bluuebunny/crossref_metadata_2025 huggingface dataset:
CAR-T cells to deliver engineered peptide antigens and reprogram antigen specific T cell responses against solid tumors.
Authors: Lee Daniel , Minn Andy J , Johnson Lexus R
Published: June 2021

2530

Background: Neoantigen depleted malignancies such as colorectal cancer demonstrate primary resistance to immune checkpoint blockade, and solid tumors in general have shown resistance to chimeric antigen receptor (CAR) T cell therapy. However, CAR-T cells have been shown to be capable of delivering various therapeutic molecules in a targeted fashion to the tumor microenvironment, in some cases through extracellular vesicles (EVs). In vivo studies have shown that the presentation of foreign viral peptides by solid tumors can reprogram bystander virus-specific cytotoxic T cells (CTLs) against tumor cells. In this study, we demonstrate that CAR-T cells can deliver engineered peptide antigens to solid tumors, leading to presentation on tumor cells and anti-tumor response. Methods: Second generation CAR-T cells (41BB endodomain) targeting human CD19 (19BBz) or human mesothelin (M5BBz) were generated via retroviral and lentiviral transduction respectively. CAR-T cells were engineered to co-express peptides such as SIINFEKL of ovalbumin and NLVPMVATV of CMV pp65 among others. Peptides were isolated from EVs via ultracentrifugation. For in vivo studies, C57BL/6 or NSG mice were injected on the flank with relevant tumors and treated with peptide-CAR-T cells. In vitro studies utilized flow cytometry and xCELLigence killing assays. Results: Murine 19BBz CAR-T cells expressing the SIINFEKL peptide of ovalbumin (ova-19BBz) were found to transfer SIINFEKL peptide to tumor cells via EVs in vitro and in vivo, leading to peptide presentation on MHC-I of tumor cells. This resulted in significantly delayed tumor growth in tumor bearing mice transfused with OT-I T cells to mimic an existing antigen specific T cell pool. We expanded on these findings by isolating EVs from human M5BBz CAR-T cells expressing CMV viral peptides. Peptide-CAR-T EVs were co-cultured with human ovarian cancer cells to assess presentation to Jurkat T cells. Finally, we utilized primary human T cells from CMV+ healthy donors to assess the clinical feasibility of our peptide delivery approach. Conclusions: CAR-T cells can be engineered to deliver peptides to tumor cells for presentation and subsequent targeting by antigen specific CTLs. This represents a novel strategy for the treatment of non-immunogenic tumors.
A single-arm phase Ib study of multiple target cytotoxic T-lymphocyte (MCTL) in combination with toripalimab as second-line therapy in advanced non-small cell lung cancer (NSCLC).
Authors: Ren Xiubao , Zhang Weihong
Published: June 2021

2535

Background: Anti-PD-1/ PD-L1 (programmed cell-death 1) mAb treatment has been approved in the US and in Europe as second-line treatment for advanced NSCLC because of the good tolerance and efficacy in comparison with docetaxel. Unfortunately, The objective response rate is only around 20%. Multiple Target Cytotoxic T-lymphocyte (MCTL) cells can restore the antitumor immunity to improve patient outcome. Combining MCTL cells with anti-PD-1 mAb may strengthen the results as second-line treatment in patients with advanced NSCLC. (NCT04193098). Methods: This is a single-center, open-label, phase 1b trial of combination MCTL cells with toripalimab (anti-PD-1 mAb)as second-line treatment for advanced NSCLC. Systemic therapy patients received toripalimab every 3 weeks for 12 cycles and received MCTL cells every 3 weeks for 9 cycles, then toripalimab and MCTL cells for maintenance therapy until disease progression or unacceptable toxicity. Results: From June 2019 to October 2020, 14 pts aged 43-70 years (median age 59 years) were enrolled. The squamous/non-squamous ratio was 50%/50%. 8 (57.1%) were men, 13(92.8%) were ECOG PS=0-1, 5 (35.7%) had pleural effusion, and 3 (21.4%) had bone metastases. Among 13 evaluable pts, the ORR and DCR were 38.4% and 71.4%, At the time of data cutoff, the median DOR was not reached (range 8.25m-NA), the median PFS was 399 days (range 192d-NA), and the median OS were not mature. Adverse events (AEs) occurred in 5 (38.4%), No grade≥3 AEs events occurred. Immune-related AEs were thyroid hypofunction (3, 23%) and weak (2, 15.4%). Biomarkers which correlated with efficacy and AEs are being analyzed. Conclusions: Multiple Target Cytotoxic T-lymphocyte (MCTL) in combination with toripalimab as second-line treatment for advanced NSCLC because of the well tolerated and encouraging efficacy. Further studies are warranted to confirm these results. Research Sponsor: Tianjin Medical University Cancer Institute and Hospital. Clinical trial information: NCT04193098.
A 4-chemokine signature to predict intermediate immunogenicity in homologous recombination repair deficient tumors.
Authors: Romero Joan Miguel , Wang Yifan , Pacis Alain , Denroche Robert Edward , Jang Gun Ho , Grunwald Barbara , Gallinger Steven , Zogopoulos George
Published: June 2021

2546

Background: Treatment responses to immune checkpoint blockade (ICB) associate with T cell tumor inflammation. Tumors with mismatch repair deficiency display an inflammatory tumor phenotype and respond to ICB. Similarly, tumors with homologous recombination repair deficiency (HR-d) may be primed for ICB treatment. We have previously shown that a panel of 4 chemokines identifies a subclass of pancreatic cancer with markers of T cell-inflammation. Here, we evaluated this 4-chemokine signature in cancer types with HR-d molecular subclasses. Methods: We combined paired transcriptomes and genomic data of breast (n = 699), ovarian (n = 174) and prostate (n = 457) cancers from the Cancer Genome Atlas and tumor-enriched pancreas cancers (n = 121) to evaluate the 4-chemokine signature in HR-d vs. HR-proficient tumors across these 4 cancers. Metrics of antitumor immunity were also compared. Results: Across tumor types, elevated expression of the 4-chemokine signature (chemokine-hi) associated with transcriptional hallmarks of a T cell-mediated antitumor response, including antigen presenting cell stimulation, antigen presentation, and T cell activity. In tumors with a predominant COSMIC signature 3, which associates with HR-d, the 4-chemokine signature predicted intermediate levels of T cell-inflammation. Conclusions: These data suggest that 1) the 4-chemokine signature may be a clinically relevant biomarker in identifying subclasses of tumours responsive to immunotherapies, and that 2) HR-d tumors harbor intermediate immunogenicity. Correlation of treatment responses to immunotherapies with the 4-chemokine signature is needed validate its predictive value as a biomarker for treatment stratification with immunotherapies.[Table: see text]
Risk of immunosuppression and hospitalization after checkpoint inhibitor therapy in patients with cancer and radiation therapy.
Authors: Lee Kate E , Bender David Andrew , Spina Catherine S. , Hyde Brigham , Faye Adam S , Cheng Simon
Published: June 2021

2588

Background: Immune checkpoint inhibitors (ICIs) are potent new cancer therapies but can cause serious immune-related adverse events. Radiation therapy (RT) also induces systemic immunologic effects, and data on the interaction and safety of combining ICIs and RT are limited. Methods: In this retrospective cohort study using a large medical claims database from 2010 to 2017, we ascertained the risk of immunosuppressive steroid therapy as well as the risk of hospitalization within 180 days of treatment with an ICI in patients with diagnoses of malignant melanoma or lung cancer. Patients were stratified by use of RT within 30 days before and after ICI therapy. ICIs included pembrolizumab, nivolumab, and ipilimumab, while immunosuppressive agents included oral prednisone and intravenous methylprednisolone. Results: 2020 patients (218 with RT, 1802 without RT) met inclusion criteria for prednisone analysis, while 3519 patients (361 with RT, 3158 without RT) met inclusion criteria for all other analyses. On univariable analysis, RT was not associated with need for prednisone or methylprednisolone (RR 1.2, 95%CI 0.8-1.9 and RR 1.2, 95%CI 0.7-2.1 respectively). When assessing hospitalization, RT was significantly associated with hospitalization following ICI therapy for certain cancer/drug combinations (RR 1.4, 95%CI 1.2-1.6, p<0.001 for lung cancer/PD-1 inhibitors, RR 2.0, 95%CI 1.0-3.5, p=0.03 for melanoma/ipilimumab). Conclusions: In patients treated with ICIs, receiving RT was not associated with a higher risk of requiring immunosuppressive steroid therapy as compared to not receiving RT. However, in those with ICIs, RT was associated with a higher risk of hospitalization as compared to no RT, though this may be a result of underlying differences in patent severity (more severe disease may require ICI and RT).[Table: see text]
Nivolumab/ipilimumab primed immunotransplant in post-CAR-T and post-ASCT DLBCL.
Authors: Fitzgerald Bailey Gleason , Marron Thomas Urban , Ostrowski Dana , Shulman Jonah , Kalac Matko , Marshall Netonia , Brody Joshua
Published: June 2021

2593

Background: Patients with refractory diffuse large b cell lymphoma (DLBCL) have poor outcomes with < 30% surviving for 12 months and especially poor outcomes for those who progress after chimeric antigen receptor T cells (CAR-T) or autologous stem cell transplant (ASCT). These therapies utilize lymphodepleting chemotherapy which induces homeostatic T cell proliferation. We have demonstrated these expanding T cells express high levels of PD1 and CTLA4. In pre-clinical models, addition of dual checkpoint blockade (DCB) with anti-PD1/anti-CTLA-4 to adoptive T cell transfer after lymphodepletion achieved a synergistic anti-tumor effect. Based on these studies, we developed a phase Ib/II study of Nivolumab/Ipilimumab primed “immunotransplant” for relapsed/refractory (R/R) DLBCL (NCT03305445). Methods: Phase Ib of the trial enrolled 6 patients with progressive disease following at least one line of standard therapy. Patients received two cycles of DCB with ipilimumab (1mg/kg) and nivolumab (3mg/kg) given at three-week intervals followed by immunotransplant (i.e. peripheral blood T cell harvest, lymphodepletion with fludarabine/cyclophosphamide, T cell reinfusion), followed by two further cycles of DCB and nivolumab maintenance. Results: Five patients received at least two cycles of DCB and the autologous T cell transfer, while one patient had progressive disease during initial DCB and required salvage chemotherapy. Treatment emergent AE (TEAE) occurred in 100% of patients. As expected with lymphodepleting chemotherapy, the most common TEAE were neutropenia (66.7% grade 1, 66.7% grade ≥ 3), fatigue (83.3%, 16.7%), fever (66.7%, 0%), and dyspnea (66.7%, 0.0%). One patient (16.7%) died during the intervention period (grade 5 TEAE), though relation to study drug is unclear. Three patients (50.0%) experienced clinical benefit with immunotransplant. One patient (a 58yo M with progression after seven lines of therapy including ASCT and CAR-T) is experiencing partial metabolic response after 4 months on protocol. One 77yo F with multiple prior lines of therapy including ASCT has experienced an extended complete metabolic response, currently 31 months post immunotransplant. A third (a 50yo F) experienced mixed radiographic response, and has not received subsequent therapy 30 months following immunotransplant. Conclusions: Nivolumab/Ipilimumab primed immunotransplant is well tolerated in patients with R/R DLBCL for whom there are few treatment options. Preliminary results demonstrate remissions in heavily pre-treated patients, including prior ASCT and CAR-T. Pre-clinical models in melanoma, non-small cell lung cancer, and T cell lymphoma all demonstrate synergy when DCB is administered with lymphodepletion and autologous T cell transfer. These data support further investigation of DCB-primed immunotransplant. Clinical trial information: NCT03305445.
MSIFinder: A python package for detecting MSI status using random forest classifier.
Authors: Zhou Tao , Chen Libin , Guo Jing , Zhang Mengmeng , Liu Huanhuan , Zhang Yanrui , Wang Huina , Cao Shanbo , Wang Haijun , Lou Feng
Published: June 2021

2601

Background: Microsatellite instability (MSI) is a common genomic alteration in several tumors, such as colorectal cancer, endometrial carcinoma, and stomach, which is characterized as microsatellite instability-high (MSI-H) and microsatellite stable (MSS) based on a high degree of polymorphism in microsatellite lengths. MSI is a predictive biomarker for immunotherapy efficacy in advanced/metastatic solid tumors, especially in colorectal cancer (CRC) patients. Several computational approaches based on target panel sequencing data have been used to detect MSI; However, they are considerably affected by the sequencing depth and panel size. Methods: We developed MSIFinder, a python package for automatic MSI classification, using random forest classifier (RFC)-based genome sequencing, which is a machine learning technology. We included 19 MSI-H and 25 MSS samples as training sets. First, RFC model were built by 54 feature markers from the training sets. Second. The software was validated the classifier using a test set comprising 21 MSI-H and 379 MSS samples. Results: With this test set, MSIFinder achieved a sensitivity (recall) of 0.997, a specificity of 1, an accuracy of 0.998, a positive predictive value (PPV) of 0.954, an F1 score of 0.977, and an area under curve (AUC) of 0.999. We discovered that MSIFinder is less affected by low sequencing depth and can achieve a concordance of 0.993, while exhibiting a sequencing depth of 100×. Furthermore, we realized that MSIFinder is less affected by the panel size and can achieve a concordance of 0.99 when the panel size is 0.5 m (million base). Conclusions: These results indicated that MSIFinder is a robust MSI classification tool and not affected by the panel size and sequencing depth. Furthermore, MSIFinder can provide reliable MSI detection for scientific and clinical purposes.[Table: see text]
YAP1 mutation as a novel predictor of response to anti-PD-1/PD-L1 treatment in pan-cancers.
Authors: Xu Wei-guo , Zhu Jing , Li Lin , Chen Dongsheng , Zhang Qin , Duan Qianqian , Li Si , Xiao Mingzhe
Published: June 2021

2604

Background: YAP1 is the main downstream target of the Hippo pathway and acts as a transcriptional coactivator to regulate development processes. YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored in nonsurgical esophageal squamous cell carcinoma (ESCC). YAP1 overexpression has been identified in multiple solid cancers, which consistently correlated with unfavorable clinical outcomes. Previous work suggested that YAP1 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of these findings in needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the YAP1 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients, and the public database of TACG was also compared. Data from MSK-IMPACT study (n = 1661, anti-PD-(L)1/CTLA-4 mono/ combined therapy) was retrieved and analysed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In clinical cohort, the frequency of YAP1 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 0.62 % (22 in 3547). Meanwhile, the frequency of YAP1 mutation in TCGA cohort was 0.90 % (99 in 10953). We further analyzed Kaplan-Meier curves from MSK-IMPACT study (n = 1661, anti-PD-(L)1/CTLA-4 mono/ combined therapy). In MSK-IMPACT cohort, mutation of YAP1 was associated with higher TMB (P = 0.022) and higher mutation count (P = 0.017) in pan-cancers. YAP1 mutation was associated with prolonged overall survival (OS) trend compared with YAP1 wt in pan-cancers (P = 0.15; HR, 2.209, 95% CI, 0.7109-6.8639). Conclusions: In our study, the frequency of YAP1 mutation was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. YAP1 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in pan-cancers via upregulating TMB and mutation count.
Investigating the various predictive values of POLE/POLD1 mutations for response to immune checkpoint inhibitors (ICIs) in different solid tumors.
Authors: Niu Yanling , Ma Tonghui , Niu Yanling , Li Tao
Published: June 2021

2606

Background: Both POLE and POLD1 encode the catalytic subunit of polymerase enzyme complexes involved in DNA replication and repair. The mutations of POLE and POLD1 have been shown to be oncogenic and lead to DNA repair defects and elevated tumor mutation burden (TMB). And patients with POLE/POLD1 mutations are more likely to benefit from ICIs therapy. Previous studies have shown that TMB has divergent predictive value for response to ICIs therapy in different cancer types. We hypothesized that the associations between POLE/POLD1 mutations and ICIs efficacy are also varied in different solid tumors. Therefore, we explored the prediction values of POLE/POLD1 mutations in some cancer types. Methods: The ICIs treatment cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of POLE/POLD1 mutations with ICIs efficacy. TCGA cohort was enrolled for characterizing tumor infiltrating lymphocytes (TILs) with CIBERSORT. The patients were classified into two groups: POLE/POLD1 mutations (Mut) and wildtype (WT). Overall survival (OS) after ICIs therapy was estimated with Kaplan-Meier method. Results: In MSKCC pan-cancer dataset, patients with POLE/ POLD1 mutations had significantly longer median OS after ICIs therapy (34.00 vs 19.00 months, P = 0.0143), indicating that POLE/POLD1 mutations were associated with better immunotherapy outcomes. Then we analyzed the predictive roles in each cancer type. Notably, we found the associations of POLE/POLD1 mutations with longer median OS in NSCLC (Undefined vs 12.00 months, P = 0.05) and esophagogastric cancer (27.00 vs 15.00 months, P = 0.05). However, the associations between POLE/POLD1 mutations and ICIs efficacy were not observed in bladder cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, and colorectal cancer. Furthermore, our data showed that the median TMB was significantly higher in the Mut group for NSCLC (20.2 vs 6.9 muts/Mb, P < 0.0001) and esophagogastric cancer (21.4 vs 5.6 muts/Mb, P < 0.0001). In TCGA esophagogastric cancer cohort, POLE/POLD1 mutations were correlated with decreased naive B cells (P = 0.0306) and increased activated memory CD4+ T cells (P = 0.0224). In TCGA NSCLC cohort, POLE/POLD1 mutations were correlated with elevated gamma delta T cells (P = 0.0219). These data suggested that POLE/POLD1 mutations were also involved in the infiltration of some immune cells. Conclusions: Although POLE/POLD1 mutations were associated with better ICIs efficacy for all the enrolled patients, the prolonged OS was only found in the Mut group for NSCLC and esophagogastric. These data suggested that POLE/POLD1 mutations may be a useful predictor for ICIs efficacy in these two types of cancer. Moreover, POLE/POLD1 mutations were correlated with the level of TILs in NSCLC and esophagogastric. The finding was consistent with the efficacy of immunotherapy.
Proton pump inhibitor use (PPI) in patients treated with immune checkpoint inhibitors (ICI) for advanced cancer: Survival and prior therapy.
Authors: Husain Marium , Xu Menglin , Patel Sandipkumar , Johns Andrew , Grogan Madison , Li Mingjia , Lopez Gabrielle , Miah Abdul , Hoyd Rebecca , Liu YunZhou , Muniak Mitchell , Haddad Tyler , Tinoco Gabriel , Kendra Kari Lynn , Otterson Gregory Alan , Presley Carolyn J , Spakowicz Daniel , Owen Dwight Hall
Published: June 2021

2633

Background: Emerging data suggest that concomitant medications (CM) influence response to ICI. CM impact the host microbiome which may mitigate tumor-immune responsiveness. PPI use in patients treated with ICI has been associated with worse survival. Few data exist regarding the effects of PPI use in terms of prior chemotherapy or in risk for immune related adverse events (irAE) (e.g., colitis). Methods: This retrospective study of patients with advanced cancer treated with ICI between 2011 and 2019 was conducted at The Ohio State University. Patients who received ICI as either single agent or combination were included. Clinical data was abstracted from chart review, including CM, toxicity, and survival. Overall survival (OS) was evaluated to date of death or last contact. Associations between OS and proton pump inhibitor (PPI) use were studied using log-rank tests and Cox regression analyses overall and by the groups of whether prior chemotherapy was administered and timing from chemotherapy to ICI. The associations between PPI and incidence of irAE (overall and colitis) were assessed by chi-square tests. Results: We identified 1,091 patients treated with ICI, of whom 415 (38%) received PPI at time of ICI. Most common cancers were NSCLC and melanoma; most common therapy was PD1/L1 (Table). PPI use was associated with shorter OS in patients treated as first line therapy (HR = 1.46, 95% CI = [1.11, 1.91], p=0.006) and in second line and beyond (HR = 1.30, 95% CI = [1.10, 1.53], p=0.002). PPI use was associated with shorter OS in patients treated with ICI for those without prior chemotherapy (HR = 1.47, 95% CI = [1.17, 1.86], p=0.001). When evaluated by timing from chemotherapy to ICI, PPI use was associated with shorter OS only in patients where last chemotherapy was > 1 year from ICI (HR = 1.99, 95% CI [1.15, 3.45], p=0.014) but not for patients with chemotherapy within 1 year of ICI (HR = 1.01, 95% CI = [0.79, 1.29], p=0.960). The use of PPI was not associated with incidence of irAE (p=0.317) or colitis in particular (p=0.781). Conclusions: PPI use was associated with shorter survival in patients treated with ICI across a broad variety of cancers and in first line of therapy or beyond. In patients with recent chemotherapy (<1 year), PPI use was not associated with survival, which may be due to disruption of the microbiome by chemotherapy. Further study is needed to determine the impact of CM (e.g, PPI), on outcomes of patients treated with ICI.[Table: see text]
Cardiovascular toxicity incidence following immune checkpoint inhibitors in randomized clinical trials: A systematic review and meta-analysis.
Authors: Xavier Camila Bragança , Lopes Carlos Diego Holanda , Harada Guilherme , Katz Artur , Fontes Jardim Denis Leonardo
Published: June 2021

2636

Background: Immune checkpoint inhibitors (ICIs) are widely used in oncology and may be associated with a variety of immune-related toxicities. Cardiovascular (CV) adverse effects (AEs) are underreported in randomized clinical trials (RCTs), and the real risk associated with ICIs use has yet to be defined. Therefore, we aimed to investigate the incidence and risk of cardiovascular toxicities in patients receiving ICIs, using an up-to-date meta-analysis of prospective RCTs. Methods: We conducted a systematic search of the literature from January 1st, 2010 until July 1st, 2020 to identify RCTs testing ICIs for solid tumors, either in monotherapy or in combination between them. Our initial search yielded a total of 21,249 relevant publications. For CV AEs incidence estimation, we included phase III RCTs testing PD-1, PD-L1, CTLA-4 inhibitors or any combination of these agents. For relative risk (RR) assessment, we included phase II or phase III RCTs testing the same agents and with placebo or best supportive care (BSC) as the comparator. Data were extracted by independent reviewers following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. CV AEs were categorized based on the Common Toxicity Criteria (CTCAE) and stratified by ICIs type. Analyses were conducted using random effects model. Results: After screening and eligibility assessment, a total of 21,118 patients (67 cohorts from 57 trials) were available for this meta-analysis. We categorized the cohorts by ICIs regimen as monotherapy with a PD-1 inhibitor (35 cohorts; 10,241 patients), PD-L1 inhibitor (12 cohorts; 3,755 patients), CTLA-4 inhibitor (11 cohorts; 4,135 patients), and combination therapy (9 cohorts; 2,987 patients). Incidence measures are described in the table. Deaths from any CV cause occurred in 0.20% of the patients (95%CI 0.10%; 0.20%). For RR analysis, we included 12 cohorts from 11 RCTs. Risk of experiencing all grade AEs was numerically higher among patients who received ICIs than placebo or BSC (RR 1.16; 95%CI 0.98; 1.37; p=0.09). When only grade 3-5 CV AEs were considered, ICIs were associated with increased risk (RR 1.36; 95%CI 1.06; 1.73; p= 0.01). Additional analyses were conducted to estimate the RR of individual CV AEs including arrhythmia, cardiac arrest, heart failure, stroke, hypertension, myocardial infarction, myocarditis, pericardial events, and thromboembolic events. None of the analysis identified a significant additional risk. Conclusions: This meta-analysis corroborates the preclinical rationale of worsen CV risk related to ICIs use.[Table: see text]
Pan-Canadian cohort of immune checkpoint inhibitor-induced insulin-dependent diabetes mellitus (CANDIED).
Authors: Pimentel Muniz Thiago , Araujo Daniel Vilarim , Savage Kerry J. , Cheng Tina , Saha Moumita , Song Xinni , Gill Sabrina , Monzon Jose Gerard , Grenier Debjani , Genta Sofia , Spreafico Anna , Hogg David
Published: June 2021

2640

Background: Endocrine immune-related adverse events (irAEs) are frequent with immune checkpoint inhibitors (ICIs); however, ICI-related insulin-dependent diabetes mellitus (IDDM) is a rare but serious endocrine irAE. We describe the characteristics of patients who developed ICI-related IDDM across five academic Canadian cancer centres. Methods: In this multicentre, retrospective study, we included both patients who developed IDDM and patients with non-IDDM (NIDDM) or pre-DM who became insulin-dependent while on treatment with ICI. We collected data on primary tumor type, ICI regimen (single agent or combination), time to development of IDDM from ICI initiation, comorbidities, laboratory parameters at the time of IDDM diagnosis, tumor response and survival. A p value < 0.05 was considered statistically significant. Results: We identified 27 patients between July 2016 and August 2019. Median age was 60 (39-79) years, 20 (74%) were male, 15 (55%) had melanoma and 4 each (15%) non-small cell lung cancer (NSCLC) and renal cell carcinoma. Seven (26%) patients had prior NIDDM or pre-DM; 5 (18%) had an auto-immune disease (2 psoriasis, 2 inflammatory bowel disease, and 1 systemic lupus erythematosus). Laboratory parameters at presentation and management of IDDM are presented in the Table. Mean A1c was not statistically different between patients with or without prior NIDDM or pre-DM (8.4% vs. 8.6%; p = 0.9). All IDDM events were irreversible; 1 (4%) patient died of diabetic ketoacidosis. At time of IDDM diagnosis, 17 (63%) patients were receiving single agent anti-PD1 and 10 (37%) anti-PD1-based combinations (7 anti-CTLA-4, and 3 other compounds). Median time for development of IDDM from ICI initiation was 2.7 months (95% CI 0.2-5.3). Patients receiving combination ICI developed IDDM earlier than those treated with single agent (1.4 vs 4.8 months; p = 0.05). Amongst patients with metastatic disease (n = 24), 9 (38%) had a complete response and 7 (29%) had a partial response. Two patients (8%) were treated in the adjuvant setting; 1 (4%) received consolidation ICI. IDDM led to ICI discontinuation in 12 (44%) patients. After a median follow up of 21 months from ICI initiation, median survival was 30 months (95% CI NE) and was not reached in patients with melanoma and NSCLC. Conclusions: ICI-related IDDM is a rare and typically irreversible irAE that occurs early in the course of treatment and develops earlier with combination ICI. In this cohort, patients who developed ICI-related IDDM had a high tumor response rate and prolonged survival, especially melanoma and NSCLC patients. Prospective evaluation of autoantibodies to predict development of IDDM is ongoing.[Table: see text]
Pancreatic volumes in immune checkpoint inhibitor-induced diabetes.
Authors: Jeun Rebecca , Yedururi Sireesha , Lavis Victor , Best Conor , Varghese Jeena , Dadu Ramona , Glitza Isabella Claudia , Thosani Sonali
Published: June 2021

2644

Background: Immune checkpoint inhibitor-mediated insulin dependent diabetes (ICI-DM) is a rare and irreversible adverse event often presenting with life-threatening diabetic ketoacidosis (DKA). Pancreatic volume changes have been studied in classic Type 1 and Type 2 diabetes as a surrogate for functional β-cell mass. In this study, we investigate longitudinal changes in pancreatic volumes in patients who develop ICI-DM. Methods: Among patients with ICI-DM seen at our institution between 2014 and 2020, 20 patients who had serial CT scans of the abdomen and pelvis before and after ICI DM diagnosis were identified for inclusion in this study. Demographic data and clinical variables were obtained from the electronic medical record. Weight-adjusted pancreatic volumes were calculated from CT scans at three time points. The most recent CT scan prior to ICI initiation was used as baseline, the CT scan immediately prior to ICI DM diagnosis was used as a midpoint, and the most recent CT scan prior to the end of the study period was used as the final time point for comparison. Results: Median age was 63 years old (range 35 to 83). Renal cell carcinoma and melanoma were the most common cancer types. Male gender predominated (80%). 18/20 patients were on a PD-1 inhibitor with the remaining two on a PD-L1 inhibitor. After initiation of ICI therapy there was a variable response in pancreatic volumes prior to the diagnosis of ICI-DM with 20% patients experiencing a volume loss of > 10% and 25% experiencing a volume gain of > 10%. Volume loss nor volume gain prior to diabetes diagnosis was associated with presentation with DKA. 9/13 (69%) of patients who had pancreatic enzymes checked at diagnosis of ICI-DM had elevated levels. Pancreatic atrophy with a median volume loss of 41% was seen in all patients at a median of 14.9 months (range 3-77 months) after ICI-DM diagnosis. Most had more than 20% volume loss from baseline to most recent scan with no correlation in degree of volume loss with the time interval. There was no evidence of pancreatic ductal dilation, increased pancreatic fat nor any changes consistent with chronic pancreatitis. Conclusions: This study shows a variable response in pancreatic volumes after initiation of ICI in patients who progress to developing ICI-DM, though most had a significant decline in volume after the diagnosis of ICI-DM with long-term pancreatic atrophy. As β-cell mass is thought to comprise 1-2% of the pancreas, these findings may suggest both endocrine and exocrine compartment changes because of ICI-DM, though exocrine dysfunction has not been clinically described in this patient population. As these patients receive frequent imaging during treatment, fluctuations in pancreatic volumes with new or worsening hyperglycemia may portend the onset of ICI-DM and clinicians should have a low threshold to screen for this diagnosis as many will present with life-threatening DKA.
Phase 1b/2a study of PLX2853, a small molecule BET inhibitor, in subjects with advanced solid tumors and lymphoma.
Authors: Gordon Michael S. , Carvajal Richard D. , Spira Alexander I. , Huang Marilyn , Watkins Paul , Powell Ben , Inokuchi Kerry , Sterba Michael , Matusow Bernice , Hope Chelsea , Halladay Jason , Zhang Chao , Walling Jacqueline M. , Tsiatis Athanasios C. , Patnaik Amita
Published: June 2021

3018

Background: PLX2853 is a potent, orally active small molecule BET inhibitor. Its unique pharmacokinetic (PK) profile is associated with less thrombocytopenia and improved tolerability by allowing transient target engagement with a prolonged pharmacodynamic (PD) response and time for recovery after dosing. Methods: We conducted a first-in-human 3+3 Ph1b/2a study of PLX2853 in adults with relapsed or refractory solid tumors and lymphoma to determine the safety, PK and recommended phase II dose (RP2D) (NCT03297424). Secondary endpoints included efficacy and PD. Results: As of 2 February 2021, 44 subjects (median age 65, range 39 - 84) received PLX2853 in escalating doses from 5mg to 120mg QD and 40mg to 60mg BID. Ovarian cancer (n = 11), uveal melanoma, colorectal, and prostate (n = 5 each) were the most represented tumor types. Adverse events (AE) occurring in ≥15% of subjects included nausea (41%), decrease appetite (39%), fatigue (27%), vomiting (25%), diarrhea (25%), dysgeusia (25%), dehydration (23%), anemia (20%), dry mouth (18%), dizziness (16%), abdominal pain (16%), and pyrexia (16%). Thrombocytopenia occurred in 11% of subjects. Most AEs ( > 85%) were grades (G) 1-2. Of all AEs, 40% were related. There were 5 treatment-related serious AEs in 2 subjects (n = 1 G4 thrombocytopenia, G4 ischemic stroke, G3 subarachnoid hemorrhage [SAH], and G3 thromboembolic event; n = 1 G3 vomiting). Dose-limiting toxicities were observed at 120mg QD (G4 thrombocytopenia, G4 ischemic stroke, G3 thromboembolic event, and G3 SAH; asymptomatic G4 thrombocytopenia), 60mg BID (G3 thrombocytopenia with recovery > 7 days), and 40mg BID (dose reduction for transient G3 fatigue). PLX2853 systemic exposure was dose-proportional up to 120mg with a short terminal half-life ( < 3.5 hr). Plasma concentrations were above the IC90 in the MYC-responsive reporter assay for 9 hr at 80mg or higher doses. RNA-seq analyses of peripheral blood mononuclear cells showed a dose-dependent modulation of BET target gene expression. One complete response (ongoing 9+ months) was seen in a patient with DLBCL, two patients had partial responses (1 uveal melanoma, 1 primary peritoneal cancer), and 14 patients had stable disease. The median PFS was 82.5 days (range: 51 – 209 days). Conclusions: PLX2853 shows encouraging signs of clinical activity and is well tolerated at the anticipated RP2D of 80 mg/day. PLX2853 is being evaluated as monotherapy and in combination. Clinical trial information: NCT03297424.
A phase 1 trial of FID-007, a novel nanoparticle paclitaxel formulation, in patients with solid tumors.
Authors: Thomas Jacob Stephen , Habib Diane , Hanna Diana L. , Kang Irene , Iqbal Syma , Nieva Jorge J. , Tsao-Wei Denice , Acosta Francisco , Hsieh Ming , Zhang Yilong , El-Khoueiry Anthony B.
Published: June 2021

3021

Background: FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. In addition to allowing the drug to remain in solution until it can enter a cancer cell, the PEOX nanoparticle preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. In xenograft studies, FID reduced or limited tumor growth in multiple tumor types including lung, gastric, breast, pancreatic, and ovarian cancer. FID was more effective at lower or comparable taxane doses with fewer side effects. We present the first-in-human trial of FID. Methods: The study is evaluating the safety, PK, and efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 125mg/m2 using a standard 3+3 dose escalation design. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and no more than 3 prior lines of cytotoxic therapy for advanced disease. Results: Twenty-five pts were treated across 6 dose levels. Median age was 62 (44-76). ECOG PS was 2 in 1 pt and 1 in 64%. Median number of cycles was 2 (1-16). There were 2 DLTs of grade 3 rash at 100 mg/m2. Given the transient nature of the rash and response to topical therapy, DLT definition was modified to exclude grade 3 rash that lasts ≤ 7 days and additional patients were treated at 100 mg/m2 which was deemed tolerable. There was 1 DLT of grade 3 neutropenia at 125 mg/m2. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts were rash (64%), alopecia (52%), pruritus (44%), anemia (44%) leukopenia, fatigue (40% each), dysgeusia, anorexia, nausea (32% each), and neutropenia (28%). Grade 3/4 TRAEs occurring in > 1 pt were anemia (20%), neutropenia, leukopenia, and maculopapular rash (16%). There were no treatment discontinuations due to toxicity. Twenty-two pts were evaluable for response by RECIST 1.1 with a PR rate of 14% (PR in pancreatic, biliary tract and NSCLC) and disease control rate of 59%. PK is linear and dose proportional. There is no paclitaxel accumulation after weekly dosing, and the t1/2 is between 18-26 hours. Conclusions: FID has a manageable safety profile with MTD not reached. Accrual is continuing at 125 mg/m2. PK is linear, dose proportional and comparable to that of nab-paclitaxel. There is preliminary evidence of anti-tumor activity in heavily pre-treated pts across different tumor types. Enrollment in dose escalation continues. Combination studies with immunotherapeutic agents are planned. Clinical trial information: NCT03537690.
Bosutinib in combination with pemetrexed in patients with selected metastatic solid tumors: A phase I study (NCT03023319).
Authors: Abdel Karim Nagla Fawzy , Shoukier Mahran , Eldessouki Ihab , Khaled Ahmed , Morris John
Published: June 2021

3022

Background: Activation of the Src kinase pathway has been observed in about 50% of cancers of the colon, liver, lung, breast and pancreas. Ceppi, et al, explored that Src inhibitors might be synergistic in combination with pemetrexed. Bosutinib is an approved oral ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an inhibitory effect on Src kinases. Methods: In this phase 1, dose-escalation study, we enrolled 10 patients with advanced metastatic solid tumors who progressed on standard of care chemotherapy, 9 of whom were evaluable, to receive bosutinib and pemetrexed. Bosutinib was administered once daily in a 3 + 3 dose-escalation study design where the first cohort started at an oral dose of 200 mg daily with I.V. pemetrexed 500 mg/m2 on a three weekly schedule. The primary objective was to determine the dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of bosutinib with pemetrexed, and the type and frequency of adverse events. Secondary objective(s) were to estimate tumor response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: All patients had progressed on prior chemotherapy and included 9 patients with adenocarcinoma of the lung, and 1 patient with metastatic adenocarcinoma of the appendix. Two patients (22%) had prior pemetrexed exposure. Median age was 62 years (range, 58-44). The median number of bosutinib and pemetrexed cycles received was 2 (range, 1-4). Nine patients were evaluable. The MTD of bosutinib was 300 mg daily in this combination as 2 out of the 3 patients who received 400 mg experienced elevated liver transaminases (>CTCAE Grade 3) and one patient experienced grade 3 fatigue. Two patients (22%) had a partial response, and 6 patients (67%) had stable disease, including 2 patients with prior pemetrexed exposure, and 1 patient had disease progression. The two responders and the subject with the longest stable disease duration demonstrated Src overexpression on immunohistochemical staining of their tumor. Two patients died of sepsis; both had stable disease. Median PFS was 4.1 months (range, 1.2-11.6), and the median OS was 11.9 months (range, 4-36.7). Adverse events included pneumonia/sepsis, diarrhea, fatigue, rash, weakness, transaminitis, hypertension, and thrombocytopenia. Conclusions: The MTD of oral bosutinib was 300 mg daily in combination with pemetrexed 500 mg/m2 every 3 weeks. Despite the limitations of this phase I study there appears potential efficacy of this combination in pretreated patients. We are currently enrolling patients in the expansion cohort. Clinical trial information: NCT03023319.
Circulating tumor DNA as markers of dynamic recurrence risk and adjuvant chemotherapy benefit in resected non-small cell lung cancer.
Authors: Guo Wei , Zhang Fan , Lv Fang , Ji Ying , Peng Yue , Chen Xiaoxi , Bao Hua , Xu Yang , Shao Yang , Tan Fengwei , Xue Qi , Qiu Bin , Gao Shugeng
Published: June 2021

3028

Background: A significant proportion of non-small cell lung cancer (NSCLC) patients relapse after surgical resection with or without adjuvant therapy. The detection of molecular residual disease (MRD) has great potentials to stratify postoperative risk and facilitate early recurrence diagnosis. Here, we aim to evaluate the clinical utility of serial plasma circulating tumor DNA (ctDNA) in MRD detection, adjuvant therapy guidance, and recurrence risk prediction in resected NSCLC patients. Methods: This prospective cohort study recruited 116 patients with NSCLC following surgery and/or adjuvant therapy. Thirteen patients discontinued, leaving 103 patients for analysis. Tumor samples were obtained at surgery. Plasma samples were collected at baseline, after surgery, after adjuvant therapy and every 3 months thereafter and were analyzed by ultradeep (30000×) next-generation sequencing with molecular barcode and in-silico error correction. Results: Pretreatment ctDNA was detected in 69.8% of patients. ctDNA positivity after surgery and after completion of adjuvant chemotherapy (ACT) were significantly associated with worse recurrence-free survival (RFS) (HR: 4.0; 95% CI: 2.0-8.0; P<.001 and HR:3.2; 95% CI: 1.3-8.2; P <.05, respectively). In stage II-III patients who were positive for ctDNA after surgery, ACT-treated patients had a better RFS than those without ACT ( P<.05), whereas ACT did not confer significant clinical benefits in patients with negative postsurgical ctDNA. During surveillance after definitive therapy, ctDNA positivity was associated with worse RFS (HR: 8.5, 95% CI: 3.7-20, P <.001) and preceded radiological recurrence by a median of 88 days. Using joint modeling of serial ctDNA and time-to-recurrence, we accurately predicted patients’ 12-month and 15-month recurrence status, with areas under receiver-operating characteristics curves (AUROC) of 0.88 and 0.84, respectively. Conclusions: These results indicate that ultradeep ctDNA sequencing could sensitively detect MRD, thus identifying patients with high recurrence risk and guiding the adjuvant therapy decision in resected NSCLC. We also demonstrate that joint modeling of serial ctDNA levels and time to recurrent can provide an accurate dynamic risk prediction for NSCLC patients during surveillance. Clinical trial information: ChiCTR1900024656.
Plasma hPG80 circulating prograstin levels in cancer patients in Nigeria: Prolevcan study.
Authors: Fatiregun Omolara A. , Joubert Dominique , Vire Berengere , Simon-Hart Abigail Anni Frances , Adekeye Olaniyi Andrew , Mahi Younes , Prieur Alexandre
Published: June 2021

3029

Background: Progastrin is a tumor-promoting peptide which is detectable in the blood of patients with different cancers. hPG80 (circulating progastrin) is produced by cancer cells. Recently it was reported that hPG80 is detected in the blood of cancer patients, suggesting its potential utility for cancer detection. In this Nigerian study, we assessed the performance of hPG80 in diagnosed cancer patients versus healthy volunteers. Methods: Plasma samples of 50 patients with breast (n = 41) and colorectal (n = 9) cancer, aged from 26 to 70 years, were assayed for hPG80 levels with the DxPG80 kit from ECS-Progastrin. The diagnostic performance (ROC AUC) of hPG80 was assessed compared to 50 healthy volunteers aged from 21 to 38 years. Results: Plasma hPG80 levels were significantly higher in cancer patients compared to controls (median values: 4.59 pM (IQR: 2.02-8.27 pM) vs 1.37 pM (IQR: 0-3.11 pM), p < 0.0001). The median value of hPG80level was 3.96 pM (IQR: 1.61-7.89 pM) for breast cancers and 6.43 pM (IQR: 2.80-15.86 pM) for colorectal cancer patients. ROC AUC for all cancers, breast cancer and colorectal cancer were 0.75, 0.74 and 0.82 respectively. There was no correlation between hPG80 blood levels with age or CA15.3 levels. Conclusions: Plasma hPG80 is a simple and relatively affordable blood test, it shows potential utility as a biomarker for cancer detection, monitoring and treatment assessment. Further prospective studies are needed to explore and confirm its potential.
Dynamics of circulating tumor DNA in patients with advanced solid tumors treated with cediranib and olaparib.
Authors: Hu Yiduo , Narayan Azeet , Wolfe Julia , Vu Dennis , Thi Trinh , Kantak Chaitanya , Ivy S. Percy , Eder Joseph Paul , LoRusso Patricia , Kim Joseph W. , Patel Abhijit
Published: June 2021

3035

Background: Circulating tumor DNA (ctDNA) has emerged as a potential biomarker to monitor treatment response in solid tumors. Our group previously showed that changes in ctDNA levels were predictive of radiographic response and survival in NSCLC patients receiving immunotherapy. Here we evaluated whether ctDNA dynamics could similarly be used to assess response in a PARP inhibitor-based therapy. Methods: A total of 122 patients with NSCLC, TNBC, PDAC or SCLC received cediranib (C) 30mg daily and Olaparib (O) 200mg twice daily in a phase II study NCI9881. Using a multigene NGS assay, ctDNA was measured longitudinally at baseline (T0), after 3 to 7 days of C monotherapy (T1), after 1 week of C+O combination (T2), after 4 weeks of C+O (T3), and every 4 weeks (T4+) thereafter. The first radiographic assessment was done after 8 weeks of C+O and every 8-12 weeks thereafter. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma. We defined an early ctDNA response (e-ctDNA-R) as a >10% decrease in mutant allele fraction from T0 to T2, and an early ctDNA progression (e-ctDNA-P) as a > 10% increase; otherwise, it was stable ctDNA (e-ctDNA-S). Results: In total, 493 samples were analyzed from 94 patients, and 40 unique patients had both T0 and T2 ctDNA measurements, as well as corresponding radiographic assessments. These included 10 NSCLC, 17 TNBC, 3 SCLC and 10 PDAC. Of these patients, 4, 21, and 15 patients had PR, SD, and PD as best overall radiographic response respectively. Twenty-three (57.5%) patients had either e-ctDNA-R (17, 42.5%) or e-ctDNA-S (6, 15.0%), 18 (78.3%) of whom subsequently had either radiographic partial response (PR) or stable disease (SD). Seventeen (42.5%) patients had e-ctDNA-P, 10 (58.8%) of whom then had PD. A fair agreement was observed between e-ctDNA-R/S or e-ctDNA-P and radiographic PR/SD or PD with Cohen’s k 0.38 (70% agreement). The correlation between early ctDNA changes and PFS/OS are summarized in the table. All 25 patients with PR/SD eventually progressed. Of these, 17 (68%) had >10% increase in ctDNA from the nadir prior to disease progression (median 94.6%, 95%CI 38.2%-389.1%). The time between ctDNA progression and ctDNA nadir was significantly shorter (median 21 days, 95%CI 21-28) than the time between radiographic/clinical progression and initial PR/SD (median 107 days, 95%CI 56-204, P=0.0015). Conclusions: Longitudinal ctDNA measurements could enable early assessment of treatment response, resistance, and disease progression in patients treated with PARP inhibitor-based therapy. However, in this study, tumor responses and ctDNA changes were generally not as robust as have been observed with other classes of therapy.[Table: see text]