bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting non-engrafting IL-2 activated intentionally mismatched donor lymphocytes with monoclonal or bispecific antibodies for treatment of otherwise incurable cancer.
Authors: Slavin Shimon
Published: May 2020

e15033

Background: Cure of certain resistant cancers by donor lymphocyte infusion (DLI) following allogeneic stem cell transplantation (SCT) suggests that alloreactive lymphocytes can eliminate otherwise resistant cancer. First patient with resistant relapse following supra-lethal chemoradiotherapy treated with DLI is alive & well > 34 years; > 400 patients with hematological malignancies confirmed DLI efficacy for prevention & treatment of relapse. Using murine leukemia (BCL1) & metastatic breast cancer (4T1), IL-2 activated mismatched lymphocytes with no prior SCT eliminated otherwise lethal minimal residual disease (MRD). Using anti-EpCAM x anti-CD3 bispecific antibody (BSA) lethal melanoma was eliminated, also resulted in long-lasting immunity against lethal tumor challenge. Graft-vs-host disease (GVHD) was prevented by consistent rejection of mismatched lymphocytes. Accordingly, our goal was to develop effective immunotherapy of cancer using non-engrafting intentionally mismatched Allogeneic Targeted Activated Cancer Killer cells (ATACK) using relevant monoclonal antibodies (MoAb) or BSA. Methods: Patients with multiple myeloma & lymphoma and advanced solid tumors were treated with haploidentical or unrelated donor lymphocytes pre-activated 5 days with IL-2, following non-myeloablative conditioning with endoxan or fludarabine and IL-2 injection x5 days for in vivo lymphocyte activation. ATACK with no MoAb was investigated in 40 patients with different cancers. Safety of ATACK with MoAb was investigated in 16 patients with resistant NHL, metastatic breast, lung & colorectal cancer, using commercial MoAbs against CD20, Her-2, EGFR or VEGF, respectively, or using anti-EpCAM BSA. Results: Protocols were well-tolerated with mild transient toxicity following ATACK and BSA. No patient developed GVHD. Disease-free survival > 15 years was documented in 2/2 patient with multiple myeloma and 2/2 patients with lymphoma. Longterm progression-free survival was observed in 5/31 evaluable patients with advanced metastatic solid tumors treated with no MoAbs. Minor toxicity in targeted ATACK recipients was manageable in outpatient clinic. Conclusions: Intentionally mismatched IL-2 activated killer cells guided by MoAbs or BSA represents a promissing approach for treatment, possibly even cure, of cancer patients with MRD while avoiding GVHD.
Novel CoupledCAR technology for treating colorectal cancer.
Authors: Xiao Lei , Li Song , Pu Chengfei , Cao Zhiyuan , Lu Cheng , Hang Yang , Huang Xi , Shen Xiaogang , Wang Xiuwen , Wu Zhao
Published: May 2020

e15035

Background: Conventional CAR-T cell therapy has thus far shown weak cell expansion in solid tumor patients and achieved little or no therapeutic responses. Methods: We developed CAR T cells based on a novel CoupledCAR technology to treat solid tumors. We engineered CoupledCAR-T cells with lentiviral vectors encoding an anti- colorectal cancer specific protein CAR molecule, and anti- colorectal cancer specific protein (CRCSP) CAR-T cells showed anti-tumor activities in vitro and in vivo experiments. Further, we conducted several clinical trials for various solid tumors, including two patients with colorectal cancer. After the infusion of CoupledCAR T cells, these two patients showed rapid expansion of CoupledCAR T cells and the killing of tumor cells. Specifically, we observed that CoupledCAR T cells expanded significantly in the patients and infiltrated tumor tissue sites. Results: Both patients achieved PR (Partial Response). Patient Profile: Patient 1: Male, 55Y, Colon Adenocarcinoma. In May 2016, 8 cycles of XELOX chemotherapy and 1 dose of radiotherapy were performed. In Step 2016, “radical rectal resection and terminal ileum double ileostomy” was performed. After surgery, gemcitabine chemotherapy was performed for 2 cycles. In January 2018, relapse and metastasis of prostate and left lung were observed. In April 2019, relapse and metastasis were observed. Patient 2: Female, 57Y, Colon Adenocarcinoma. In December 2014, DT46Gy/2Gy/23 radiotherapy was performed. In December 2014 and January 2015, the single drug chemotherapy of Xeloda was taken orally. In February 2015, laparoscopic radical resection of rectal cancer was performed. In April, May, June, and July 2015, mFOLFOX6 chemotherapy was performed. In June 2019, CT showed tumor metastasis. Observations and Results: Patient 1: One month after infusion (M1), the patient was evaluated as PR; most of the target lesions were significantly reduced by more than 50%, and the primary tumor volume was reduced by ~45%. Patient 2: M1, the patient was also evaluated as PR; the tumor in the left upper lobe tip posterior segment was reduced by approximately 75%. Conclusions: The clinical data demonstrated that CoupledCAR-T cells effectively expanded, infiltrated tumor tissue sites, and kill tumor cells in patients with colorectal cancer. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-CRCSP CoupledCAR T cells. Further, since our CoupledCAR technology is a platform technology, we are developing it to treat other solid tumors using different target markers.
Aristotle: A single blood test for pan-cancer screening.
Authors: Dempsey Adam A , Tripp James Howard , Chao Samuel , Stamatiou Dimitri , Pilcz Tanya , Ying Jay , Burakoff Robert
Published: May 2020

e15037

Background: Blood participates in physiological and pathological changes throughout the body which are reflected as changes in cellular gene expression. The involvement of the immune system in cancer suppression and promotion through immunoediting exemplifies this. These characteristics make blood a promising non-invasive surrogate tissue for cancer diagnosis and monitoring. Methods: A multi-class cancer classification model, Aristotle, was developed with logistic regression using Affymetrix gene expression profiles generated from 2,845 unique human whole peripheral blood samples. The model was evaluated through 100 iterations of 2-fold cross-validation. Results: The 1,013 cancer patient samples (age 61±13, 40.6% ♀), include cancer of the bladder (n = 87, age 65±11, 23.3% ♀), breast (n = 94, age 54±10, 98.4% ♀), colon (n = 205, age 64±13, 39.5% ♀)/colon polyps (n = 226, age 61±11, 36.0% ♀), cervix (n = 36, age 55±13), endometrium (n = 25, age 49±12), liver (n = 16, age 57±11, 12.5% ♀), nasopharynx (n = 78, age 51±13, 26.9% ♀), ovaries (n = 64, age 55±12), prostate (n = 160, age 68±9) or stomach (n = 22, age 59±11, 28.6% ♀); and 1,832 control samples (age 53±16, 38.9% ♀), including healthy subjects (n = 1,042, age 55±16, 37.0 ♀) and subjects with ankylosing spondylitis (n = 59, age 39±12, 18.6% ♀), heart failure (n = 193, age 67±12, 40.0% ♀), inflammatory bowel disease (n = 51, age 37±9, 40.0% ♀), osteoarthritis (n = 248, age 53±15, 45.6% ♀), rheumatoid arthritis (n = 40, age 57±17, 84.6% ♀), schizophrenia (n = 110, age 36±13, 43.6% ♀) or other (n = 89, age 50±14, 41.1% ♀). Aristotle classified cancer profiles with sensitivities from 55.6-100% and positive predictive values from 5.6-77.7% at a specificity of 99.0% (Table). The mean false positive rate for the 11 cancer classes ranged from 0.3- 6.8%. Conclusions: Our study demonstrates the clinical viability of using whole peripheral blood for multi-class cancer classification. Aristotle was capable of classifying patients with different types of cancer with clinically relevant accuracy. We are confident that Aristotle holds great promise to help address the need for practical and non-invasive early-stage cancer diagnostics. [Table: see text]
Baseline circulating myeloid-derived suppressor cells subpopulations, neutrophils/lymphocytes ratio, and response to PD-1/PD-L1 inhibitor in non-small cell lung cancer patients.
Authors: GarcIa SAnchez JosE , Benet Gimenez Marta , Cordón Lourdes , De Julian Maria , Piqueras Marta , Ruiz Veronica , Garde Javier , Piera Nuria , Sanchez Alfredo , Lorente David , Carretero Julian , Juan-Vidal Oscar , Lahoz Agustin
Published: May 2020

e15042

Background: Inhibitors of immune checkpoint PD-1/PD-L1 (ICI) have become a care standard in non-small cell lung cancer (NSCLC). Despite promising results, some patients cannot take advantage of immunotherapy effects. Nowadays, neither predictive nor prognostic circulating biomarkers have been found in order to select patients or to predict response to ICI. Myeloid-derived suppressor cells (MDSC) are potent immunity suppressors and may represent both a potential prognostic and a predictive biomarker. We aimed to assess the role of pretreatment circulating MDSC subpopulations on ICI outcomes in NSCLC patients. Methods: 86 NSCLC patients treated with ICI and 10 healthy donors in 3 centers between 02/2018 and 10/2019 were eligible. Pretreatment immunophenotyping of monocytes, early-MDSC (e-MDSC: CD14-/CD15-/HLA-DR-/CD33+/CD11b+), monocytic-MDSC (M-MDSC: CD14+/CD15-/HLA-DR-/CD33+/CD11b+) and polymorphonuclear-MDSC (PMN-MDSC: CD14-/CD15+/HLA-DR-/CD33+/CD11b+) was prospectively performed by flow cytometry in fresh whole blood. Correlation between baseline circulating MDSC subpopulations and Neutrophils/Lymphocytes Ratio (NLR) was evaluated as well as their impact on outcomes. Results: 86 patients who received at least one previous platinum based combination chemotherapy for stage III-IV NSCLC were prospectively included; 82 (95%) smokers, median age 62 years; 52 (60%) non-squamous; 69 (93%) ECOG PS 0-1; 43 (50%) PDL1 ≥ 1% and 65 (76%) were treated in a second line setting. Median PFS (mPFS) was 2.79 months (m) [95% CI, 1.3-4.2] and mOS 11.6 m [9.3-13.9]. Overall, 3m-death rate was 18.6%. Pretreatment high-NLR (NLR > 3) (62/86; 72%) was correlated with poor PFS (p = 0.03), OS (p = 0.01) and a 3m-death rate of 22.6%. High level of global MDSC before anti-PD-1/PD-L1 therapy, defined by the median value as a cut-off ( > 6.3%), was associated with poor OS (p = 0.03). Pretreatment low e-MDSC ( < 21.7%), were also associated with poor PFS (p = 0.01), OS (p = 0.006) and a 3m-death rate of 23.8%. There was not correlation between M-MDSC and PMN-MDSC and clinical outcomes. Conclusions: Our study suggests that a baseline circulating low level of e-MDSC and high-NLR are associated with early failure to ICI and poorer survival. The role of e-MDSC appears interesting as a potential predictive and prognostic biomarker in NSCLC patients treated with anti-PD1/PD-L1. Dynamic assessment of MDSC levels over time and further validation with longer follow up in larger cohorts are needed.
Leukocytes with bound platelets as a predictive biomarker for immune-related adverse events (irAEs) in advanced non-small cell lung cancer (NSCLC) patients (pts) receiving anti-PD-(L)1 agents.
Authors: Riudavets Mariona , Zamora Carlos , Sullivan Ivana , Alserawan Leticia , Barba Andrés , Gallardo Pablo , Gavira Javier , Serra Jorgina , Anguera Georgia , Barnadas Agusti , Vidal Sílvia , Majem Margarita
Published: May 2020

e15047

Background: Anti-PD-(L)1 blocking agents can induce irAEs, compromising treatment continuation and patient safety. Since complexes of leukocyte-platelet have been shown to play a role in inflammation by reducing cytokine production, we hypothesize that the percentage of these complexes could be used as a predictor of irAEs in pts receiving anti-PD-(L)1 agents. Methods: From May 2015 to January 2019, 87 advanced NSCLC pts treated with anti-PD-(L)1 agents at our institution were prospectively included. Percentages of circulating CD4+T lymphocytes and monocytes with bound platelets (CD4+PLT+ and CD14+PLT+, respectively) were obtained by flow cytometry and compared between NSCLC pts and healthy donors (HD, n = 26). The association of leukocyte-platelet complexes with the presence of irAEs was analyzed. According to CD4+PLT+ and CD14+PLT+ levels, NSCLC pts were grouped as CD4+PLT+ high (n = 29), CD4+PLT+ low (n = 58) and as CD14+PLT+ high (n = 36) and CD14+PLT+ low (n = 51). Frequencies and grade of irAEs were compared between groups using Chi-square test. Results: NSCLC pts showed significant higher percentages of circulating CD4+PLT+ and CD14+PLT+ than HD (9.41±0.54% vs. 6.01±0.45% and 57.44±2.42 vs. 35.43±2.22, respectively; p< 0.001). No significant differences in CD4+PLT+ and CD14+PLT+ were found according to the presence of irAEs. CD4+PLT+ high group presented a higher rate of dermatological irAEs while CD4+PLT+ low group showed higher rate of non-dermatological irAEs (dermatological: 44.85% vs. 8.6%; non-dermatological: 10.3% vs. 39.7%, respectively; p< 0.001). Lower percentage of grade ≥2 irAEs was observed in the CD4+PLT+ high group than in the CD4+PLT+ low group (17.3% vs. 41.4%; p< 0.05). No significant differences in the type of irAEs were observed between CD14+ PLT+ high and low groups. Pts with CD4+PLT+ high and CD14+PLT+ low levels showed the lowest rate of irAEs, presenting only grade ≤1 irAEs (53.8% dermatological, 7.7% dermatological + non-dermatological, 38.5% no-irAEs). In contrast, pts with CD4+PLT+ low and CD14+PLT+ high levels presented higher rate of grade ≥3 irAEs (50% grade 0-1, 20% grade 2, 30% grade ≥3; p< 0.05) and predominantly developed non-dermatological irAEs (45% non-dermatological, 30% dermatological + non-dermatological, 25% no-irAEs; p< 0.01). Conclusions: Combining CD4+ PLT+ and CD14+ PLT+ levels may be used as predictive of development and severity of irAEs in advanced NSCLC pts receiving anti-PD-(L)1 agents.
Serine/threonine kinase 11 (STK11) mutations and immunotherapy resistance in patients with non-small cell lung cancer.
Authors: Uba Richie , Raez Luis E. , Dumais Katerine , Gentile Frank , Powery Herman W. , Domingo Gelenis Calzadilla , Izquierdo Paola , Hunis Brian
Published: May 2020

e15055

Background: There is immune evasion and resistance to checkpoint inhibitors (CPI). Programmed death-ligand 1 (PD-L1) and Tumor mutational burden (TMB) might help us predict response, but we have not yet validated biomarkers that can predict resistance. Mutations (mut) in STK11 can induce epigenetic changes that confer proliferative advantages to cancer cells and preliminary reports have suggested that they can confer resistance to CPI. We investigated the role of STK11 and KRAS mut as markers of poor response to CPI in patients (pts) with non-small cell lung cancer (NSCLC). Methods: Clinical outcomes of 127 pts with stage IIIB-IV NSCLC who were tested for KRAS and STK11 mut and received CPI were evaluated for progression free survival (PFS) and overall survival (OS). For statistical analysis log-rank tests were used to compare OS and PFS, chi-squared tests were used to compare 1-year survivals and proportions among different variables, and Kaplan-Meier survival curves were used to report OS and PFS. Results: Of the 127 pts: 31 had STK11 mut, 14 had STK11+KRAS mut (SKM group), and 10 pts were in the SKMP group (STK11+KRAS mut+PD-L1 (-)). Median age was 65y (27-88y). Males were 54% of the total and 30 pts (24%) were Hispanic (H). STK11 mut patients had an inferior PFS and OS as shown in table. Pts in SKM and SKMP groups had worse outcomes; however, not all the P values were significant. The difference in OS and 1-year OS were very impressive and significant when compared between the SKMP group (4m and 30%) and the wild type group (15m and 73%). There were no significant differences in clinical outcomes for H vs. non-H White pts. Conclusions: The presence of STK11 mut were associated with shorter OS/PFS in NSCLC pts treated with CPIs, proving its utility as a negative predictive marker. This can be enhanced combining STK11 and KRAS mut and possibly adding PD-L1 (-). These findings are consistent with recent studies that have reported STK11 mut as a genomic driver of primary resistance. Due to the small sample size further studies will be needed to validate these findings. [Table: see text]
Predictive factors for combined anti-PD-1 and anti-angiogenic therapy in multiline treatment of advanced non-small cell lung cancer.
Authors: Wang Yina , Li Xiaobin , Chen Yao , Xu Mingyan , Song Lele
Published: May 2020

e15059

Background: Immune checkpoint inhibitors (ICIs), such as PD-1/ PD-L1 inhibitors, have made a significant breakthrough in lung cancer first-line treatment. However, there are few reports on stratification, therapeutic response and prognosis prediction of NSCLC patients treated with immunotherapy combined with anti-angiogenic therapy in multiline therapy. The aim of this study was to investigate the clinical efficacy of anti-PD-1 plus anti-angiogenic therapy in the second-line or multiline treatment of NSCLC, and to explore potential predictive biomarkers for response and prognosis in this combined therapy. Methods: A total of 22 advanced NSCLC patients were recruited in this study, in which 14 patients received this combined immunotherapy as second-line therapy, and 8 patients as multiline therapy. Genomic profiles were determined with blood by a 451-gene next-generation sequencing panel. Sequencing data were analyzed with R packages and statistics analysis was performed with SPSS 20 software. P ≤ 0.05 was regarded as statistically significant. Results: All patients were followed up until progression or the end of this study. The objective response rate (ORR) assessed by an independent radiology review was 22.7%, and the median progression-free survival (PFS) time for all patients was 5.25 months. Surprisingly, the pre-therapeutic blood tumor mutation burden (bTMB) could not discriminate clinical benefit from non-benefit group in this combined therapy (P = 0.167). However, we found that the concentration of pre-therapeutic blood circulating free DNA (cfDNA) was an independent predictor of PFS (HR = 27.75, P = 0.003), in which higher cfDNA concentration correlated with poorer outcomes. Meanwhile, patients harboring MIKI67 gene mutations or gene variations related to hyper-progressive disease showed significantly shorter PFS time (p < 0.05). In addition, patients with negative ctDNA before therapy might benefit more from this combined immunotherapy (P = 0.068). Conclusions: Our study suggested that the combined strategies may improve clinical efficacy of ICIs in second and multiline therapy. The pre-therapeutic bTMB was not predictive for clinical benefit in multiline combined therapy. Patients with pre-therapeutic high concentration of cfDNA, MIKI67 mutations or gene variations related to hyper-progressive disease may be less likely to benefit from the combined therapy. Our findings may improve the prediction of therapeutic effect and prognosis in future combined treatment involving immunotherapy.
The effect of concomitant cannabinoids during immune checkpoint inhibitor treatment of advanced stage malignancy.
Authors: Biedny Adam , Szpunar Susan , Abdalla Ahmed , Kafri Zyad , Hadid Tarik H.
Published: May 2020

e15064

Background: Immune checkpoint inhibitors are used in treatment of advanced neoplasms. Immunotherapy agents create a potent pro-inflammatory effect in cancer. The efficacy of immunotherapy may negatively be impacted by the use of anti-inflammatory agents. An anti-inflammatory effect of cannabinoids has been described in literature in several models. Recent data suggests a negative impact of cannabis on tumor response to immunotherapy. Methods: We retrospectively reviewed medical records of all patients with metastatic cancer who received at least 2 months of immune checkpoint inhibitors between August 2014 and August 2018. The patients were stratified by use of cannabis (cannabis vs non-cannabis users). Baseline patients’ characteristics were compared. Overall survival was estimated and compared between the two groups. An analysis was performed using analysis of variance, Student's t-test, correlation, chi-squared test, and logrank test. All data were analyzed with SPSS v. 26.0 and a p-value less than 0.05 was set to indicate statistical significance. Results: A total of 104 patients with advanced-stage malignancy met the inclusion criteria. The median age was 63.9±10.5 years, 48.1% males and 81.7% Caucasians. 41.3% of patients has lung adenocarcinoma, 20.3% has squamous cell carcinoma of the lung, 11.5% has squamous cell carcinoma of the head and neck and 26.9% have other tumor types. Twenty patients (19.2%) had brain metastasis and twenty-three patients (22.1%) had bone metastasis. Seventy patients (66.8%) received Nivolumab, and twenty-seven patients (26%) received Pembrolizumab. The mean duration of immunotherapy use was 10.2 months. Characteristics of patients were similar between the groups except for a higher prevalence of tobacco use in the cannabis group. Twenty-eight patients (26.9%) reported concomitant cannabis use during immunotherapy treatment, 23 were prescribed (dronabinol) and 5 used it recreationally (smoking marijuana/cannabis oil). Non-cannabis users had significantly longer overall survival (OS) compared to cannabis users (40 months vs 16 months, p = 0.004). Conclusions: This study shows significant association between the use of cannabis during immunotherapy treatment and worse OS. This can be explained by an anti-inflammatory effect of cannabis, which may decrease response to immune checkpoint inhibitors. This observation should be further investigated in randomized trials. Health care professionals should be aware of the potentially harmful effect of cannabis on cancer care.
Impact of systemic corticosteroids on survival outcomes in patients with immune-checkpoint inhibitor enterocolitis.
Authors: Thompson Leah L. , Katznelson Ethan , Leet Donna E. , Durbin Sienna , Yoon Jaewon , Park Jin K. , Dougan Michael L. , Chen Steven T.
Published: May 2020

e15065

Background: Current guidelines for immune-checkpoint inhibitor enterocolitis (ICI-EC) recommend systemic corticosteroids (SCS) for moderate to severe cases, but whether these therapies have an impact on survival outcomes remains unclear. Prior work has been limited, considering only select cancer types, ICI regimens, and indications for immunosuppression. We therefore sought to examine the relationship between SCS for ICI-EC and survival outcomes, accounting for all other steroid exposures. Methods: We retrospectively reviewed the medical records of patients with biopsy-confirmed ICI-EC seen at our institution between August 2011 and April 2019, collecting patient demographics, cancer features, anti-neoplastic therapies, other immune-related adverse events (irAEs), SCS exposures, progression-free survival (PFS), and overall survival (OS). We further categorized SCS exposures by indication (ICI-EC, other irAE, other medical reason) and previously established dose thresholds (“high” ≥1mg/kg for ≥1 week; “moderate” ≥7.5mg for ≥2 months, or “none”). We assessed the relationship between SCS use for ICI-EC and PFS/OS using Cox proportional hazards models adjusted for age, sex, cancer type and stage, baseline brain metastases, functional status (Eastern Cooperative Oncology Group score), anti-neoplastic therapies, and other SCS exposures. Results: 90 patients (mean age 62.5 years, 37.8% female) had biopsy-confirmed ICI-EC, most commonly precipitated by CTLA-4 monotherapy (43.3%). Nearly all (80.0%) required SCS for their first episode of ICI-EC, with half (46.7%) requiring doses exceeding the highest threshold. Patients who received high-dose SCS for first ICI-EC episode had reduced PFS (HR = 2.50, p = 0.028) compared to those who did not receive SCS for this indication. OS was not affected by SCS therapy for ICI-EC at any dose. Conclusions: In cancer patients with biopsy-proven ICI-EC, receipt of high-dose SCS for first ICI-EC episode was associated with decreased PFS, but not OS. These findings suggest a nuanced and potentially dose-dependent relationship between SCS and survival outcomes meriting further investigation for a larger array of immunotoxicities.
Predicting cardiac adverse events in patients receiving immune checkpoint inhibitors: A machine learning approach.
Authors: Dreyfus Brian , Heilbroner Samuel P , Few Reed , Kratt Christine , Gomez Andres
Published: May 2020

e15075

Background: Many oncology treatments have been associated with cardiovascular (CV) adverse events. Cases of CV events, including myocarditis have been reported for PD-1 and PD-L1 therapies. We created a machine learning model to predict potential CV events in PD-(L)1 patients using the CancerLinQ database. Methods: A XGBoosted decision tree model was trained to predict a patient’s risk of serious CV adverse events. The model was trained on 80% of all advanced non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) patients from our database including those who received PD-(L)1 therapy. Index date was defined as date of first PD-(L)1 administration or date of advanced diagnosis if no PD-(L)1 drug was given. The model contained approximately 400 potential risk factors for cardiac disease including elements of past medical history, social history, vitals, common labs, cancer history (e.g. stage, cancer type), medication history, and PD-(L)1 specific factors including PD-(L)1 expression status and PD-(L)1 therapy administered. The model was tested on two separate validation sets (patients not used in training): one using advanced NSCLC, melanoma, and RCC patients and another with PD-(L)1 patients only. Each factor’s importance to the model’s predictions was calculated using SHAP summary plots, a qualitative technique for interpreting machine learning models. Results: A total of 27,172 advanced cancer patients were included in our study. 4,966 received PD-(L)1 therapy. The model was trained on 21,758 patients and 5,414 patients were set aside for testing. The model predicted serious cardiac events within 100 days of index with an AUC-ROC of 0.75 in all patients and 0.79 in PD-(L)1 patients. The top predictors of cardiac risk in PD-(L)1 patients included a history of heart disease, weight loss, the % lymphocyte count, and median LDH. The % lymphocyte count and weight loss were noticeably more predictive in PD-(L)1 patients than in non-PD-(L)1 patients. However, in general SHAP summary plots of all and PD-(L)1 patients were nearly identical, suggesting that both cohorts’ cardiac risk is determined in a similar way. PD-(L)1 and autoimmune disease associated factors did not appear in the top 40 most predictive risk factors. Conclusions: Using traditional cardiac risk factors, our model was able to predict potential cardiac events in PD-(L)1 patients. Our model found that high lymphocyte count may be protective while weight loss and a history of cardiac disease (e.g. heart failure) could indicate a poor prognosis.
Multidisciplinary team management for high grade immune-related adverse events (irAEs): A single center experience.
Authors: SINGH PRABHSIMRANJOT , Abu-Shawer Osama , Brito Amanda , Yenulevich Eric , Grover Shilpa , Abdulnour Raja-Elie E , LeBoeuf Nicole R. , Ott Patrick Alexander , Hodi F. Stephen , Jacobson Joseph O. , Rahma Osama E.
Published: May 2020

e15076

Background: Immune checkpoint inhibitors (ICIs) are increasingly used in the management of cancer. High grade irAEs are uncommon but can be severe and require hospital admission. There is an urgent need for early identification and triage of patients with irAEs in order to improve their management and outcomes. Methods: We established Immunotherapy toxicity (ITOX) team as the first in nation inpatient service at DFCI and Brigham and Women's Hospital (BWH) along with our partners at Massachusetts General Hospital (MGH) that is specifically devoted to mitigating irAEs. The ITOX service is consistent of 2 PAs and a medical oncology attending with an expertise in immunotherapy. The service utilizes algorithms that are modified from the ASCO and NCCN guidelines by our medical subspecialty experts at BWH. The service uses a multi-disciplinary approach with around the hour consulting service from experts in the field including GI, pulmonary, endocrinology and others. We leveraged EPIC to triage patients who are admitted to BWH and have ever received or currently on immune checkpoint inhibitors (ICIs). The daily list generated by EPIC is then curated manually by a PA to identify patients with potential irAEs. Results: A total of 138 patients with high grade irAEs were admitted to BWH between June 2018 and June 2019. Seventy percent of the 201 irAEs- related admissions were to ITOX service (70% accuracy in triaging). Most common irAEs was colitis (31%), pneumonitis (28%) and hepatitis (13%) which is consistent with the most common reported irAEs due to ICIs. Eighty five percent of the patients had grade 3 irAEs and 15% were admitted with life threatening grade 4 adverse events. About half of the patient had received ICI monotherapy; 33% received combination of ICI and non-ICI (chemotherapy or targeted therapy) and 17% received combination of ICIs. Most patients responded to steroids and only 9% had steroid-refractory irAEs requiring other immunosuppressive agents. The average length of stay for irAEs-related admission was 11 days with readmission rate of 26% within a year. Over 50 patients consented for tissue and blood biospecimen collection at the time of toxicity. Conclusions: We demonstrated the feasibility of empowering EMR to accurately triage patients with suspected irAEs to the ITOX service that is supported by institution developed guidelines and specialists. Our model is adaptable in major academic centers and can have major impact on quality improvement and future research studies that can be conducted in this unique setting.
Nephrotoxicity due to immune checkpoint inhibitors in rural oncology.
Authors: Leon Chady Abboud
Published: May 2020

e15084

Background: Case studies and retrospective chart reviews of health system data have demonstrated an increased risk of nephrotoxicity in patients receiving immune checkpoint inhibitors (CPIs) compared to the incidence of nephrotoxicity reported in clinical trials. The primary objective of this study is to determine the extent to which CPIs may induce nephrotoxicity in a real-world, rural population. The secondary objectives are to identify risk factors for renal dysfunction and describe real-world use of this relatively new class of medications. Methods: This represents a retrospective review of patients receiving at least one dose of a CPI at Marshfield Clinic Health System (MCHS) in Central Wisconsin from May 2013 to November 2019. Baseline serum creatinine, defined as the average of all serum creatinine values obtained within 6 months of the CPI start date, was compared to all serum creatinine measurements during CPI therapy and through 60 days after the last CPI dose. Acute kidney injury (AKI) was defined using the Kidney Disease Improving Global Outcomes definition. Patients developing an AKI of at least three day duration were further assessed to determine the likely cause of AKI. The incidence of potentially CPI-induced AKI was our primary outcome. Chi-square test will be used to compare incidence of AKI among different CPIs. A subdistribution hazard regression will be used to assess the association between the incidence of potentially CPI-induced AKI and patient characteristics (including comorbidities, type of cancer diagnosis, demographics, baseline ECOG score, CPI line in therapy, time lapse between diagnosis and CPI start, and concomitant nephrotoxic medications) while accounting for the competing risk of death. Results: A total of 922 patients received at least one dose of a CPI at MCHS during the study period. After applying exclusion criteria, a total of 920 patients were included in the analysis. The incidence of AKI of any duration and due to any cause was 29.5% (272 of 920 patients). Conclusions: The raw incidence of AKI in our patient population receiving CPIs is higher than previously published studies. However, our data are still being refined and research is in progress.
Immunohistochemistry analyses of LAG-3 expression across different tumor types and co-expression with PD-1.
Authors: Chen Francine , Sherwood Thomas , De Costa Anushka , Yee-Toy Nicholas , Lung Peter , Easton Ann , Sumrow Brad , Bonvini Ezio , Moore Paul A.
Published: May 2020

e15086

Background: Concomitant blockade of LAG-3 and PD-1 has been shown to restore T-cell activation and enhance anti-tumor immunity in preclinical models. Clinical trials evaluating anti-LAG-3/anti-PD-1 mAb combinations or bispecific molecules are ongoing. Establishing the tumor expression profile of LAG-3 and its relationship to PD-1 will aid in patient selection and interpretation of clinical responses to combined inhibition. Methods: LAG-3 Ab clone EPR4392(2) (Abcam) and PD-1 Ab clone NAT105 (Ventana) were developed as individual or combined dual IHC assays on the Ventana Discovery Ultra platform. LAG-3 IHC was performed on panels of commercially available tissues: 33 normal human tissues (2 each) and various tumor types including anal (n = 39), cervical cancer (40), cholangiocarcinoma (11), DLBCL (40), gastric cancer (34), HCC (18), SCCHN (39), HER2-positive breast cancer (48), mesothelioma (40), NSCLC (39), ovarian cancer (47), SCLC (48), and TNBC (40). LAG-3 IHC expression was confirmed by in situ hybridization (ACD RNAScope). Positivity was defined as at least one LAG-3+ve or PD-1+ve tumor-infiltrating lymphocyte (TIL) per 40x magnification hot spot field (HSF); high LAG-3 expression was defined as > 15 LAG-3+ve TILs per HSF. Results: LAG-3-specific staining in normal tissues was limited to mononuclear cells in lymphoid organs and GALT, with no staining observed in normal parenchyma. Across various tumor types, the frequency of LAG-3+ve tumor samples and high expression, respectively (%, %), were as follows: cervical (100; 57.5), anal (97.4; 30.8), DLBCL (95; 75), NSCLC (92.3; 25.6), TNBC (90; 22.5), gastric (88.2; 44.1), SCCHN (87.2; 56.4), HER2-positive breast (85.4; 39.6), HCC (83.3; 22.2), cholangiocarcinoma (81.8; 9.1), ovarian (70.2; 21.3), SCLC (50; 14.6) and mesothelioma (25; 10). In addition to TILs, LAG-3 expression was observed on tumor cells in DLBCL and a fraction of anal, breast, cervical, gastric, hepatocellular, SCCHN, NSCLC and ovarian cancers. LAG-3/PD-1 double IHC staining revealed dual positivity across 92.3% of NSCLC samples, with approximately 60% demonstrating TIL co-expression of PD-1 and LAG-3. Conclusions: LAG-3 expression was detected on TILs across a broad range of solid tumors and DLBCL, with varying level of intensity or association with PD-1 expression. Correlative assessments of LAG-3/PD-1 expression with clinical responses to MGD013, an investigational bispecific DART(R) molecule targeting LAG-3/PD-1 (NCT03219268), will be undertaken.
Incidence and risk factors for pneumonitis associated with immune checkpoint inhibitors in advanced-stage non-small cell lung cancer: A single center experience.
Authors: Soto Felipe , Zhong Linda , Shannon Vickie R , Wilson Nathaniel , Zarifa Abdulrazzak , Akhmedzhanov Fechukwu , Heymach John , Arain Muhammad H , Lewis Jeff , Rinsurongkawong Waree , Lee J. Jack , Zhang Jianjun , Swisher Stephen , Mendoza Tito R. , Naing Aung , Sheshadri Ajay , Altan Mehmet
Published: May 2020

e15089

Background: Conventional treatments for advanced-stage non-small cell lung cancer (NSCLC) confer a progression-free survival of only about 6 months. Immune checkpoint inhibitors (ICIs) have become standard therapies in the management of advanced NSCLC, but are associated with a variety of immune-related adverse events that may be dose-limiting (irAEs). Risk factors for ICI-related pneumonitis, a potentially fatal irAE, have not been well established. We sought to determine the incidence and risk factors for ICI-related pneumonitis in NSCLC in a cohort of patients treated with ICIs as standard of care or as part of a clinical trial. Methods: We performed a retrospective review of 525 patients with advanced NSCLC who received ICI therapy with PD-1 inhibitors, with or without CTLA-4 inhibitors, at MD Anderson Cancer Center between 2015 and 2018. Patients with incomplete data were excluded from the study. Clinical data was collected at the time of ICI therapy and at the time of irAE. The diagnosis of pneumonitis was based on clinical presentation, imaging findings, and microbiological results. We constructed a Fine-Gray competing risks regression model with pneumonitis as the outcome of interest and all-cause mortality as the competing risk. Results: In our initial data analysis based on available data shows a 9.7% raw incidence of pneumonitis (17/177). We found no association between age, race, gender, type of anti-PD-1 therapy, concurrent use of CTLA-4 inhibitors, tumor histology, cumulative radiation dose, or smoking pack-years with the risk for pneumonitis. Patients who were therapy-naïve at the initiation of ICI therapy (hazard ratio [HR] 3.3, 95% confidence interval [CI] 1.0-10.6, p = 0.04), and patients with prior lung disease (HR 2.7, 95% CI 0.8-8.5, p = 0.1) had around a three-fold increase in the risk for pneumonitis after accounting for the competing risk of mortality. Conclusions: NSCLC patients who are therapy-naïve or have prior lung disease on initiation of ICI therapy have a higher risk for pneumonitis. Other studies have shown an increase in pneumonitis in therapy-naïve patients, but the association with prior lung disease is novel. Further analysis on this cohort is ongoing.
Smoking status and immunotherapy outcomes in smoking-associated cancers.
Authors: Jun Tomi , Ganta Teja , Qin Qian , Patel Vaibhav G. , Wang Bo , Mellgard George , Gogerly-Moragoda Mahalya , Leiter Amanda , Gallagher Emily J. , Oh William K. , Galsky Matt D. , Tsao Che-Kai
Published: May 2020

e15097

Background: Improved immunotherapy (IO) outcomes have been observed among non-small cell lung cancer patients with a current or former smoking history. This is thought to be a consequence of increased immunogenic mutation burden among smoking-related cancers. We set out to explore the association between smoking status and immunotherapy outcomes in lung and other smoking-associated cancers. Methods: This was a retrospective analysis of 200 consecutive patients with advanced, smoking-associated solid tumor types, treated with single-agent anti-PD1/PDL1 therapy at a single center between July 2014 and February 2018. The primary outcome was overall survival from date of IO initiation. The secondary outcome was overall response, defined as radiographic complete response or partial response, by RECIST 1.1 criteria. The primary predictor was smoking status (former/current smoker vs. never smoker). The primary and secondary outcomes were analyzed using multivariable Cox proportional hazards models and multivariable logistic regression models, respectively. Models were adjusted for age and sex, and stratified by cancer type. Results: The majority of patients were male (64%) with a history of smoking (72%); the average age was 67.1 ± 11.4 years. Cancer types represented were: non-small cell lung cancer (NSCLC, N = 81), hepatocellular carcinoma (HCC, N = 41), urothelial carcinoma (BLCA, N = 39), head and neck squamous cell carcinoma (HNSC, N = 21), and renal cell carcinoma (RCC, N = 18). Over a median follow-up of 11.3 months (range 0.5-53.2), there were 96 deaths and 27% of evaluable patients achieved radiographic response. Response was not evaluable in 27 patients. In multivariable regression analysis, smoking status was not significantly associated with overall survival nor overall response in any cancer type examined (Table). Conclusions: Smoking status was not associated with outcomes in our cohort of IO-treated patients with smoking-associated cancers, though sample size was limited. [Table: see text]
Pharmacokinetic (PK)-pharamcodynamic (PD) analysis and receptor occupancy data to support every other week maintenance dosing of magrolimab in combination with azacitidine in MDS/AML patients.
Authors: Agoram Balaji , Jin ChaoYu , Maute Roy , Takimoto Chris H.M. , Chao Mark , Sallman David Andrew
Published: May 2020

e15098

Background: Magrolimab (Hu5F9-G4) is a monoclonal IgG4 antibody that binds to CD47 receptor and blocks its interaction with SIRPA, thereby enabling tumor cell phagocytosis and activation of an anti-tumor T-cell response. Magrolimab has shown encouraging efficacy and tolerable safety profiles in treatment-naïve myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) patients on an every week (QW) maintenance dosing schedule. Reduced dosing frequency (e.g. every other week – Q2W) is desired to enhance patient convenience and quality of life. Methods: Interim pharmacokinetic (PK) and CD47 receptor occupancy (RO) data from study 5F9005 (Clinical Trial: NCT03248479) were used for this analysis. A previously developed population PK (PopPK) model of magrolimab was verified with observed PK data from study 5F9005. The PK model was linked to peripheral blood and bone marrow blast CD47 RO. The model-predicted RO was validated with observed RO data. Simulations of PK and RO were conducted to justify the proposed reduced dosing frequency of Q2W starting in Cycle 3 onward. Simulations were compared with preliminary observed RO data from the ongoing 5F9005 study after switching to Q2W dosing. Results: The results showed that observed magrolimab PK in study 5F9005 was consistent with model predictions. Model predicted RO was aligned with observed RO data. PK and RO simulations based on the model indicated > 99% RO in peripheral blood and ~90% RO in bone marrow are expected after switching to Q2W dosing regimen from Cycle 3 onward. Preliminary observed RO data confirmed these predictions. Conclusions: Magrolimab PK in AML/MDS is consistent with other patient populations including solid tumors and lymphomas. Model-based simulations and preliminary RO data support Q2W dosing of magrolimab from Cycle 3 onward as optimal RO is expected with the proposed dosing regimen. Clinical trial information: NCT03248479 .
Oral adverse events in cancer patients treated with immune checkpoint inhibitors.
Authors: Xu Yuanming , Sonis Stephen T. , Wen Natalie , Salous Moaiad , Villa Alessandro
Published: May 2020

e15106

Background: Immune-checkpoint inhibitors (ICIs) are increasingly used to treat a variety of cancers. Immune-related adverse events (irAEs) have been reported. Oral manifestations of irAEs include stomatitis, oral ulcers, and xerostomia. However, the trajectory and frequency of oral irAEs remain unclear. This study aims to evaluate the prevalence, trajectory and nature of oral irAEs and their association with primary cancer diagnosis and other irAEs. Methods: A retrospective electronic chart review using the Partners Research Patient Data was performed for all patients treated with ICIs at Partners Healthcare hospitals and the Dana-Farber Cancer Institute between 12/2011 and 9/2019. Keywords specific to oral irAE such as oral mucositis, stomatitis or mouth sore were used. We collected data on demographics, cancer features, treatments, and characteristics of oral irAEs. Results: 822 of 4683 patients who received ICIs therapy were identified by keyword filtering. Lung cancer, gastrointestinal cancer, and skin cancer (including melanoma) were the most common types of primary malignancies with a frequency of 35.5%, 12.4 % and 11.7%, respectively. Oral irAEs were identified in 106 patients with the median age of 69 (range: 29-92) years and the female to male ratio of 1:1. 57.5% (n = 61) presented with symptomatic oral mucosal lesions. 47.2% (n = 50) had xerostomia and 17.0% (n = 18) had dysgeusia. The median time from the date of ICIs initiation to the date of oral irAE onset was 105 days (range: 2-631 days) in patients presented with oral mucosal lesions, 103 days (2-860 days) in xerostomia patients, and 156 days (range: 5-836 days) in dysgeusia patients. Melanoma was the most common cancer seen in oral irAE patients (30.2%), followed by lung cancer (26.4%) and oral/oropharyngeal cancer (12.3%). 60, 42, and 12 patients received pembrolizumab, nivolumab, and ipilimumab, respectively. 86.8% of oral irAE patients received only one type of ICIs therapy. Concomitant cutaneous, intestinal, and rheumatological irAEs were commonly reported with a frequency of 19.4%, 15.3%, and 12.2%, respectively in those patients. Conclusions: Oral irAEs can present with both acute and chronic onset in patients with ICIs therapy but are not as common as oral AEs associated with conventional cytotoxic regimens. While data relative to capturing oral irAEs is still preliminary, the current provides insight into their nature and course. Prospective studies focused on assessing the impact of ICI on oral irAEs are likely to provide additional insight into the character, course and impact of these conditions.
IBI310 monotherapy or in combination with sintilimab in patients with advanced melanoma: An open-label phase Ia/1b study.
Authors: Lian Bin , Cui Chuanliang , Si Lu , Sheng Xinan , Chi Zhihong , Mao Lili , Tang Bixia , Wang Xuan , Yan Xieqiao , Li Siming , Bai Xue , Zhou Li , Guo Jun , Zhou Hui , Xia Huan
Published: May 2020

e15111

Background: IBI310 is a humanized IgG1 monoclonal antibody against CTLA-4. The study evaluates the safety and tolerability of IBI310 alone or in combination with sintilimab, a PD-1 inhibitor, in patients (pts) with advanced melanoma. Methods: This phase 1a/1b study contained three parts: Part A, Part B and Part C (NCT03545971). In Part A, pts with advanced melanoma were treated in an accelerated titration design with 0.3 mg/kg IBI310 (Q3W, IV), or a 3+3 escalation design with 1, 2 or 3 mg/kg IBI310 (Q3W, IV), up to 3 cycles. In Part B, pts with advanced melanoma were administrated in a 3+3 escalation design with 1, 2 or 3 mg/kg IBI310 (Q3W, IV) plus sintilimab (200 mg, Q3W, IV) for 4 cycles, followed by sintilimab maintenance therapy (200 mg, Q3W, IV). Part C was dose expansion of the combination therapy. The primary objective was to determine dose-limiting toxicity (DLT) of IBI310 monotherapy and the second was efficacy of the combination therapy. Tumor evaluation was based on RECIST 1.1. Results: As of Nov 12, 2019, 10 pts were enrolled in Part A (median age 55.5), 6 were mucosal melanoma, 3 were acral melanoma and 1 was non-chronic sun damaged (NCSD) melanoma; 17 pts were enrolled in Part B and C (median age 47.0), only 1 (5.9%) was chronic sun damaged (CSD), and 16 (94.1%) were other melanoma types, including 12.5% (2/16) acral, 31.3% (5/16) mucosal and 56.3% (9/16) NCSD melanomas. No DLTs were observed in both Part A and B. In Part A, 9 pts occurred treatment-related adverse events (TRAEs), most commonly pruritus (4 pts), blood thyroid stimulating hormone increased (2 pts), and asthenia (2 pts). No AEs of ≥ grade 3 were reported. Five pts had stable disease (SD). In Part B and C, 13 pts reported TRAEs, only 1 pt occurred grade 3 TRAE (aspartate aminotransferase increased in 3mg dose level), and others reported grade 2, most commonly pruritus (8 pts), rash (7 pts) and alanine aminotransferase increased (6 pts). No AEs leading to death. In evaluable pts in combination with sintilimab, 1 (NCSD melanoma) of 7 pts (3 NCSD, 1 acral, 2 mucosal and 1 CSD melanoma) reached confirmed partial response (PR) in 2 mg group, and 1 (acral melanoma) of 3 pts (1 acral, 1 mucosal and 1 NCSD melanomas) reached confirmed PR in 3 mg group. Five pts had SD. Part C is currently ongoing. Conclusions: IBI310 monotherapy or in combination with sintilimab were well-tolerated without unanticipated AEs in pts with advanced melanoma. The data preliminarily demonstrate an antitumor activity of the combination therapy in previously treated advanced melanoma (acral and NCSD melanomas). Clinical trial information: NCT03545971 .