 5 years he progressed on Sunitinib and began Nivolumab. His cancer stabilized but hypophysitis, diarrhea, severe jaw pain ended his treatment. After COVID-19 booster vaccine, he became anorexic, lost 50 lbs over 8 weeks (267 to 211 lb). Relapse was suspected but PET CT showed complete resolution of his lung nodules and adenopathy. Asymptomatic and in remission over 9 months post vaccine. Case 2: 51 year old male heavily pretreated stage 4 renal cell cancer, bone, liver, nodal metastases. On Nivolumab with stable disease but after COVID booster vaccine had high fever, fatigue, myalgia. PET CT scans later showed near complete resolution of his bony, hepatic and nodal metastatic sites. Case 3: 75 year old male with unresectable cholangiocarcinoma on second line Atezolizumab. COVID-19 infection was followed by complete radiographic remission. Conclusions: Effects of SARS-CoV-2 (COVID-19) on cancers remain unknown. Few case reports of cancer remissions after infections are emerging. These are two cases of renal cell cancers in complete remission after COVID-19 vaccination while on immunotherapy. Both followed low glycemic diets. Third case was a complete remission of biliary cancer after an acute COVID-19 infection. Proposed anti-cancer mechanisms - pathogen specific T cell action, anti-inflammatory effects against COVID-19 infection, cross-reactivity against tumor antigens, natural killer cell activation. COVID-19 proteins have oncolytic properties - HIV related B cell apoptosis and Coxsackievirus A21 oncolytic effects on myeloma and CD138+ plasma cells via intercellular adhesion molecule interaction. COVID-19’s effects plus the anti PD-1/PD-L1 antibodies immune response may be synergistic and merits further research.
Are severe immune-related adverse events more likely in patients with pre-existing autoimmune disease?
Authors: Isaacs Dayna Jill , Hilder Robin , Drakaki Alexandra , Lechner Melissa G 
Published: June 2023

e14599 Background: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system to treat malignancy. As a consequence of this activation, ICIs may cause autoimmunity in healthy tissues, termed “immune-related Adverse Events” (irAEs). The literature reports a wide range in irAE incidence (10-80%), with a higher incidence in patients exposed to combination therapy. ICI treatment of patients with pre-existing autoimmune disease presents a dilemma for oncologists because of concern that immune activation will lead to more frequent or severe irAEs. As a result, these patients have been excluded from ICI clinical trials. Prior studies suggested that approximately 40% of patients with pre-existing autoimmune disease experience an autoimmune exacerbation during ICI treatment, but more data are needed on the incidence and severity of irAEs in other tissues. Methods: This retrospective case-control study included adult patients who received an FDA-approved ICI for treatment of a solid malignancy (excluding non-melanoma skin cancer) from 2015-2021 at an academic medical center. Cases were patients with pre-existing autoimmune disease. Controls without pre-existing autoimmunity were matched 2:1 based on age, sex, ICI class, and cancer type. Severe IrAEs were defined as grade three or higher by CTCAE definitions and occurring after ICI exposure. ICD-9 and 10 codes were used to identify patients with subsequent data extraction by manual chart review. Results: Of 3,130 adult cancer patients treated with ICIs, 28 cases were identified with pre-existing autoimmune disease: antiphospholipid syndrome (n=1), inflammatory polyarthritis (n=3), juvenile arthritis (n=1), multiple sclerosis (n=3), psoriatic arthritis (n=3), rheumatoid arthritis (n=14), and type I diabetes (n=3). Six out of 28 cases (21.4%) developed severe irAEs, including three (50%) who received anti-PD1/PDL1 monotherapy and three (50%) who received ICI combination therapy. One case experienced a grade five irAE (death) attributed to ICI-colitis; the remaining five patients (83.3%) successfully recovered with suspension of ICI therapy and treatment with immunosuppressive medications. By comparison, 9/56 (16.1%) controls developed severe irAEs. The odds of developing a severe irAE were not significantly different in patients with pre-existing autoimmunity compared to controls (OR 1.42, 95% CI 0.42-4.68, p=ns). Subgroup analysis of 23 cases and 46 controls treated with anti-PD1/PDL1 monotherapy also found no difference in the odds of severe irAE development (OR 0.84, 0.22-3.70, p=ns). Conclusions: Our data suggest that the majority of solid tumor patients with pre-existing autoimmune disease can safely receive ICI monotherapy and combination therapy. Severe (grade 3 or higher) irAEs were infrequent, often treatable, and did not occur more frequently than in patients without pre-existing autoimmunity.
The association between body mass index and immune checkpoint inhibitors outcomes in melanoma: Results from real-world data.
Authors: Elantably Dina , Wang Jiasheng , Al Armashi Abdul Rahman , Al Zubaidi Anas , Alkrekshi Akram 
Published: June 2023

e14604 Background: The “obesity paradox” refers to increase cancer risk in obesity with paradoxical improved outcomes. This phenomenon was previously reported in melanoma patients on immunotherapy; however, results are uncertain. Immune checkpoint inhibitors (ICI) are the mainstay of melanoma treatment. There is a lack of real-world data on the impact of body mass index (BMI) on overall survival (OS) and immunotherapy-related adverse events (irAEs) in melanoma patients on ICI. Methods: Data were retrospectively collected from an electronic health record database (TriNetX) which includes over 89 million patients from 56 healthcare systems in the United States. We identified adults with melanoma who received ICI; pembrolizumab, nivolumab, or a combination of ipilimumab and nivolumab between 2012 and 2022. Patients were stratified based on the WHO body mass index (BMI) classification. Overweight and obese patients were 1:1 propensity score-matched for age, sex, race, and use of ICI, with patients with normal BMI. Results: Ourcohort included 11,656 melanoma patients on ICI. 62% were males, 91% were white, and 86% were non-Hispanics. OS was significantly improved in overweight and obese compared to normal BMI patients (HR 0.72, 95% CI, 0.60-0.86; P < 0.001, and HR 0.53, 95% CI, 0.43-0.65); P < 0.001, respectively). Nearly one-third of all weight categories had an irAE. Skin toxicity was the most common, 16.5%-18.2%, while pneumonitis was the least common, 1.0% -2.0%. There was no statistically significant difference between the groups in all included irAE; skin toxicities, thyroid dysfunction, colitis, pneumonitis, or hepatitis. Conclusions: This is the largest real-world data study describing the association between weight status and the outcomes of ICI in melanoma. Our study showed that overweight and obese melanoma patients treated with single or combination ICI had a significantly improved OS compared to patients with normal BMI, in keeping with the “obesity paradox” phenomenon. Intriguingly, high BMI wasn’t associated with an increased risk of irAE. Studies to clarify the underlying mechanisms in melanoma and other malignancies are needed. [Table: see text]
Evaluation of immune related adverse events following extended interval dosing of immune checkpoint inhibitors.
Authors: Deviley Jake Anthony , Hayashi-Tanner Yacki , Frankki Susan M , Marinier David E. 
Published: June 2023

e14605 Background: Increased use of immune checkpoint inhibitors (ICI) has resulted in a rise in immune related adverse events (irAEs). In 2019, pembrolizumab and nivolumab received approval for extended interval (EI) dosing at 400 mg intravenous (IV) every 6 weeks and 480 mg IV every 4 weeks, respectively, compared to the standard interval (SI) dosing of 200 mg IV every 3 weeks and 240 mg IV every 2 weeks, respectively. Since EI dosing has been implemented, clinicians have hypothesized increased dosing may lead to more irAEs. Mixed results have been published to date with discordant results between studies. The aim of this study was to investigate the incidence and grade of irAEs, including multisystem adverse events (ms irAEs) in SI versus EI dosing in a real-world community-based hospital system in the United States of America. Methods: We performed an Institutional Review Board approved retrospective study of all patients 18 years or older who received SI or EI dosing of pembrolizumab or nivolumab from 2015 through 2021. An irAE was considered connected to the specific dosing group if it was observed after the first date of stated dosing and within 90 days after last dose of such dosing. Statistical analysis included descriptive statistics, Wilcoxon signed-rank test, Fisher’s exact test, and Kaplan-Meier survival analysis and was performed in R version 4.2.2 at a significance level of 0.05. Results: Our study included 458 patients who were 99% white, 59% male, and an average age of 67 years. There were 354 (77%) patients in the SI group and 104 (23%) in the EI group. The overall incidence of irAEs was 32% (146 patients), of which 37% (54 patients) presented at some point with ms irAEs. There was no significant association between dosing group and presence of irAEs (p = 0.087), grade groups 1-2 vs > 3 (p = 0.7), or ms irAEs (p = 0.13). The incidence of irAEs was 34% (120 patients) in the SI group with a distribution of grades 1-2-3-4-5 being 39-62-25-5-1, respectively. The incidence of irAEs was 25% (26 patients) in the EI group with a distribution of grades 1-2-3-4-5 being 18-27-11-1-0, respectively. In the SI group there were 41 (34%) patients with ms irAEs compared to 13 (50%) in the EI group. There was a significant association between dosing groups and overall survival (p < 0.001). Conclusions: Our results lend data to suggest there is indeed no statistically significant risk of increased irAEs with EI dosing. However, there may be a clinically significant trend toward increased ms irAEs in EI dosing that needs further investigation with comparisons of comorbid conditions that increase risk of autoimmune reactions. Of note, the OS in EI dosing group was statistically significant but likely heavily confounded due to patient selection bias, this may also be an avenue for future research to be conducted with a randomized clinical trial.
Effect of hypofractionated radiotherapy, PD-1 immunotherapy, and anti-angiogenic therapy on abscopal responses and the tumor microenvironment.
Authors: Han Guang , Dong Zhiqiang , Li Chunhui , Bi Jianping , Yi Ding , He Hanping , Wei Wei , Pi Guoliang , Li Ying , Li Yanping , Zhang Li , Verma Vivek , Hu Desheng 
Published: June 2023

e14609 Background: Hypofractionated radiotherapy (HFRT) of the primary tumor can induce abscopal effects in metastatic cancer, which could be enhanced by adding PD-1 immunotherapy (IO) and low-dose radiotherapy (LDRT) of distant disease. However, this strategy remains with suboptimal efficacy. Translational research has shown that LDRT primarily modulates the immune microenvironment of tumors in the irradiated area, a mechanism shared by anti-angiogenic therapy (AAT). Therefore, this study aimed to compare the efficacy (abscopal responses and cytokine levels in the tumor microenvironment) between HFRT+IO+AAT and HFRT+IO+LDRT. Methods: Bilateral mouse tumor models were divided into seven groups for various treatments (Table 1). After treatment, blood and tumor samples of mice were collected for analysis. We evaluated clinical effects of HFRT+IO+AAT in 4 patients with unirradiated lung metastases in a currently-accruing phase Ib study of stereotactic body radiotherapy (SBRT) plus anlotinib (AAT) with or without toripalimab (PD-1 IO) in driver mutation-negative non-small cell lung cancer (NCT05021328). Results: The results of animal studies are shown in Table 1. HFRT to the primary tumor combined with AAT and IO enhanced the abscopal response in secondary tumor compared to HFRT, HFRT+IO, HFRT+AAT, IO+AAT, as well as HFRT+LDRT+IO. The most noteworthy secondary tumor control was observed in mice receiving HFRT+IO+AAT. The enhanced abscopal responses were associated with increased infiltration of CD8+ effector T cells, increased expression of IFN-γ and levels of TNF-α. From the prospective trial population, 4 unirradiated lung lesions in the HFRT+IO+AAT cohort decreased by an average of 48% in size (n=3 partial response, n=1 stable disease). No grade 3 treatment-related toxicity was observed. Conclusions: HFRT+IO+AAT is a promising therapeutic combination that may optimize abscopal responses, potentially even further than HFRT+LDRT+IO. This new “triple therapy” was safe and efficacious in patients and deserves further study. [Table: see text]
Outcomes for immuno-chemotherapy based treatment in patients with poorly differentiated extrapulmonary neuroendocrine carcinoma.
Authors: Kumar Sakthi , Talabi Toluwalase , Mahmoudieh Mahta , Pennington Daniel , Saboda Kathylynn , Arshad Junaid , Scott Aaron James 
Published: June 2023

e14619 Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) represents a rare collection of neuroendocrine cancers characterized with a poor prognosis and modest treatment benefit similar to small cell lung carcinoma (SCLC). Platinum-based chemotherapy (cisplatin or carboplatin) and etoposide is the preferred 1st line therapy for patients (pts) with metastatic EP-NEC who are not eligible for curative surgery (Frizziero et al. 2019). Studies in pts with advanced SCLC have shown improved progression free survival (PFS) and overall survival (OS) with the addition of atezolizumab, an anti-PD-L1 monoclonal antibody, to induction chemotherapy (4 cycles) versus chemotherapy alone (Horn et al. 2018). Prospective trials investigating immune checkpoint inhibitors such as atezolizumab plus chemotherapy have yet to be published in EP-NEC. Methods: We retrospectively reviewed all registered pts at the Gastrointestinal Medical Oncology Clinic at Banner-University of Arizona Cancer Center who received at least 1 dose of atezolizumab from 1/2017 through 3/2022 (UAIRB00001593). Criteria for pt selection for analysis was based on the following: pts diagnosed with grade III, Ki 67>20%, poorly differentiated, metastatic EP-NEC and treated with ≥ 1 dose of atezolizumab plus chemotherapy as 1st line treatment. Results: Ten pts received atezolizumab based therapy during this timeframe. 6 pts met criteria for analysis and 4 pts were excluded for alternative diagnoses. 4 pts were female, 2 pts were male, and the average age at diagnosis was 63.8 years. The median number of chemotherapy cycles was 7.0 [4-17]. The median number of atezolizumab doses was 7.5 [6-28]. The median PFS was 7 months (95% CI 5-*). The median overall survival (mOS) was 13 months (95% CI 8-*). The mOS since starting atezolizumab was 12 months (95% CI 8-*). [*Upper bound of 95% CI cannot be determined.] Five pts (83%) demonstrated a partial response per RECISTv1.1. All pt tumors were MMR-proficient/MSI-stable and PD-L1 expression was negative in 3 pts (PD-L1 status unavailable for 3 pts). No hospitalizations related to immunotherapy or chemotherapy were observed. The most common adverse events included nausea, diarrhea and fatigue. One immune-mediated adverse event of thyroid dysfunction was observed and successfully medically managed. Conclusions: Our experience with atezolizumab plus chemotherapy for 1st line EP-NEC pts demonstrated efficacy via high response rate and survival rates above historical experience. Continuing chemotherapy beyond the induction phase until maximum clinical response demonstrated tolerability with manageable side effects. Although the scope is limited due to sample size, this data supports further investigation of this combination. There is an ongoing large, randomized, prospective trial investigating this regimen in frontline, metastatic EP-NEC pts ( NCT05058651 ).
Peripheral immunological response to treatment with a novel bifunctional anti-PD-L1/TGFβRII agent in recurrent/metastatic nasopharyngeal carcinoma.
Authors: Kam Ngar Woon , Lau Jeffrey Yan Ho , Dai Wei , Chiang Chi Leung , Che Chi Ming , Lee Victor Ho-Fun , Kwong Dora Lai Wan 
Published: June 2023

e14622 Background: Anti-programmed cell death protein-ligand 1 (PD-L1) monotherapy has not shown promising anti-tumor effects in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) in first-line settings. Consequently, second-generation checkpoint inhibitors via targeting multiple pathways are urgently needed. Bintrafusp alfa (also known as M7824) is one of such agents that targets both the transforming-growth factor beta (TGF-β) and PD-L1 pathways. As T cells are the major immune cell subset responsible for tumor destruction, we focus on the peripheral memory T-cell subsets. Through the evaluation of peripheral biomarker analysis and their correlation with clinical outcomes, we have characterized blood-based dynamic phenotypes that predict responses to M7824 in NPC. Methods: Biomarker analysis was performed as part of a phase II clinical trial (NCT04396886) in patients with treatment-refractory histologically confirmed recurrent NPC (n=32) who received M7824. Peripheral blood samples were obtained at baseline before treatment (D0) and every 2 weeks during treatment. Samples collected at D0 and at time of best response assessment (DR) were analysed using multicolor flow cytometry. Patients with complete/partial response or stable disease for at least 6 months were considered responders (R), those with stable disease less than 6 months or progressive disease were considered non-responders (NR). Results: Peripheral T cells between R (n=10) and NR (n=22) patients were compared. While the overall percentage of memory T-cell subsets was similar in both groups after treatment, R patients displayed a significantly lower amount of prototype cell death receptor, CD95, among terminally differentiated effector memory (TEMRA; CD45RA+CD62L+) T cells (CD45+CD3+and CD45+ CD3+CD4+: p<0.0001; CD45+CD3+CD8+: p=0.0047) (CD95DR/RvsNR) as compared to patient in NR group. Besides, reduced expression of CD95DR on TEMRA CD4 T cells was significantly associated with longer overall survival (OS), regardless of response status (median OS: 16.26 months for patients with lower CD95 levels; median OS: 5.29 months for patients with higher CD95 levels [p < 0.0001]). Notably, we noticed that R patients displayed a lower frequency of CD95-expressing TEMRA at the baseline (CD95D0/Rvs NR) as compared to NR group. Conclusions: The apoptotic response of peripheral blood TEMRA CD4 T cells (CD95DR/R vsNR) may be a useful surrogate biomarker for predicting prognosis to M7824 therapy in NPC. The finding of a lower frequency of CD95D0TEMRA in R patients suggesting that CD95 may potentially act as a biomarker for predicting treatment response as well as reveal a possible target for guiding therapeutic strategy for R/M NPC.[Table: see text]
Neoadjuvant tislelizumab, a PD-1 mAb plus nab-paclitaxel (nab-P) followed by tislelizumab plus epirubicin/cyclophosphamide (EC) for triple-negative breast cancers (TNBC): Interim analysis of clinical response in a phase 2 TREND trial.
Authors: Xu Yingying , Zhang Qiang , Zhu Bo , Wang Mozhi , Yao Litong 
Published: June 2023

e14623 Background: Chemo-based immunotherapy improves the prognosis of TNBC. However, the dominant population and optimal chemo-backbone of neoadjuvant immunotherapy remain undefined. Aim of TREND trial was to assess the efficacy and safety of tislelizumab in combination with nab-P and EC (nab-P-EC) in neoadjuvant therapy of TNBC. Methods: In this prospective, single-arm phase 2 clinical study, untreated TNBC patients who have clinically node-positive or at least T2 disease without distant metastasis were eligible. Before surgery, enrolled patients received tislelizumab (200 mg IV Q3W) plus weekly nab-P (100 mg/m² IV Q3W) for 12 weeks, followed by tislelizumab (200 mg IV Q3W) plus epirubicin (75 mg/m² IV Q3W) and cyclophosphamide (600 mg/m² IV Q3W) for the subsequently 12 weeks. The primary endpoint was pCR (ypT0/Tis ypN0) and secondary endpoints was objective response rate (ORR, RECIST v1.1). Combined positive score (CPS) of PD-L1 expression in pre-treatment biopsy samples was tested by PD-L1 IHC 22C3 PharmDx. Single-cell RNA sequencing, single-cell TCR sequencing, mass cytometry by time of flight, whole exome sequencing, RNA-seq and olink-assay were performed on pre- and post-treatment samples from primary tumors, metastatic lymph nodes and peripheral blood. Results: Of 43 enrolled patients from Nov 2020 to Nov 2022, 21 patients completed neoadjuvant therapy and accepted surgery in per protocol set (PPS; median age 48 years; range 25-69 years), and 16 were still on treatment. In PPS, the pCR (ypT0/is ypN0) rate was 71.43% (15/21). For different target lesions, 15 patients achieved ypT0/Tis (pCR rate = 71.43%) and 20 reached ypN0 (pCR rate = 95.24%). When stratified by CPS, pCR (ypT0/is ypN0) rate were 68.4%,72.2% and 76.9% in CPS ≥ 1, CPS ≥ 5 and CPS ≥ 10 subgroups, respectively. The ORR in PPS was 90.48% (n = 19/21, 95% CI: 68.18 - 98.33) and DCR reached 95.24% (n = 20/21, 95% CI: 74.13 - 99.75), including 9 complete response and 10 partial response. Treatment emergent adverse event (TEAE) occurred in 74.4% patients (32/43), of which 69.8% were Immune-related adverse event (irAE) (30/43). Grade ≥ 3 IrAE was 7.0% (3/43) and no treatment-related deaths were found. Conclusions: Combining tislelizumab and neoadjuvant nab-P-EC achieved favorable efficacy in TNBC, supporting that platinum-free regimen was non-inferior as a chemo-backbone. For heterogeneity of efficacy to immunotherapy, metastatic tumors in lymph nodes responded better to tislelizumab than primary tumor, suggesting that node-positive patients were potentially dominant population of neoadjuvant immunotherapy. Further results from the ongoing TREND trial and subsequent analysis of mechanism are urgently awaited. Clinical trial information: ChiCTR2000035262 .