bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary safety and pharmacodynamic (PD) activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in a phase I dose escalation study of patients with selected advanced solid tumors.
Authors: Hickingbottom Barbara , Clynes Raphael , Desjarlais John , Li Caiyan , Ding Ying
Published: May 2020

e15001

Background: Interim safety and PD data from an ongoing first-in-human, multi-center, open-label dose escalation study of XmAb20717 (XmAb20717-01; NCT03517488) are reported here. The primary objectives were to determine safety, tolerability, and the MTD and/or recommended doses (RDs). Secondary objectives included preliminary anti-tumor activity and PK/PD. Methods: A 3+3 dose escalation design was used to establish an MTD/RD(s) for infusions on Days 1 and 15 of each 28-day cycle. DLT evaluation was based on Cycle 1 through Day 28. Patients with selected solid tumors (in indications both with and without approved checkpoint therapy) who have exhausted standard of care are eligible. Results: As of 05FEB 2020, 34 patients were treated in cohorts 1-6 at fixed doses of 0.15 to 10 mg/kg. Patients had a median age of 57 years (range 32-81), a median time since initial diagnosis of 42 months (range 3 -313), and a median of 4 prior systemic therapies (range 0-9). 68% of patients had a TNM stage of III/IV, and 68% had been exposed to checkpoint therapy. XmAb20717 treatment was generally well tolerated through the highest dose cohort tested. Overall rates of Gr3/4 immune-related AEs occurred in 8 (24%) patients including elevations of transaminases 3 (9%), rash 2 (6%), lipase and amylase 1 (3%, without clinical symptoms or radiographic evidence of pancreatitis), lipase (alone) 1 (3%), pruritus 1 (3%), hyperglycaemia 1 (3%), arthritis 1 (3%) and colitis 1 (3%), all reversible. Responses were evaluated based on RECIST 1.1 criteria, and there was 1 CR reported (melanoma, progressed on prior pembrolizumab) at 10 mg/kg (highest dose level). Dose-dependent pharmacodynamic activity consistent with dual PD-1/CTLA-4 blockade was noted, namely a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Table). Conclusions: XmAb20717 is generally safe and has demonstrated PD activity in heavily pretreated patients with selected advanced solid tumors. Dose escalation continues. Clinical trial information: NCT03517488 . [Table: see text]
A novel CSF-1R neutralizing antibody, DCB-AB21, as a potential therapeutics for tumors.
Authors: HO Chen-Hsuan , Liao Chu-Bin , Kai Yu , Yang Tze-Ping , Lai Sze-Liang , Chien Yin-Chieh
Published: May 2020

e15006

Background: Tumor-associated macrophages (TAMs) represent the major cell components of immune infiltrate in solid tumors, and it has been reported that high TAMs density is associated with poor clinical prognosis. Within the tumor microenvironment, TAMs rely on signaling through colony stimulating factor 1 receptor (CSF-1R)/CSF-1 axis for various tumor promoting processes such as tumor growth, drug resistance, angiogenesis, and metastasis. Therefore, decrease of TAMs density in tumors through CSF-1R inhibition is considered an attractive therapeutic target for drug development. Methods: DCB-AB21 was screened from immunized mouse hybridoma clones. ELISA-based and flow cytometry-based affinity screening is performed and then the growth inhibition test by cell-based CSF-1-dependent cell line were further used as antibody screening assay. Results: A novel anti-CSF-1R monoclonal antibody DCB-AB21 which specifically binds to CSF-1R and inhibits CSF-1R downstream signaling. Our results showed DCB-AB21 can block the CSF-1 and IL-34-induced cell proliferation. Potent inhibition of CSF-1R-dependent signaling was observed in the Ba/F3 CSF-1R driven model cells, and in human THP-1 leukemia monocytic cell lines. Humanization engineering further improves this antibody’s affinity and anti-proliferative efficacy. The discovery of novel binding epitope of DCB-AB21 differentiates itself from the current CSF-1R targeting antibodies testing in clinical trials. In vivo efficacy of DCB-AB21 showed AB21 alone has moderate anti-cancer activity and it further potentiate anti-PD-1’s efficacy. Conclusions: These data demonstrate that DCB-AB21 can potently inhibit CSF-1R in cellular contexts and in vivo model, and has the potential to induce a phenotypic effect on macrophages. These data suggest that DCB-AB21 is a promising new agent with possibility to combine with immune checkpoint inhibitors to relief macrophage-dependent immune suppression and would yield clinical benefit.
Profiling antigen specificity concurrently with protein and mRNA quantification using high throughput single-cell multiomics reveal surprising similarities between bystander and tumor specific CD8+ tumor-infiltrating lymphocytes (TILs) in renal cell carcinoma (RCC).
Authors: Tyznik Aaron , Simoni Yannick , Li Shamin , Zhuang Summer , Newell Evan
Published: May 2020

e15014

Background: Recently, using human colorectal and lung cancer, we showed that CD8+ T cells infiltrating tumor tissue (TILs) are not only specific for tumor antigens, but are also composed of CD8+ TILs specific for cancer unrelated epitopes – called bystander – such as HCMV, EBV or flu epitopes. We also showed that the surface marker CD39 can be useful for discriminating bystander (CD39−) from tumor-specific (CD39+) CD8+ TILs (Simoni et al, Nature, 2018). Methods: Here, our aim was to test these findings in human Renal cell Carcinoma (RCC) and to better understand the biology of these bystander CD8+ TILs. Results: Surprisingly, our primary CYTOF analyses showed heterogeneity within bystander CD8 TILs that possess various phenotypes including effector (CD45RO+), memory (CD45RO+ CCR7+), Trm (CD69+ CD103+/–), and senescent (CD57+ KLRG1+) cell features. Using targeted mRNA single-cell sequencing combined with BD AbSeq assay, we analyzed sorted CD8+ TILs from RCC patients and identified bystander CD8+ TILs using oligo-tagged tetramers. Gene signature analysis of these different subsets revealed transcriptomic similarities with the tumor-specific CD8+ TILs. Conclusions: Our data provide a comprehensive perspective of cancer unrelated CD8+ TILs in RCC and suggest functional roles for these cells in tumor immune responses, which could lead to new diagnostic and therapeutic strategies.
Analysis of the efficacy of CIK therapy in adjuvant treatment of colorectal cancer.
Authors: Guo Rui , Piao Haiyan , Shi Gang , Zhang Guirong , Zhang Rui
Published: May 2020

e15022

Background: In the past decade, cell-based immunotherapy has been reported to improve the clinical outcomes by altering tumor immune responses, improving prognosis and overall survival rates in cancer patients.This retrospective study aimed to evaluate the efficacy of cytokine-induced killer (CIK) cell infusion as an adjuvant therapy in patients with colorectal cancer. Methods: A total of 370 patients with colorectal cancer admitted to Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute from March 2013 to April 2015 were retrospectively analyzed.All patients were treated with surgery for primary lesions, and then adjuvant chemotherapy was determined according to the guidelines. Among these patients, 201 patients received CIK therapy (CIK group),while the other 169 patients who had similar demographic and clinical characteristics did not receive a CIK cell infusion therapy (non-CIK group). Then we followed up these patients. Data were analyzed by Kaplan-Meier. Results: Our results showed that the 1,3,5-year overall survival (OS) rate for the CIK group versus the non-CIK group was 98.46 versus 93.61%, 85.4 versus 71.61%, 79.39 versus 67.9%, respectively. The OS was significantly longer in CIK group than in non-CIK group (P = 0.009). Meanwell, the OS of stage II and III colorectal cancer was significant in CIK group than in non-CIK group (P = 0.02 and 0.02). But the OS was not significant in Stage I and IV colorectal cancer (P = 0.347 and 0.285). We analyzed the patients between chemotherapy plus CIK therapy group and chemotherapy only group. We find that the OS has significant difference in two groups (P < 0.001). Conclusions: CIK therapy can improve the efficacy of adjuvant therapy in patients with colorectal cancer. But multicenter, large-sample randomized controlled trials are still needed to confirm it.
CoupledCAR technology for treating thyroid cancer.
Authors: Xiao Lei , Liu Xingchen , Zhou Keshu , Liu Yu , Huang Yong , Pu Chengfei , Cao Zhiyuan , Lu Cheng , Hang Yang , Huang Xi , Shen Xiaogang , Song Yongping , Liu Renbin , Wu Zhao
Published: May 2020

e15027

Background: Significant challenges restrict CAR-T cell therapy to treat solid tumors. Methods: Here, we generated CAR-T cells using a novel CoupledCAR technology. Specifically, we engineered CoupledCAR T cells with lentiviral vectors encoding an anti-thyroid stimulating hormone receptor (TSHR) CAR molecule, and anti-TSHR CAR-T cells showed anti-tumor activities in vitro and in vivo experiments. Further, we treated refractory/relapsed post-thyroidectomy thyroid cancer patients using anti-TSHR CoupledCAR T cells, and observed the rapid expansion of CAR-T cells and the enhanced killing of tumor cells. Results: Both patients achieved PR (Partial Response). Patient Profile: Patient 1 Male, 64Y, Papillary Thyroid Carcinoma. In May 2017, thyroid cancer was diagnosed, bilateral total thyroidectomy, and right cervical lymph node functional dissection were performed in June, followed by iodine 131 isotope therapy. In December 2018, bilateral multiple cervical lymph nodes were enlarged. In February 2019, right neck lymphadenectomy was performed. Patient 2 Female, 60Y, Thyroid Carcinoma. In Aug 2013, a "double lobectomy of the thyroid gland” was performed. From Oct 2013 to Jan 2014, she received iodine 131 isotope therapy. In Sep 2014, she was diagnosed with iodine-resistant thyroid cancer. In 2016, 5 cycles of chemotherapy were performed. In Mar 2019, multiple metastases in both lungs and multiple enlarged lymph nodes were observed. Observations and Results: Patient 1: One month after infusion (M1), the patient was evaluated as PR: lymph node metastasis became undetectable and the size of the thoracic paratracheal tumor nodules decreased significantly. Three months after infusion (M3), the patient was evaluated as having a durable response, and the tumor tissue was substantially smaller than M1. Patient 2: M1, the patient was evaluated as PR (Partial Response): the tumor volume in the right lower lobe of the lung was reduced by approximately 67.51% (decreased from 65*55mm to 42*39mm). Three months after infusion (M3), compared with that before, the tumor volume was reduced by approximately 73.54% and SUV max value decreased from 14.9 to 2.8, therefore, the patient was evaluated as nCR (near complete remission). Conclusions: We show that TSHR is a good target for treating thyroid cancer, and our anti-TSHR CoupledCAR T cells are safe and effective for treating thyroid cancer. Recruitment is ongoing to evaluate the safety and efficacy of our 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.
Predictive value of circulating B cells and T cell subsets in melanoma patients treated with neoadjuvant ipilimumab and interferon.
Authors: Khunger Arjun , Sarikonda Ghanashyam , Tsau Jenn , Alfonso Zeni , Gao Jane , Pahuja Anil , Laing Christian , Kim Ju Young , Bordeaux Jennifer , Vaupel Christine , Dakappagari Naveen , Tangri Shabnam , Tarhini Ahmad A.
Published: May 2020

e15036

Background: Patients with locally/regionally advanced melanoma were treated on a clinical trial with a neoadjuvant combination of ipilimumab (ipi) and high dose IFNα2b (HDI) (Tarhini et al, JITC 2018). In this study, immune cell composition in peripheral blood samples collected at various time points was measured to determine any correlation with clinical outcomes and investigate the immune modulating effect of the combination therapy. Methods: Patients were randomized to neoadjuvant ipi at 3 mg/kg or 10 mg/kg, both given in combination with HDI. Tumor radiologic responses were designated as complete (CR), partial (PR), stable disease (SD) or disease progression (PD). Pathologic complete response (pCR) was defined as absence of viable tumor on histologic assessment. Peripheral blood mononuclear cells (PBMC) from treated patients (N = 28) were tested at baseline (before initiating ipi-HDI), then at 6-weeks, 3-months and 12-months (following neoadjuvant ipi-HDI). High complexity (14-color) flow cytometry analysis was performed to detect key immunological biomarkers including myeloid derived suppressor cells (MDSCs), B cells, regulatory T cells (Tregs), PD-1 and TIM3 expression on T-cells, and differentiation of T-cells into Th1, Th2 or Th17 phenotype at different time points during systemic immunotherapy. Statistical significance was determined using R-package employing Kruskal’s test. Results: Lower levels of peripheral Tregs (p = 0.02), MDSCs (p = 0.05), and CD4 effector memory cells (p = 0.04) at 3-months post treatment correlated with radiologic response. In addition, lower change from baseline at 3 months in CD4/CD8 ratio (p = 0.04), levels of Tregs (p = 0.01) and CD4 effector memory cells (p = 0.02) was associated with radiologic response. Patients exhibiting pCR had significantly lower Tregs (p = 0.04) at 6-months post treatment and significantly higher CD8 central memory cells at both 3 months (p = 0.04) and 12 month time-points (p = 0.01) as compared to patients without pCR. Finally, patients without pCR had significantly lower change from baseline in CD19 B cells at 6 months (p = 0.01) and 12 months (p = 0.04) as compared to patients with pCR. Conclusions: Our data demonstrates that the levels of immunosuppressive cells including Tregs and MDSCs in periphery are negatively associated with response. Higher levels of CD8 memory cells and B cells on-treatment are associated with clinical benefit.
The validity and predictive value of blood-based biomarkers in prediction of response in the treatment of non-small cell lung cancer: A systematic review.
Authors: IJzerman Maarten J. , van Delft Freek Anne , Koffijberg Hendrik , Retel Valesca P. , van den Heuvel Michel
Published: May 2020

e15053

Background: With the introduction of targeted therapies and immunotherapy, molecular diagnostics gained a more profound role in the management of non-small cell lung cancer (NSCLC). Currently, tissue biopsies (TB) are used as primary source for molecular testing and generally require an invasive procedure. The introduction of liquid biopsies (LB) not only decreases patient burden, but it also allows for more frequent testing. Which might be of value in the monitoring of treatment response. This study aimed to systematically search for studies reporting on the use of LB, the correlation between LB and TB, and finally the predictive value in the management of NSCLC. Methods: A systematic literature search was performed using Scopus and PubMed, including results published in English after 01-01-2014. Articles were included when 1) describing the predictive value of a LB with regard to overall and/or progression-free survival, or 2) describing the validity of a marker by comparing LBs to TBs regarding sensitivity, specificity, or concordance. Results: 1705 articles were identified in the search, 1323 articles were excluded after title and abstract screening, leaving 382 articles for full-text evaluation. Of the 137 articles included after full-text evaluation, 78 articles described the validity, and 65 articles described the predictive value of LBs. In studies describing the predictive value of LBs, the majority of articles reported on the predictive value of biomarkers in relation to targeted therapies (n = 31). In studies describing the validity of LBs, the majority of studies report on EGFR mutations including, exon 19 deletion (n = 23) and L858R (n = 26). Looking at the validity of LBs, we saw a large variation in reported sensitivity (range 20-100%), specificity (range 30-100%), and concordance (range 40-99%). Conclusions: Although a variety of blood-based biomarkers has been investigated, most studies have limited their evaluation to sensitivity and specificity of liquid biopsies to determine EGFR mutation status compared to tissue and the subsequent targeting of EGFR tyrosine kinase inhibitors based on the mutation status found in LBs of NSCLC patients. The first adoption of LBs in practice is expected to involve the detection of EGFR mutations by LB analysis in addition to TBs.
Application of PD-1/PD-L1 immune checkpoint inhibitors treating lung cancer in Yerevan Armenia: Two-center experience.
Authors: Karapetyan Nune , Zohrabyan Davit , Arakelyan Jemma , Harutyunyan Lilit , Bardakhchyan Samvel , Avagyan Armen , Safaryan Satenik , Harutyunyan Martin , Safaryan Liana
Published: May 2020

e15058

Background: Over the past few years PD-1/PD-L1 pathway blockade through immune checkpoint inhibitors appeared to be an effective treatment approach in advanced lung cancer. The current study aims to investigate the utilization of immunotherapy for lung cancer management purposes in Armenia. Methods: For this retrospective, hospital-based cohort study census sampling method was approached. Data was collected on all the patients who were diagnosed with stage III and IV lung cancer and passed treatment in the departments of Adult Solid Tumors in Hematology Center after prof. Yeolyan and Institute of Surgery after Mikaelyan from 01.05.2019 till 12.01.2020. The time period was selected based on the initiation of PD-L1 testing in Armenia. The prevalence of non-small cell (NSCLC) and small cell (SCLC) lung cancer was calculated. The patients’ PD-L1 testing performance, subsequent immunotherapy utilization, and developed adverse effects were evaluated. Results: According to the hospital-based data, during the mentioned time period 60 patients diagnosed with stage III and IV lung cancer received treatment in the two units. In the cohort, the patients’ median age was 65,5 years (range 46 – 88). The male-to-female ratio was 5.6. The prevalence of NSCLC and SCLC was 61.7% and 28.3% respectively. At the time of follow-up on 10.02.2020, 74.4% of NSCLC patients and 64.7% of SCLC patients were alive. Of the 43 NSCLC subjects, only 11 were checked for the PD-L1 status. Among them, 7 were determined to be PD-L1 positive and 5 of them received immunotherapy. For SCLC patients PD-L1 status wasn’t checked. Of 17 SCLC patients, only one has received immunotherapy. Overall only one case of immunotherapy related adverse effect was observed (severe rash and pruritus). At the time of follow-up, one of the six patients who underwent immunotherapy was dead. Conclusions: The presented data demonstrate a lack of PD-L1 test performance and underutilization of immunotherapy treatment. In the future, it is recommended to perform a nationwide study on the current topic to assess the immune checkpoint inhibitors impact on the survival rates of advanced lung cancer patients.
Real-world usage and outcomes for patients treated with immune checkpoint inhibitors across multiple treatment indications in the Veterans Affairs system.
Authors: La Jennifer , Cheng David , Do Nhan , Brophy Mary T. , Fillmore Nathanael , Tuck David P.
Published: May 2020

e15063

Background: Increasingly broad patient groups are being treated with immune checkpoint inhibitors (ICIs) in clinical practice, but few studies have assessed their usage and outcomes in large, comprehensive real-world cohorts. In this study, we identified patients who received ICI therapy through April 2019 in the Veterans Affairs (VA) system. We described patient characteristics and assessed survival outcomes for patients across multiple treatment indications based on the cancer type and line of therapy. Methods: We conducted a retrospective analysis using electronic health record data captured from VA facilities nationwide. Patients treated with ICI were identified based on pharmacy and orders records. The associated cancer type and line of therapy (first line 1L or later line 2L+) was ascertained based on data on patients’ treatment history, administrative codes, and VA cancer registry records. The distribution of time from ICI treatment initiation to death was separately assessed by treatment indication using Kaplan-Meier estimates. Results: We identified 13,276 patients treated with ICI. The mean age was 69 years old. A majority of patients were male (97.2%) and white (76.9%), and a substantial minority were African-American (16.9%). Among patients treated with ICI for an identifiable cancer type, the most common cancer types included non-small lung cancer (NSCLC; 47.2%), melanoma (22.2%), renal cell carcinoma (RCC; 6.7%), squamous cell carcinoma of the head and neck (SCCHN; 10.4%), and urothelial cancer (6.4%). For major treatment indications, VA patients generally exhibited lower rates of survival than those reported in many ICI clinical trials, but the results are more comparable to those in trials among a subgroup of non-frail patients. Conclusions: This study describes ICI utilization and outcomes across multiple tumor types in a real-world population at the VA. The results offer evidence on the utilization and performance of ICIs in a real-world population. In addition, this work establishes a platform for further analyses of ICI outcomes in real-world practice at the VA. [Table: see text]
Changing paradigm in oncology clinical trials: Cox-TEL—Adjustment made ready for early crossover and tail tale.
Authors: Lin Emily Pei-Ying , Hsu Chih-Yuan , Yang Pan-Chyr , Shyr Yu
Published: May 2020

e15067

Background: Approvals of immune checkpoint inhibitors (ICI) were made based on positive clinical trial results analyzed by the Cox proportional hazards (PH) model. With ICI data, however, long tails and early crossover in survival curves, which violate the Cox PH assumption, can lead to misinterpretation of clinical significance of findings. Here we introduce the Cox-TEL and show the differences of study results before and after Cox-TEL adjustment using KEYNOTE 042 and 045 as examples. Methods: Cox-TEL is built on the mathematical foundation of Taylor expansion. As an easily implemented alternative of PH cure model, it not only infers associations between survival probabilities of the two study arms among patients without long-term survival (poor-responders), but also estimates differences in proportion (DP) between arms among patients in the long-tail segment of the survival curve (true-responders). Results: In KEYNOTE 042, the Cox-TEL HRs for death were statistically insignificant across all subgroups. The trend of DP, on the other hand, is positively related to that of PD-L1 TPS and inverted related to that of Cox HR when the PD-L1 ≥50% cohort is covered. In KEYNOTE 045, the Cox-TEL HRs suggested that for the poor-responders, pembrolizumab did not do better than chemotherapy in terms of overall survival (OS) and might do harm to the patients in terms of progression-free survival (PFS). For the true-responders, DPs of OS and PFS were both statistically significant (Table). Conclusions: Our data demonstrated the biases derived from insufficient data analyses and strengthened the necessity of analytic model revisits in the new oncology era of which cure for advanced cancers is no longer impossible. [Table: see text]
Macrophage determines immnophenotype and predicts anti-PD-L1 response of urothelial cancer: Results from phase II clinical trial.
Authors: Zeng Dongqiang , Ye Zilan , Wang Gaofeng , Fan Xinxiang , Wu Jiani , Huang Yiqiang , Li Nailin , Shi Min , Liao Wangjun
Published: May 2020

e15093

Background: Immune-checkpoint blockades (ICBs) are revolutionizing treatment of advanced or metastatic urothelial cancer (mUC) whereas the promising response merely occurred in a subset of patients. To dig into underlying determinants, we investigated the comprehensive tumor microenvironment (TME) of 348 tumor samples derived from a large phase II trial (IMvigor210: NCT#02108652). Methods: Based on the 348 pre-treatment samples, the LASSO-Bootstraping algorithm were applied to figure out the optimal predictive biomarker. Assessment of immune-cell proportions, pathway activity, and tumor purity used CIBERSORT algorithm, ssGSEA methodology, and ESTIMATE algorithm, respectively. Unsupervised clustering methods were applied to identify TME infiltrating patterns. Moreover, the predictive value of M1 infiltration in mUC were systematically explored, as well as its correlation to integrative molecular subtypes, tumor intrinsic mutation and metabolic pathways. An additional TCGA dataset was applied to validate the results. Results: Bootstrapping and ROC curve analysis indicated that M1 was non-inferior to TMB in predicting ICBs response (M1: AUC = 0.706; TMB: AUC = 0.728; Delong test: P = 0.333), but surpassed more-than-10,000 counterparts covering TME-infiltrating cells, metabolic pathways, tumor intrinsic pathways and hallmarks of cancer. Kaplan-Meier survival analysis (M1: P < 0.0001, Hazard Ratio = 0.25, 95% CI: 0.14 − 0.44) supported its promising prognostic value. Moreover, study into TME patterns demonstrated its role in determining immunophenotypes (AUC = 0.785). M1 frequency is positively correlated with CD8+ T cells fraction (P = 7e-04), whereas the Treg cell, neutrophil and monocyte infiltration which refer to suppressive immune microenvironment were negatively correlated (P = 0.0066, P = 7e-04, P = 2e-04, respectively). Furthermore, significant correlation was observed between M1 and tumor intrinsic characteristics, including TMB, neoantigen and PD-L1 level of tumor (P = 3.83e-5, P = 1.69e-7, and P = 0.0018, respectively). The TCGA data reproductively supported the majority of aforementioned results. Conclusions: Our study lend statistical power to the notion that Macrophage independently contribute to anti-tumor immune function in the context of ICB therapy. Nonetheless, these findings provide important insight into the role of M1-Macrophage, macrophage polarization and innate immune machinery in therapeutic responses to ICB. Clinical trial information: NCT02951767 .
Neurotoxicity associated with immune checkpoint inhibitors: Systematic review and meta-analysis.
Authors: Farooq Muhammad Zain , Ba Aqeel Sheeba Habeeb , Lingamaneni Prasanth , Banskota Shristi Upadhyay , Pichardo Rayli , Siddiqui Mahrukh , Shrivastava Trilok , Mangla Ankit
Published: May 2020

e15096

Background: Immune checkpoint inhibitors (ICI) are associated with multiple immune related adverse events (irAE). Moderate to severe neurotoxicity is reported in less than 1% of all patients treated with ICI. We performed a systematic review and meta-analysis to assess neurotoxicity associated with anti-PD-1/PD-L1 and anti-CTLA4 therapy. Methods: The Embase, Ovid, Pubmed and Scopus database were comprehensively searched by two independent reviewers, from inception to 2019, to include Phase II and III clinical trials reporting neurotoxicity with the combination of, or monotherapy with anti-PD-1/PD-L1 and/or anti-CTLA4 therapies. Our primary outcome was assessment of neurologic irAE of all grades. We divided neurotoxicity into two groups: peripheral nervous system (PNS) including peripheral neuropathy (PeN), fatigue, Guillain-Barre syndrome (GBS), myelitis; and central nervous system (CNS) including stroke, myasthenia gravis (MG), encephalopathy/encephalitis, altered mental status (AMS), decreased appetite and headache. Statistical heterogeneity was quantified using I2 statistics and publication bias was assessed with Eggers regression test. The estimates were reported as odds Ratio (OR) with 95% confidence intervals (CI) using random effect model. Results: A total of 2,876 full text articles retrieved in the initial database search were analyzed according to PRISMA guidelines. The final analysis included 39 trials, evaluating 10,595 patients in the control arm and 13,110 patients in the immunotherapy arm. All-grade neurotoxicity events with ICI were significantly lower compared to placebo or standard of care (OR 0.55, 95% CI 0.38-0.81, I2 96.82%, P < 0.001). Only significant CNS irAE observed was fatigue (OR 0.82, CI 0.71-0.96, I2 81.75%, P < 0.001). Other CNS irAE including AMS (OR 1.318, 95% CI 0.86-2.0, I2 0%, P = 0.442), encephalopathy/encephalitis (OR 1.36, 95% CI 0.38-4.96, I2 0%, P = 0.82) and seizures (OR 1.96, 95% CI 0.64-6.02, I2 0%, P = 0.56) had statistically non-significant increased risk in ICI group. Only one case of myelitis was reported in placebo group. The ICI arm had statistically significant lower rates of PeN (OR 0.28, CI 0.16-0.49, I2 87.31, P < 0.001). One trial reported 1 patient with MG and 5 trials reported 1 patient each of GBS in the ICI arm. Conclusions: Our meta-analysis concludes that use of ICI is associated with lower rate of neurotoxicity overall. Fatigue and PeN are lower with ICI compared to standard of care or placebo. Although, CNS irAE are increased with ICI, they do not reach statistical significance.
Clinical efficacy of immunotherapy for the treatment of solid tumors in patients with chronic kidney disease.
Authors: Ganta Teja , Jun Tomi , 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

e15109

Background: Regulatory T cells play a key role in protecting kidney cells from ischemic injury. Immune checkpoint inhibitors (ICIs) may increase the risk of acute kidney injury via inhibition of regulatory T cells [1, 2]. Prospective clinical trials have largely excluded patients with chronic kidney disease (CKD); thus, we have limited knowledge of the safety and efficacy of ICI in these patients. Herein, we hypothesize that patients with CKD receiving ICIs have worse clinical outcomes. Methods: This single-institution retrospective cohort study included adult patients with solid tumors who were treated with ICIs at The Mount Sinai Hospital between 2011 and 2017. Clinical endpoints [response to treatment, progression of disease (POD) on treatment, mortality] were compared between patients with and without CKD using multivariate logistic regression. Odds ratios were controlled for demographics, primary tumor type, presence of cardiovascular comorbidities, smoking status, incidence of renal adverse events, and a composite of stage of illness with indication for treatment [localized—neoadjuvant, localized—adjuvant, regionally advanced, metastatic disease]. Data were analyzed using R version 3.5.1 with the following packages: readr, dplyr, broom, lubridate, tableone. Results: 420 patients met inclusion criteria: 399 patients without CKD and 21 patients with CKD. Cohorts are well matched for demographics, smoking status, stage/indication for treatment. The CKD cohort has a higher proportion of patients with urothelial cancer compared to patients without CKD (33% vs 11%) as well as a higher proportion of patients with HTN (81% vs 53%), HF (14% vs 3%), and DM (48% vs 21%). There was no statistical difference in odds of response to treatment [OR 0.76, 95% CI 0.26-2.23], POD [OR 0.42, 95% CI 0.15-1.17], or mortality [OR 2.05, 95% CI 0.71-5.96] between the CKD and non-CKD cohort. Conclusions: The data suggest the presence of CKD is not associated with worse clinical outcomes in cancer patients treated with ICIs. As a small retrospective study, the conclusions are hypothesis-generating but support continued use of immunotherapy in CKD in clinical practice and the inclusion of patients with CKD in immunotherapy clinical trials to further clarify safety and efficacy. [Table: see text]
The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: A pooled analysis of 23 clinical trials and 8,436 patients.
Authors: Tang Si-Qi , Xu Cheng , Tang Ling-Long , Mao Yan-Ping , Li Wen-Fei , Chen Lei , Zhang Yuan , Guo Ying , Liu Qing , Sun Ying , Ma Jun
Published: May 2020

e15110

Background: Immune checkpoint inhibitors (ICIs) yield remarkable clinical efficacy in the treatment of cancer. With the increasing use of ICI therapies, the dissemination of immune-related adverse events (irAEs) data is essential. This study aimed to investigate the pattern of onset and resolution of ICI-induced irAEs in cancer. Methods: Phase II–III clinical trials with single or multiple arms studying ICI-based treatments in cancer published between January 2007 and December 2019 were included. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were analyzed based on irAE categories and severity grades using the metamedian package of the R software. Subgroup analyses were performed based on different ICI drugs, ICI doses, and cancer types. Results: Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. On average, irAEs occurred at 6.1 weeks (95% confidence interval [95% CI], 5.7–7.4) after the initial ICI-based treatment. The first four irAEs with the shortest PMT-O were hypersensitivity/infusion reaction (3.1 weeks), neurological (4.0 weeks), skin (4.1 weeks), and gastrointestinal (6.1 weeks) events. IrAEs were resolved within 4.5 weeks (95% CI, 4.0–6.1), with the shortest and longest PMT-R for hypersensitivity/infusion reaction (0.1 weeks) and endocrine events (28.7 weeks), respectively. The application of immune-modulation drugs prolonged the general resolution time to 5.9 weeks, with the shortest and longest PMT-IMR for hypersensitivity/infusion reaction (0.2 weeks) and endocrine events (56.6 weeks), respectively. Grade ≥ 3 irAEs showed a significantly longer PMT-O (7.9 vs. 6.1 weeks; P < 0.01) compared with all grade irAEs. Nivolumab + ipilimumab had a significantly shorter PMT-O than nivolumab alone (6.0 vs. 8.2 weeks; P < 0.01). A significantly shorter PMT-O was observed for lung cancer compared with that for melanoma (4.7 vs. 6.1 weeks; P = 0.02). Conclusions: This study revealed the pattern and kinetics of the time to onset and resolution of irAEs in pan-cancers, which will promote the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.
Effect of STK11 mutations on efficacy of PD-1 inhibition in non-small cell lung cancer (NSCLC) and dependence on KRAS mutation status.
Authors: Ricciuti Biagio , Arbour Kathryn Cecilia , Lin Jessica Jiyeong , Vokes Natalie , Vajdi Hoojghan Amir , Li Yvonne Y. , Cherniack Andrew D. , Recondo Gonzalo , Lamberti Giuseppe , Venkatraman Deepti , Rizvi Hira , Egger Jacklynn V. , Plodkowski Andrew J. , Khosrowjerdi Sara , Digumarthy Subba R , Nishino Mizuki , Sholl Lynette M. , Gainor Justin F. , Hellmann Matthew David , Awad Mark M.
Published: May 2020

e15113

Background: STK11 mutations ( STK11m) have been associated with resistance to ICI in KRAS-mutant ( KRASm) NSCLC. Whether STK11m status also impacts clinical outcomes to ICI in KRAS wild-type (wt) NSCLC is unknown. Methods: We analyzed clinical outcomes of patients (pts) with NSCLC treated with ICI according to KRAS and STK11 mutation status in independent discovery (DFCI+MGH) and validation (MSKCC) cohorts. TCGA and xCell data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/ STK11 co-mutation status. Results: Of 1195 pts with advanced nonsquamous NSCLC treated with ICI, 447 (37.4%) had a KRASm, 252 (21.1%) had pathogenic STK11 mutations, and 128 (10.7%) had concurrent KRASm and STK11m. ICI outcomes for the discovery and validation cohorts in KRASm and KRASwt cases by STK11 mutation status are shown in Table. In the combined cohort (discovery+validation), STK11m was associated with significantly worse outcomes to ICI among KRASm cases: ORR 10.2% vs 30.7%, P < 0.001; median progression-free survival (mPFS): 2.0 vs 4.8 months (mo), HR:0.49 [95%CI:0.39-0.61], P < 0.0001; median overall survival (mOS): 6.1 vs 16.9 mo, HR:0.50 [95%CI:0.39-0.63], P < 0.0001. In multivariable analysis, STK11m was associated with significantly shorter PFS (HR:0.56, P = 0.002) and OS (HR:0.57, P = 0.006). By contrast, STK11m had no impact on ICI outcomes among KRASwt cases: ORR 24.2% vs 19.2%, P = 0.21; mPFS: 2.5 vs 2.8 mo, HR:0.98 [95%CI:0.79-1.21], P = 0.89; mOS: 12.0 vs 11.5 mo, HR:1.06 [95%CI:0.85-1.33], P = 0.57. Among KRASwt cases, STK11m had no impact on ICI outcomes among both smokers and never smokers, when analyzed separately. Gene ontology analysis from TCGA revealed that among KRASm but not KRASwt NSCLC, STK11m was associated with the downregulation of MHC class II-related genes (P = 0.02). Cell subset transcriptome analysis showed significantly lower proportions of M1 macrophages among KRASm/ STK11m but not among KRASwt/ STK11m NSCLCs (P < 0.01). Conclusions: STK11m are associated with resistance to ICI in KRASm but not KRASwt NSCLC. STK11m/ KRASm vs STK11m/ KRASwt NSCLC have distinct immunophenotypes. [Table: see text]
Ophthalmic immune-related adverse events following anti-CTLA-4 or PD-1 therapy recorded in the American Academy of Ophthalmology IRIS Registry.
Authors: Sun Michel M. , Kelly Scott P. , Mylavarapu Apoorva Lakshmi , Coleman Anne L. , Holland Gary N. , Yu Fei , Singh Sukhminder , Hsu Stephen , Lum Flora , Gordon Lynn K.
Published: May 2020

e15124

Background: The detailed study of ophthalmic immune-related adverse events (OirAEs) is of integral importance in the evolving field of cancer immunotherapy to inform management and treatment guidelines. This study seeks to quantify the differences in incidence and recurrence rates of OirAEs by immune checkpoint inhibitor (ICI) status in a longitudinal big-data registry in patients who are seen in ophthalmic clinics. Methods: This retrospective registry study examined patients newly diagnosed with OirAEs between January 1, 2013 and December 31, 2017 in the American Academy of Ophthalmology’s IRIS Registry. The primary exposure of interest was prior initiation of ICIs. Incidence of OirAEs within 1 year following initiation of ICIs, including anti–PD-1 or anti-CTLA-4 therapy was determined. Incidence rate ratios (IRR) were derived by comparing incidence of OirAEs after ICIs versus rates of non-drug related ocular complications in the entire registry population. Rates of OirAEs in patients with a past history of ocular inflammation or other specific ophthalmic condition prior to initiation of ICIs were further examined. Results: A total of 3,123 patients were identified to have received anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapy, 111 of whom developed an OirAE (3.6%). All OirAE patients had a documented initial pre-drug cancer ICD code, when available, of malignant metastatic melanoma or choroidal melanoma, with the exception of one patient. Incidence rates for anterior uveitis, the most common OirAE, were found to be 3,736 per 100,000 among all ICIs. Rates of all analyzed OirAEs among patients on ICI therapy were elevated compared to baseline ocular complication rates (IRR = 3.5 - 43.0). Time to development of OirAE was drug dependent, with anti-CTLA-4 monotherapy demonstrating rapid onset of OirAE, with most cases within 20 days of starting drug administration. Patients with a prior history of uveitis or other ocular inflammation demonstrated extremely high recurrence rates of OirAEs after initiating ICIs (51.1% for intermediate/posterior/panuveitis, 38.9% for anterior uveitis). Conclusions: Patients initiating ICI therapy are at risk of a number of ocular complications. Rates of OirAEs following ICI therapy are as high as 50% in specific patient populations, including those with a previous history of any uveitis or autoimmune ocular disease. Early coordination with ophthalmic subspecialist care, possibly before ICI is initiated, is critical for optimal care of these high risk populations.
Immune toxicity and flow cytometry of circulating blood cells in cancer patients receiving immune therapy.
Authors: Khan Saad A. , Sorrelle Noah , Brekken Rolf A. , Lu Rong , von Itzstein Mitchell S. , Xie Donglu , Hsieh David , Gloria-McCutchen Yvonne , Saltarski Jessica , Watters Mary , Bleiberg Benjamin Aaron , Popat Vinita , Ahmed Murtaza , Zhang Yuqing , Fattah Farjana , Khan Shaheen , Park Jason , Gerber David E.
Published: May 2020

e15126

Background: The mechanisms by which immune checkpoint inhibitors (ICI) cause immune related adverse events (irAE) are not clear. No current blood tests predict which patients will suffer irAEs. Methods: 70 cancer patients had blood drawn prior to ICI and then 4-6 weeks later. 63 had lung cancer; median age was 69 yrs; 21 were female and median ICI treatment duration was 142 days. Patient blood samples were analyzed using flow cytometry for over 50 lymphoid and myeloid markers to determine levels of circulating white blood cells, as well as their changes over time. Medical records were reviewed for irAE’s grades in 8 groups: rash, colitis, hypothyroidism, hyperthyroidism, hypophysitis, hepatitis, adrenal insufficiency, and pneumonitis. To determine association between toxicity and cell counts we used logistic regression and random forest for the univariate and multivariate analysis. We included a random permutation of the baseline age (which is associated with higher toxicity rates) as the analytical control in the random forest model to help identify the threshold of association strength of a random noise and to identify only those cell subsets that were statistically significant (reported below). Results: Patients with elevated baseline levels of specific subsets of T-cells were more likely to develop irAE’s, and elderly patients were more likely to develop Grade 2 irAE’s. T-cell populations associated with any toxicity included CD3+CD8+PD1+; CD3+CD8+; CD25+CD127lowFoxP3+ and CD3+CD8+Ki-67+. Also, patients who developed any irAE’s demonstrated changes in the following cell types after 2 doses of immune therapy compared to their baseline readings. These included changes in the percentage of circulating cells that were CD3+CD8+PD1+; CD3+CD8+HLA-DR+; CD3+CD4+HLA-DR+; CD3+CD8+CCR7-; CD56+; CD3-CD19-; CD3+CD8+; CD16+CD56dim. Patients with grade ≥2 toxicities, or organ specific toxicities demonstrated statistically significant differing levels of T-cells subsets, though the number of patients in each group was limited. Patients with > median baseline expression of CD3+ CD8+ PD1+ cells had greater survival compared with those that had < median levels. Conclusions: Flow cytometry analysis of patients receiving immune therapy at baseline and 6 weeks after initiating therapy may predict which patients are at greater likelihood of any/organ specific irAEs, potentially leading to an improved understanding their mechanisms. Responding to leukocyte changes by substitution of drugs or shortening of treatment duration may reduce irAEs.
Pre-treatment predictors of immune-mediated hepatitis in non-small cell lung cancer patients treated with immune-checkpoint inhibitors: A retrospective study.
Authors: Shek Dmitrii , Read Scott A. , Carlino Matteo S. , Nagrial Adnan , Gao Bo , Ahlenstiel Golo
Published: May 2020

e15136

Background: Immune-checkpoint inhibitors (ICIs) have become standard of care for patients with non-oncogenic driven metastatic non-small cell lung cancer (NSCLC); a feat that has dramatically changed prognosis for these patients. Nevertheless, ICIs can cause immune-related adverse events (irAEs) requiring steroid administration or treatment cessation. This cohort study aimed to examine the incidence of ICI related hepatitis and determine potential predictors of immune-mediated hepatitis. Methods: We retrospectively collected clinicopathological data from 139 patients with metastatic NSCLC treated at Westmead and Blacktown Public Hospitals between 2017 and 2019. Blood tests results were collected longitudinally with a particular focus on liver function tests (LFTs). Further, parameters associated with acute or chronic liver hepatitis were statistically analyzed regarding their association with toxic elevation of LFTs. In particular we were interested in body weight, liver fibrosis (measured by AST to Platelet Ratio Index [APRI] and Fib-4 score), AST/ALT ratio, albumin, globulin, direct/indirect bilirubin, gamma-glutamyl transferase, ratio of serum protein (SP) to total bilirubin (TB) and C-reactive protein. Results: ICIs were more effective in terms of overall (p = 0.0001) and progression-free (p = 0.007) survivals compared to chemotherapy. Pre-treatment blood tests revealed no abnormalities in LFTs, however, at week 9 we first detected elevated LFTs in 29% (n = 18) and 6.5% (n = 5) of ICI and chemotherapy groups, respectively (p = 0.0003). Multivariate regression found that abnormal transaminases at week 9 significantly correlated with high pre-treatment ratio of SP/TB (p = 0.001) in the ICI group only. Specifically, a pre-treatment SP/TB ratio of was > 5 associated with increased ALT at week 9 (odds ratio 92%; positive and negative predictive values: 74% and 97% respectively; sensitivity 94%; specificity 86%). Interestingly, no other significant correlations with elevated transaminases at week 9 were established. Conclusions: In this real-world cohort, we confirmed that ICI therapy results in improved PFS and OS comparing to chemotherapy alone. Moreover, a pre-treatment ratio of SP/TB > 5 was significantly associated with elevated LFTs at week 9 suggesting that it may have a predictive role.
Risk factors for emergency room and hospital care for patients with advanced solid tumors on immune checkpoint inhibitor therapy.
Authors: Parikh Anish B , Mellgard George , Qin Qian , Patel Vaibhav G. , Wang Bo , Zhong Xiaobo , Leiter Amanda , Gallagher Emily J. , Galsky Matt D. , Oh William K. , Clinton Steven K. , Mortazavi Amir , Monk Paul , Folefac Edmund , Yin Ming , Yang Yuanquan , Tsao Che-Kai
Published: May 2020

e15142

Background: Immune checkpoint inhibitors (ICIs) are increasingly utilized across cancer types. Risk factors for emergency room (ER) and inpatient (IP) care in this patient (pt) population remain poorly defined. Methods: We retrospectively reviewed charts for pts with (w/) advanced solid tumors who received more than 1 ICI dose at Mount Sinai from 1/1/11 – 4/28/17. Demographics, medical history, cancer diagnosis and therapy (tx) details, and outcomes were recorded. Descriptive data detailing ER/IP care during ICI tx (from first dose to 3 months after last dose) were collected. Fisher’s exact test and multivariable regression analyses were used to study differences between pts w/ versus w/out ER/IP care during ICI tx. Significance level was set at 0.05 for all tests. Results: 345 patients met the inclusion criteria for this study. Mean age was 64 years. Common tumor types were non-small cell lung cancer (n = 87), melanoma (n = 78), hepatocellular carcinoma (n = 53), and urothelial carcinoma (n = 38). 83% of patients had metastatic disease. Median duration of ICI tx was 2 months. During ICI tx, 50% received ER care and 43% received IP care, resulting in 369 total episodes of ER and/or IP care. 12% of episodes were attributed to ICI toxicity; 6% required intensive care. Median time to ER/IP care was 111 days. Median IP length of stay was 2 days. Several factors were found to be significant predictors of risk for ER or IP care on multivariable analysis (Table). African-American race and Hispanic ethnicity were each predictive of increased risk for both ER and IP care. Conclusions: ER/IP care is common among pts w/ advanced solid tumors on ICI tx. Understanding demographic and clinical risk factors can help prospectively identify higher-risk pts to inform preventive programs aimed at reducing such care. [Table: see text]