bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vivo-like model of glial tumors: Creation of primary cell lines.
Authors: Timofeeva Sofia V. , Kit Oleg I. , Sitkovskaya Anastasia O. , Mezhevova Irina V. , Filippova Svetlana Yu. , Shamova Tatiana V. , Rostorguev Eduard E. , Ignatov Sergey N. , Kuznetsova Natalya S. , Atmachidi Dmitriy P. , Kavitskiy Sergey E. , Novikova Inna A.
Published: May 2020

e14515

Background: The choice of cell source for 3D bioprinting of in vivo-like models of glial tumors is crucial and must take into account the ability to proliferation and stable metabolism. Oral administration of 5-aminolevulinic acid (5-ALA) in patients prior to surgery increases the fluorescent contrast between tumor and surrounding tissue, but the effect of contrast agents on cells in vitro is unknown. The aim of the study was obtaining viable glial tumor tissues using 5-ALA, as well as the development of a stable primary cell culture for 3D bioprinting. Methods: Tumor tissue was obtained from patients with glioblastoma during surgery under visual control using the Opmi Pentero Blue E400 microscope and 5-ALA. Material was disaggregated on a BD Machine using Medicons 50 μm (BD). Glioblastoma cells were cultured in DMEM/F12 medium with L-glutamine (Gibco) containing 10% fetal bovine serum (Biolot, Russia), 1% non-essential amino acids (NEAA, Sigma-Aldrich) and 0.5% penicillin-streptomycin (Biolot) at 37C. Glial cell lines were characterized immunohistochemically using antibodies to the glial fibrillary acidic protein (GFAP) and proliferation index (Ki-67). Microsatellite analysis was performed using three dinucleotide repeat markers D2S123, D17S250, D5S346 and five mononucleotide loci BAT25, BAT26, NR21, NR24 and NR27. Results: The positive expression of GFAP on the cell processes of the star-like shape was clearly visualized, indicating a morphological feature of glial tumors. The Ki-67 labeling index was 70%. Changes were observed at the D17S250 locus (148-148/148-152) for the glial tumor primary cells after the sixth passage. Microsatellite instability was not observed in the primary cell culture. Conclusions: The accumulation of porphyrins from 5-ALA in glial tumor cells does not prevent the in vitro creation of a cell culture from tumor tissue. Microsatellite analysis showed that the obtained glioblastoma cell lines remain stable for at least 10 passages. Material obtained during resection using 5-ALA is a reliable source of stable glial tumor cell lines.
A retrospective analysis of cost and survival outcomes based on consolidation regimens in primary central nervous system lymphoma.
Authors: Gelhard Savannah , Maxwell Amiee , Colman Howard , Cohen Adam Louis , Mendez Joe Sammy
Published: May 2020

e14544

Background: Treatment for Primary Central Nervous System Lymphoma (PCNSL) includes induction therapy consisting of polychemotherapy including high-dose methotrexate followed by consolidation therapy. There are various induction and consolidation regimens with wide variability in their treatment duration, inpatient vs outpatient administration, and the number of chemotherapeutic agents utilized. We performed a comparative cost and efficacy analysis of three consolidation techniques in an effort to provide insight into the cost-benefit of these treatment regimens. Methods: Patients treated for newly diagnosed PCNSL at our institution after July 1, 2012 were retrospectively reviewed. Patients who completed one of the following regimens and received consolidation therapy at our institution were included: rituximab/methotrexate/vincristine/procarbazine (R-MVP), rituximab/methotrexate/temozolomide (R-MT), or rituximab/methotrexate (R-M) for induction followed by consolidation with etoposide/cytarabine (EA), high-dose cytarabine (HIDAC), or high-dose chemotherapy with autologous stem cell rescue (HDC-ASCR). Cost to health system was derived from a Value Driven Outcomes tool and filtered to compare major costs of treatment. Survival was calculated from the date of diagnosis and last date of known survival. Results: Twenty-two patients met eligibility criteria and received the following four treatment regimens: R-MT+EA (12), R-MT+ HDC-ASCR (3), R-M+ HDC-ASCR (1), and R-MVP+HIDAC (6). Patients receiving HDC-ASCR (4) had a trend towards a more favorable overall survival (p = 0.0880) compared to the other two consolidation therapies with no recurrence or death in those patients treated with HDC-ASCR. Comparative cost analysis of facility and pharmacy costs of the three consolidation techniques found that HDC-ASCR was 40 times the cost of the cheapest treatment, HIDAC. Conclusions: This small retrospective review provides evidence that HDC-ASCR may be a superior consolidation strategy but with a profound increase in financial cost. To our knowledge this is the first study completed in the U.S. comparing treatment outcomes and cost in PCNSL. Based on our results, it is clear that a larger and prospective review could potentially shed light on selecting a standard of care based on cost-benefit analysis.
Characterization of BDG8: An antibody-human IL-2 complex that selectively activates the effector arm of the immune system.
Authors: Wyant Timothy , Amit Inbar , Levin Itay , Levitan Natali , Grossman Noam , Bluvshtein Olga , Barak Ruet , Nimrod Guy , Fischman Sharon , Strajbl Marek , Sasson Yehezkel , Zehnin Michael , Ofran Yanay
Published: May 2020

e15004

Background: Interleukin 2 is a 15.4 kDa type I cytokine of the four helix bundle structure. IL-2 signaling has two opposite effects, it can enhance immune response by activation of effector cells and regulate immune response by activation proliferation of regulatory T cells (Tregs). IL-2 mediates its effect by binding to two forms of IL-2 receptor: i) trimeric receptors made of IL-2Rα (CD25), IL-2Rβ (CD122), and a common IL-2Rγ (γc, CD132) chains or ii) a dimeric receptor of only the IL-2Rβ and IL-2Rγ subunits. In Tregs, activation of the trimeric receptor is associated with FoxP3 mediated transcription leading to the production of suppression factors. Tregs express higher levels of the αβγ trimeric IL-2 receptor than effector cells. However binding of IL-2 to the βγ dimer is associated with activation of effector cells expressing relatively high levels of the βγ dimer and express low levels of trimer. High dose IL-2 therapy is used in melanoma and metastatic renal cell carcinoma with response rates 10%-15%. While efficacious, this approach has several disadvantages: 1) IL-2 dependent adverse effects such as Vascular Leak Syndrome (VLS) excluding many patients from being considered 2) The short half-life of IL-2 requires frequent administration, resulting in repeated spikes in the level of circulating IL-2. 3) Administered IL-2 is not selective and enhances a non-desired activation of Tregs. Methods: Antibodies were computational designed to bind to a specific epitope on Il-2 allowing for the binding to the CD122/CD132 complex and exclude the CD122/CD132/CD25 complex. Results: Here we show that we specifically designed and tested a humanized antibody (BD8) that: i) binds tightly the human IL-2 (hIL-2) and ii) the antibody- hIL-2 complex preferentially to bind the IL-2Rβ sub-unit and blocks the IL-2Rα subunit. We show administering the BD8 Ab-IL-2 complex to C57BL/6 mice has a profound effect on activation of MP CD8+, NK and NKT effector cells with minimal effect on Tregs. In mice the antibody-hIL-2 complex serum half -life is much longer then the half-life of hIL-2. In the B16-F10 Melanoma model, BD8-hIL2 resulted in robust effect compared to hIL-2 alone. Conclusions: BD8 is a computationally designed antibody specifically binds to IL-2 inducing the activation of effector cells without stimulating Tregs and demonstrates efficacy in animal cancer models.
Lymphoma cell-killing activity and cytokine release by CD20-directed bispecific IgM antibody-based T-cell engager (IGM-2323).
Authors: Keyt Bruce , Baliga Ramesh , Li Keyu , Manlusoc Marigold , Hinton Paul , Ng Dean , Tran Madeline , Shan Bing , Lu Hai , Rahman Sachi , Saini Avneesh , Cao Yuan , Saraiya Chitra , Peterson Marvin , Godfrey Wayne R , Carroll Steve
Published: May 2020

e15007

Background: Bispecific antibodies which tether T-cells to cancer cells, and additionally activate T-cell mediated killing, have shown promise in treating B-cell malignancies. Dose intensity, however, is limited by cytokine release from the activated T-cells. Side effects include fever, hypotension, and hypoxia. Methods: A novel type of bispecific antibody (IGM-2323) was constructed using the pentameric IgM framework. Recombinant IgM heavy chains and kappa light chains with high affinity variable domains derived from an anti-CD20 IgG, were co-expressed with a J-chain fused to anti-CD3 single chain Fv domain. IGM-2323 has 10 binding domains for CD20, and one binding domain for CD3. Results: IGM-2323 binds to the CD20 antigen with > 1000-fold increased avidity relative to an IgG antibody format. IGM-2323 in human cell cultures shows highly potent T cell dependent cytotoxicity (EC50 20 pM), even on cells with very low cell surface expression of CD20, rituximab-resistant lymphoma cell lines, and patient derived CLL cells. Significantly, IGM-2323 exhibits vastly reduced cytokine release, with equivalent T cell dependent killing of CD20-expressing cancer cells, as compared to corresponding IgG-based T cell bispecifics made with the same binding domains. IGM-2323 mediated killing can occur at low T-cell/cancer cell ratios, as low as (1:5). In addition, IGM-2323 mediates complement dependent cytotoxicity (CDC) of CD20-expressing cells with > 100-fold higher potency than IgG. IgM-based bispecific (anti-CD20 x anti-CD3) completely depletes circulating B cells in cynomolgus monkeys at doses of > 300 µg per kg. Furthermore, durable depletion of B cells in spleen and lymphoid tissues was noted with multiple doses of > 1 mg/kg. Importantly, in these studies no observable adverse effects were seen, despite repeated doses at up to 25 mg/kg (the highest dose tested). Low levels of transiently increased circulating IL-6 and no increased levels of circulating TNF-α and IFN-γ were observed in these primate studies. Conclusions: These data indicate that IgM-based bispecifics can induce T cell engagement and very potent cytotoxicity that can be dissociated from cytokine release syndrome in the primate model. These preclinical data demonstrate the potential for broad application of this novel modular IgM-based bispecific antibody format. A Phase I dose-escalation study of IGM-2323 in patients with relapsed/refractory Non-Hodgkin’s lymphoma has been initiated (NCT04082936) and is currently enrolling patients.
Impact of type of salvage therapy (ST) and response to bridging therapy (BT) on CAR-T therapy outcomes for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL).
Authors: Khurana Arushi , Al Saleh Abdullah S. , Gandhi Sangeetha , Truong Tuan , Brandes Eva , Estby Breanna , Lange Gina , Villasboas Jose Caetano , Paludo Jonas , Bennani N. Nora , Ansell Stephen M. , Johnston Patrick B. , Lin Yi
Published: May 2020

e15020

Background: Durable responses were seen in registration trials for CAR-T in NHL across poor prognostic groups including early relapse post stem cell transplant (ASCT). Multi-center reports of real-world practice noted patients who received BT prior to CAR-T had decreased survival. The impact of last ST and response to BT on clinical outcome are examined here. Methods: Retrospective chart review was performed on 47 patients who received axicabtagene ciloleucel from June 2016 – September 2019 at Mayo Clinic, Rochester. ST was defined as last therapy prior to leukapheresis and grouped into categories – non-ASCT (chemotherapy, and immunotherapy), and ASCT. BT was defined as therapy given between leukapheresis and CAR-T. Response to therapy was evaluated using 2014 Lugano criteria. Event free survival (EFS) was defined as time from CAR-T infusion to progression, next treatment, or death. Results: The ST distribution was 77% non-ASCT [chemo 66% (31), and immunotherapy 11% (5)], and 23% (11) ASCT. EFS was significantly prolonged for the ASCT (median not reached) vs non-ASCT (median 3.8 months, p = 0.03) despite no difference in median prior lines of therapy. This may reflect more aggressive disease in the non-ASCT arm, as time from start of ST to leukapheresis was shorter (median non-ASCT 2.2 months vs. ASCT 4.4 months, p = 0.0008). Patients received BT if there were concerns for symptomatic progression during CAR-T manufacturing that would reduce the likelihood to receive CAR-T. Sixty-two percent (29) patients received BT (11 chemo, and 18 immunotherapy). The EFS did not differ between the type of BT. However, patients who progressed after BT had worse EFS than those who achieved stable disease or partial response (median 2.8 vs 8.7 months, p = 0.03). Conclusions: Patients who received CAR-T as the next treatment after ASCT had better EFS than those after other types of ST. While patients who received BT have worse survival than those who didn’t, having some control of lymphoma progression with BT was associated with better EFS than those who continued to have progressive disease.
Correlation between JAK1/2 expression and immune-related genes and JAK2 gene variants: A pan-cancer analysis.
Authors: Xu Lichao , Zhang Ding , Wang Guoqiang , Chen Chao , Wang Ying , Huang Haozhe , Zhang Zhenghua
Published: May 2020

e15057

Background: Loss of function mutations for Janus kinases 1/2 (JAK1/2) have shown to be the underling mechanism of primary resistance to immune checkpoint inhibitors (ICIs). However, the correlation between JAK1/2 expression and immune-related genes have not been studied. Methods: Survival, mRNA expression and whole-exome sequencing data from 32 pan-cancer atlas studies were obtained from The Cancer Genome Atlas (TCGA). Correlations between JAK1/2 expression and immune-related genes were depicted in heatmaps. We also analyzed the association between JAK2 gene variants and JAK2 expression. Results: In total, 10071 samples with mRNA expression data were included for analysis. Expression of 46 immune-related genes were positively correlated with JAK2 expression in 25 tumors instead of JAK1 expression. Patients with higher expression of JAK2 had better prognosis than patients with lower expression of JAK2 in 13 tumors. Among 10071 patients, 363 (3.60%) patients harbored JAK2 variants, including 8 with frame shift mutations, 44 with nonsense mutations, 142 with missense mutations, 11 with splices, 8 with fusions, 90 with copy-number reduction and 116 with copy-number amplification. There was no difference in JAK2 expression between patients with JAK2 variants and those without JAK2 variants. However, JAK2 fusion (2.20%, 8/363) and amplification (31.96%, 116/363) were associated with higher JAK2 expression. Conclusions: Our pan-cancer analysis found that JAK2 expression was correlated with immune-related genes and the prognosis of cancer patients. JAK2 fusion and amplification increased the expression of JAK2. Altogether, patients with high JAK2 expression may benefit from ICIs.
A prospective cohort study of HLA-B44 supertype as predictor of response to novel immune checkpoint combinations.
Authors: Hernandez-Guerrero Tatiana , Doger Bernard , Morillo Daniel , Casado Victoria , Domine Manuel , García Foncillas Jesús , Moreno Victor
Published: May 2020

e15071

Background: To date there are no clear predictors of response to novel immune checkpoint inhibitor (ICI) combinations. Recent reports suggest that HLA-I (Human Leukocyte Antigen Class I) supertype B44 may predict survival to PD1(L)1 inhibition in patients with melanoma and non-small cell lung cancer (NSCLC) ( Chowell et al, Science 2018). We sought to study if this effect is exclusive for PD(L)1 inhibition alone and the impact of HLA-B44 on ICI combinations with new immunotherapeutic agents. Methods: Between 2017 and 2019, 77 patients treated across 11 different early phase clinical trials (NSCLC: 64: (83,1%); melanoma: 4: (5,2%), bladder 8 (10,4%); and one nasopharynx carcinoma), ICI-naive were prospectively evaluated for HLA-I subclass. All patients were ECOG 0 or 1 (50 and 27 respectively). Most patients had ≤ 2 metastatic sites (55: 71,4%); 24 (31,2%) patients were treated with PD(L)1 inhibitors as monotherapy, and 53 (68.8%) with PD(L)1-containing combinations including ICI and agonists such as ICOS, OX40 or GITR monoclonal antibodies. HLA-I was classified for supertypes and the variables of progression-free survival (PFS) and overall survival (OS) were compared for patients with HLA-B44+ and B44-, in both groups (monotherapy and combinations). Results: 44 patients were HLA-B44+ and 33 were negative. For patients treated with anti-PD(L)1 agents as monotherapy, those that were HLA-B44+ had a longer PFS: [medianPFS: 22,38 months (m) (95% CI: 13,39 – 31,37); vs 3,8m (95% IC: 2,05 – 5,65); p: 0,002] and OS: [median: 33,2 m (95% CI: 23,7 – 42,6) vs 14,46 m (95% IC: 7,86 – 21,1); p: 0,13]. In contrast, these marked differences were not evident in patients receiving PD1 combination therapies [HLA-B44+ mPFS: 7,17m (95% CI: 4,41 - 9,93) vs 9,46 m (IC95% 6,8 m – 12,07); p:0,290], and OS: 11,53m (95% IC: 8,33 – 14,7) vs 18,9 m (IC 95% 13,3 – 24,5) p: 0,24. Lastly, response rate was also better for patients with HLA-B44 positive treated with PD1 monotherapy (66,7% vs 16,7% in HLA-B44 negative patients) p: 0,048, whilst when administering ICI combinations, HLA-B44 negative patients seemed to have a better response rate (44% vs 27% in HLA-B44 positive patients; p = 0,148). Conclusions: These results confirm in a prospective cohort the predictive impact of HLA-B44 supertype for patients treated with anti-PD(L)1 agent and suggest a potential benefit of combining checkpoint inhibitors in patients with other HLA supertypes (non-HLA-B44+).
Immortal time bias in the association between toxicity and response for immune checkpoint inhibitors: A systematic review and meta-analysis.
Authors: Dall'Olio Filippo G. , Rizzo Alessandro , Mollica Veronica , Massucci Maria , Maggio Ilaria , Massari Francesco
Published: May 2020

e15080

Background: A number of studies have addressed the association between Immune related Adverse Events (IrAE) and outcome in patients treated with Immune Checkpoint Inhibitors (ICI). Only a minority of them considered the effect of immortal time bias (ITB), and results of these papers are conflicting. The aim of our meta-analysis was to assess the relationship between IrAE and outcomes for patients treated with ICIs, with a focus on ITB in weighing the role of this association. Methods: PubMed, Embase (Ovid), and Scopus were searched through January 2, 2020. Studies reporting the prognostic impact of IrAE development on outcome in advanced cancer patients treated with anti PD-1 or PD-L1.Two investigators independently extracted data from each study following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. Author name, cancer type, PD-1 and PD-L1 inhibitor used, number of patients, number and type of all adverse events, presence of a landmark analysis, median OS and PFS and difference between patient with or without IrAE in terms of OS and PFS (Hazard Ratio) and ORR (Odds Ratio) were extracted. Data were pooled using a random-effects model. Main outcome were Overall Survival (OS), Progression Free Survival (PFS) and Overall Response Rate (ORR). Analysis was performed with dedicated software (R studio version 1.2.1335, metafor package). Results: A total of 29 articles comprising 7430 patients were included. 7 papers published the results of survival analysis according to landmark analysis, 2 papers published only the naïve analysis while stating that a landmark analysis resulted non significant, and the others did not perform a landmark analysis. IrAEs were associated with improved outcomes with high heterogeneity ( I2 70.8%, p < 0.001 for OS; 65.7%, p 0.002 for PFS; 62.1%, p 0.001 for ORR). When subgroup analysis was performed according to the adoption of a landmark approach, the association between IrAE and outcome remains significant for OS, PFS and ORR but the effect size was smaller ( HR 0.61 vs 0.41 for OS, ANOVA Q-test for difference between subgroup p = 0.015; HR 0.66 vs 0.47 for PFS, ANOVA Q-test p 0.029; OR 2.59 vs 6.77 for ORR, ANOVA Q-test p < 0.001) while heterogeneity was substantially reduced (I2 for papers using LM 43% for OS, p 0.115; 9.7% for PFS, p 0.355; 0.0% for ORR, p 0.556). Conclusions: Our analysis suggests a significant confounding effect of ITB as well as a real effect of IrAE development on outcome.
A rational approach to nivolumab dosing using cost analysis.
Authors: Renner Alex , Samtani Suraj Rajesh , Salinas Carlos , Rojas Carlos , Burotto Pichun Mauricio Emanuel
Published: May 2020

e15101

Background: Immune checkpoint inhibitors have changed the landscape in oncology, offering durable responses and improved survival across several tumor types. A significant problem in many countries is access to these drugs, as the yearly treatment cost can exceed $100,000. One of the alternatives to reduce the total cost of therapy is to optimize the dosing strategy. Nivolumab was initially approved with a 3mg/kg Q2W dosage, later fixed dose nivolumab 240mg Q2W was also approved. Fixed dose regimens can lead to unnecessarily high doses for patients under 80 kg. Methods: We performed a cost analysis using weight data from 53 patients diagnosed with melanoma or metastatic renal cell carcinoma who were treated with nivolumab at our institution. With that information we generated a model which calculated the total cost if they were to receive the 240mg fixed dose regimen, versus a a cost-saving strategy as follows: all patients weighing up to 79.9Kg were to be dosed at 3mg/kg, while patients 80kg or more were to use the fixed 240mg dose. Since nivolumab is available in 100mg, 40mg and 240mg vials, there is dose wastage when using the 3mg/kg calculation, this was considered for the cost analysis. Results: The median weight of our patients was 73.6kg (range 56,0kg - 103,1kg). Analyzing individual patient data, 75% of them would receive a higher dose if treated with the fixed dose regimen, versus 3mg/kg dosing. Among them, the median comparative overdosage is 50,9mg (range 3.0mg - 87.0mg). Considering drug wastage, and a USD 12.96 per mg local price for nivolumab, treating our 53 patients with the proposed model for one year would result in USD 366.886 in cost savings, versus using the 240mg fixed dose regimen, equivalent to a 9.3% of the total treatment costs. Conclusions: Expanding access to immunotherapy is a challenge for health systems. We have shown a potential 9.3% cost savings using a rational dosing regimen for nivolumab, which could be very important in cost-constrained scenarios which many countries are facing. Considering the world average weight is 62.0kg, it is plausible than even greater cost savings could be realized in many other locations around the globe.
Hepatitis B reactivation with pembrolizumab, atezolizumab, and nivolumab: A pharmacovigilance study and literature review.
Authors: Muhsen Ibrahim , Burns Ethan , Umoru Godsfavour , Arain Abeer , Xu Jiaqiong , Abdelrahim Maen
Published: May 2020

e15127

Background: Chronic Hepatitis B virus (HBV) impacts 257 million people worldwide. Chemo- and immunotherapies may predispose to HBV reactivation (HBVr), which can negatively impact oncologic outcomes. Programmed death (PD) and programmed death ligand (PDL)-1 inhibitors have been implicated in HBVr. The aim of this study is to report HBVr in patients who are treated with PD-1/PD L-1 inhibitors by utilizing the FDA Adverse Events Reporting System (FAERS) and literature review. Methods: This is a retrospective pharmacovigilance study using FAERS. We reviewed cases of HBVr reported in patients treated with pembrolizumab, atezolizumab, and nivolumab from 2016-2019. Signal disproportionality analysis was conducted using a reporting odds ratio (ROR). A systematic review using Ovid MEDLINE(R) was conducted for additional reports of HBVr and associated outcomes. Results: There were 15 cases of HBVr associated with the use of PD1/PDL1 inhibitors on FAERS (ROR 1.2, 95% CI [0.72-1.99]). Only pembrolizumab was shown to a have significant association with HBVr (ROR 2.93, 95% CI [1.57-5.46]) (Table). Moreover, 7 cases of HBVr were reported in the literature, 3 with pembrolizumab and 4 with nivolumab. Median time to diagnosis following initiation of immunotherapy was 12 (5-24) weeks and 8 (3-10.5) weeks for resolution of HBVr. Conclusions: Pembrolizumab was the only agent with a significant association of HBVr. Future institutional studies in both endemic and nonendemic areas are warranted to determine the true incidence and necessity of pretreatment screening for HBV in patients on PD-1/PDL-1 therapy. [Table: see text]
What happens at radiographic disease progression in patients with metastatic cancer receiving immune checkpoint inhibitors? A single institution analysis.
Authors: Lin Justin , Patel Vaibhav G. , Qin Qian , Wang Bo , Mellgard George , Gogerly-Moragoda Mahalya , Leiter Amanda , Gallagher Emily J. , Zhong Xiaobo , Oh William K. , Galsky Matt D. , Tsao Che-Kai
Published: May 2020

e15157

Background: Immune checkpoint inhibitors (ICIs) are widely adopted for multiple indications across various malignancies. Despite the surge in their use, what occurs at radiographic progression (rPOD) remains poorly characterized. Herein, we describe patients at our institution that experienced rPOD on ICIs. Methods: We retrospectively reviewed charts of patients (pts) with solid tumors that received at least 2 doses of ICI at our institution from 12/01/2010 to 04/25/2017. Patients’ demographic data, medical history, ICI course, and outcomes were recorded. Characteristics at rPOD included change in tumor size by metastatic site, symptoms, and hospital utilization. Additionally, we characterized outcomes of pts who continued ICIs after rPOD. Fisher’s exact test was performed to identify potential clinical predictors of hospitalization at rPOD. Results: Of the 361 evaluable pts, 238 experienced rPOD. In this cohort, the most common primary sites of disease are: genitourinary (24%), thoracic (24%), skin (21%), and hepatobiliary (15%). At rPOD, 71 (30%) patients were hospitalized within 30 days, with infection (27%) and pain (18%) being the most common reasons. Median survival of pts with hospitalization was 2 months (mos; 95% CI: 0-4), compared to 10 months (95% CI: 8-12) for those not hospitalized (p<0.001). Forty-six (19%) pts continued ICI treatment after rPOD (median duration = 2.8 mos), with eleven (5%) pts continuing for at least 6 months (median duration = 8 mos). Conclusions: In our study of real-world cancer pts treated with ICI, a higher than expected proportion was hospitalized within 30 days after rPOD, and this population had a worse overall survival compared to those that were not. A subgroup of pt with rPOD did not experience clinical progression, and thus treatment was continued, although further benefit was limited to a small subset. Further studies are needed to better understand the underlying mechanism to identify those who benefits from treatment beyond rPOD. [Table: see text]
Investigating the impact of medical comorbidities in patients taking beta blockers and treated with immunotherapy for metastatic melanoma.
Authors: Hong Paul Pyunggang , Zhu Junjia , Drabick Joseph J. , Schell Todd D.
Published: May 2020

e15162

Background: Combined administration of β-adrenergic antagonist with IL-2, anti-PD-1, and/or anti-CTLA-4 immunotherapy was associated with a better overall survival in metastatic melanoma patients. This result was also reinforced by the significant reduction in tumor growth in a murine melanoma model when a β2-selective antagonist was combined with anti-PD1/IL-2 immunotherapy. Here we sought to elucidate the impact of the various comorbidities behind the indications of β-blockers, and how they might have influenced the patients’ immunotherapy treatment response. Methods: A single-institution retrospective chart review was performed to examine the medical comorbidities with indications for β-blockers in the melanoma patients who received IL-2, αPD-1 and/or αCTLA-4 immunotherapy between January 2000 and March 2015. Two groups were identified: one that took a selective β-1 blocker (N = 41), and another that took a nonselective pan β-blocker (N = 17). The primary analysis compared the distribution of different comorbidity types between two groups, using the Fisher’s exact test. A secondary analysis examined the association of overall survival and the β-blocker groups by further controlling for comorbid conditions, using the multivariate Cox Proportional-Hazard regression model. Results: Seven different comorbidities with indications for β-blocker usage were identified. Of those comorbidities, only the presence of ischemic heart disease was marginally different between the two groups (β-1 group 19.5% vs. pan-β group 47.1%, p-value = 0.0697). There was no difference for overall survival between each of the comorbidity conditions. When performing the multivariate Cox Proportional-Hazard regression model, β-blocker usage still remained statistically significant for the overall survival (HR 0.27, CI 0.0966-0.768, p = 0.0139), even after controlling for the comorbid conditions. Conclusions: Immunotherapy with pan β-adrenergic blockade was associated with a significantly improved overall survival rate for metastatic melanoma. Furthermore, having a comorbid condition that indicated for the prescription of β-blockers was not a factor in establishing this survival rate.
Management of immune-related adverse events: A single-center retrospective analysis in a real-world scenario.
Authors: Iacono Donatella , Vitale Maria Grazia , Cortiula Francesco , Macerelli Marianna , Cinausero Marika , Minisini Alessandro Marco , Valent Francesca , Tullio Annarita , Palmero Lorenza , Targato Giada , Zara Diego , Fasola Gianpiero
Published: May 2020

e15163

Background: Immune checkpoint inhibitors (ICI), anti CTLA-4 and anti PD-1/PD-L1 agents, have demonstrated an improvement in survival outcome in several malignancies. Therapy with ICI is characterized by immune-related adverse events (irAEs) as a result of exuberant immune system activation. Despite good tolerance for ICI, the potentially severe and life-threatening irAEs underscore the importance of investigating optimal management strategies. Methods: A retrospective series of 130 consecutive patients (pts) treated with ICI from Jan 2012 to Dec 2017 was analyzed. Adverse events with a potential immunological etiology were defined as irAEs and graded according to CTCAE v.4.0. The aim of the study was to evaluate irAEs management in an academic hospital center. Results: Pts with a diagnosis of NSCLC n = 64 (49%), melanoma n = 55 (42%), kidney n = 9 (7%) and others n = 2 (2%) were investigated. Baseline ECOG PS was ≤ 1 in 96% of the pts. ICI represented first line treatment for 27% pts, second line for 57% and third or further line for the remaining 16%. 18% were treated with ipilimumab and 82% with anti PD-1/PD-L1 agents (nivolumab 60%, pembrolizumab 21%, atezolizumab 1%). Overall, 50 (38% of pts) developed an irAE.42% of irAEs were grade 1, 38% grade 2, 14% grade 3 and 6% grade 4. The most frequent irAEs were endocrinopathies in 17 pts (34%), followed by cutaneous toxicity in 9 pts (18%) and colitis and diarrhea in 7 pts (14%). A total of 373 unscheduled accesses were observed, 89 (24%) of them were due to irAEs: 78 were unplanned consultations in the oncology department and 11 in the emergency department. irAEs led to hospitalization in 14 pts for 118 days, cumulatively. Grade ≥ 2 colitis was the most frequent irAE associated with hospitalization, it occurred in 4 pts (29%). Colitis and diarrhea required the longest hospitalization (range 4-31 days). 48% (24 pts) required immunosuppressive treatment. Systemic steroids were the most common immunosuppressive agents used. Only one patient received infliximab as second line immunosuppressive treatment after steroid failure. Totally, irAEs required 67 specialist consultancies and additional diagnostic examinations. 15 pts required ICI discontinuation because of irAEs. Conclusions: In our center prevalence and severity of irAEs were similar to literature data. Considered the complexity of irAEs management, multidisciplinary approach and a trained hospital network plays a key role for a more efficient diagnostic and treatment work-up in pts who received ICI therapy and experienced irAEs.
Outcome of immune checkpoint inhibitor (ICI) related diarrhea/colitis (IMDC) in cancer patients with superimposed GI infections.
Authors: Ma Weijie , Abu-Sbeih Hamzah , Peng Yuanzun , Okhuysen Pablo , Wang Yinghong
Published: May 2020

e15166

Background: ICI therapies have revolutionized the landscape of cancer treatment. However, their increased use has also contributed to adverse events, e.g. IMDC. Clinically it is difficult to distinguish between infectious etiology or IMDC. It is unclear whether antimicrobial treatment substantially impacts the disease course. Here, we evaluated the characteristics and outcome of IMDC in cancer patients with superimposed diarrheagenic GI infections. Methods: We retrospectively evaluated cancer patients who received ICI with clinical symptoms of IMDC and confirmed stool microbiology of E. coli or non-CMV viral infections either at the time of IMDC, or within 60 days after IMDC diagnosis at MD Anderson Cancer Center 01/2011-08/2019. We described the disease course and outcome of IMDC based on their status of GI infection and antimicrobial treatment. Results: Total 72 patients were included, among them, 50 control patients with IMDC and no GI infection, 22 had diarrheagenic infections, composed of 17 E coli pathogens: Enteropathogenic, Enterotoxigenic, Enteroaggregative, and E coli 0157:H7 serotype; and 5 viral etiologies: Adenovirus, Norovirus, and Sapovirus. Patients in the infection group had higher grade of colitis (42.9% vs 18.4%, P = 0.041), and more frequent hospitalization (86.4% vs 62%, P = 0.052). 68.2% patients in the infection group received infliximab/vedolizumab add-on treatment compared to 40% in the no infection group (P = 0.078). Patients with GI infection and antimicrobial treatment had much higher IMDC recurrence rate than no antimicrobial treatment (50% vs 0, P = 0.015). GI infection was not associated with higher IMDC recurrence or worse overall survival of these patients. Conclusions: IMDC can occasionally be complicated by infection from common GI pathogens. Antimicrobial treatment was mostly used in severe IMDC cases and did not circumvent the need for immunosuppressant or improve the clinical outcomes. GI infection was not associated with higher IMDC recurrence or worse overall survival of these patients. [Table: see text]
Comparative study between image-guided percutaneous biopsies and matched surgical specimens for the evaluation of PD-L1 status in non-small cell lung cancer.
Authors: Zhao Liang , Chen Haojun , Fu Kaili , Zhuang Yanzhen , Lin Qin
Published: May 2020

e15168

Background: Programmed death-ligand 1 (PD-L1) expression status is a crucial index for identifying patients who will benefit from anti-programmed cell death protein 1 (PD-1)/PD-L1 therapy for non-small cell lung cancer (NSCLC). However, the concordance of Tumor Proportion Score (TPS)between biopsies and matched surgical specimens remains controversial. This study aimed to evaluate the concordance of PD-L1 expression between image-guided percutaneous biopsies and matched surgical specimens. Methods: We evaluated 157 patients diagnosed with operable NSCLC on both surgical tissue sections and matched lung biopsies. The patients underwent either regular computed tomography (CT)-guided biopsy (n = 82) or positron emission tomography (PET)/CT-guided biopsy (n = 75). The concordance between surgical specimens and lung biopsies for PD-L1 TPS was evaluated using Cohen’s kappa (κ) coefficient. Results: Immunohistochemical expression of PD-L1 was evaluated in both surgical resected specimens and matched biopsies in the eligible 138 patients. The concordance rate of PD-L1 expression between surgical tissue sections and matched biopsies was fairly high at 83.3% (115/138), and the κ value was 0.73 (95% CI: 0.63–0.83, P < 0.001). The concordance rate was higher for tissue sections from PET/CT-guided biopsy than for tissue sections from CT-guided biopsy (88.6% [62/70, κ value: 0.81] vs 77.9% [53/68, κ value: 0.66]). Conclusions: PD-L1 TPS was strongly concordant between surgical specimens and matched lung biopsies. Thus, routine evaluation of PD-L1 expression in diagnostic percutaneous biopsies could be reliable for identifying patients who will benefit from anti-PD-1/PD-L1 immunotherapy. [Table: see text]
Association of immune-related adverse effects and survival in responders treated with immune checkpoint inhibitors.
Authors: Kapoor Akhil , Noronha Vanita , Patil Vijay Maruti , Joshi Amit , Menon Nandini Sharrel , Prabhash Kumar
Published: May 2020

e15172

Background: The development of immune-related adverse effects (irAEs) can corroborate with the response to immune checkpoint inhibitors (ICIs). However, there is very limited data on the association of irAEs with survival in patients who have shown response to ICIs. Methods: This study is a retrospective audit of prospectively collected database of patients who received ICIs for advanced solid tumors. Responders were defined as patients who attained best response of either complete response (CR) or partial response (PR). Time-to-event analysis was done using Kaplan-Meier estimator and hazard ratio was calculated by using Cox proportional model. Results: A total of 155 patients who received ICI during the specified period were evaluated for this study. The response rate was 19.4%. One year OS for responders was 75.6% (SD 8.8) versus 26.1% (SD 5.1). The median OS for patients who developed irAE was 12.3 months (95% CI: 8.9-15.6) while it was not reached for patients without irAE (HR 10.5, 95% CI 1.2-NR, p=0.007). One-year OS for the corresponding group of patients was 53.6% (SD 15.6) versus 92.9% (SD 6.9), respectively. Conclusions: This study reports negative association of immune-related adverse effects and survival in responding patients of solid tumors treated with immune checkpoint inhibitors. [Table: see text]
Analysis of microsatellite instability differences in eight types of tumors.
Authors: Zhang Zhen , Zhang Xing , Ge Minhui , Qin Huijuan
Published: May 2020

e15174

Background: Microsatellite instability-high (MSI-H) is the gain or loss of nucleotides from repetitive DNA caused by genomic hypermutability and a powerfully predictive phenotype for diagnosis, immunotherapy and prognosis in various types of cancer. Herein, we analyze the frequency of MSI-H for the understanding of epidemiology of MSI-H across major types of human cancer. Methods: MSI value was calculated by bioinformatics algorithm based on NGS from 539 genes panel in tumor tissue. Patients were divided into three classes as MSI-H, MSI-L and MSS based on MSI value. MSI-H was defined as above 10% positive of the 195 tested microsatellites sites, and this method was totally consistent with conventional MSI-PCR testing in research and development sample verification. We compared the differences of MSI-H ratio in eight types of human cancer including liver cancer, bile duct cancer, gastric cancer, colorectal cancer, pancreatic cancer, melanoma, glioma and lung cancer from 874 cancer cases via χ2 test, adjusted standardized residual or Fisher's exact test. Results: The ratios of MSI-H in eight types of solid tumors were 0% in 32 patients with bile duct cancer or 27 patients with pancreatic cancer, 0.6% (1/174) in liver cancer, 1.9% (1/54) in gastric cancer, 6.7% (8/119) in colorectal cancer, 3.1% (1/32) in melanoma, 4% (1/25) in glioma, and 0.5% (2/411) in lung cancer, respectively. Significant correlations between the MSI-H and cancer types were found by χ2 test (χ2 = 26.571, Cramer’s V coefficient = 0.174, p = 3.980×10−4). Only patients with colorectal cancer had absolute values of adjusted standardized residual above 3, its observed counts of MSI-H significantly higher than expected counts. Fisher’s exact test was performed to analyze the differences of MSI-H ratio across hepatobiliary (liver and bile duct) cancer, digestive tract (gastric and colorectal) cancer and lung cancer, and we found the MSI-H ratio of patients with digestive duct cancer was significantly higher than patients with hepatobiliary cancer ( p = 0.007) or lung cancer ( p = 4.599×10−4). Conclusions: Our study provided new references to cancer-specific properties and clinical diagnosis of MSI especially in East Asian populations. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
Monitoring of inflammatory response to cancer immunotherapies.
Authors: Quan Qimin , Geanacopoulos John , Ritchey Joshua , Clenow Mark , Wilkinson Joe , Boyce John
Published: May 2020

e15199

Background: Inflammation observed in response to some monoclonal antibody drugs and adaptive T-Cell therapies has become a major issue in cancer immunotherapy. Prognostic monitoring of the inflammatory response requires simultaneous measurement of multiple cytokines at widely divergent concentrations. At present, no analytical method, known to us, can provide large dynamic range (> 6 logs), high sensitivity (< 1pg/ml) and high multiplex in a single test. Methods: The NanoMosaic platform is a cytokine quantification technology powered by silicon nanoneedle biosensors that are densely integrated on a plate and manufactured with CMOS-compatible nanofabrication processes. Each nanoneedle is a label-free biosensor, functionalized with capture antibodies. Each analyte specific sensing area consists a total of ~23k nanoneedles divided into a digital region (~20k nanoneedles) and an analog region (~3k nanoneedles), combined to cover the entire range of inflammatory biomarkers from 0.1pg/ml to 1ug/ml. Results: We demonstrated that the digital nanoneedles achieve the single molecule sensitivity. Therefore, at ultra-low concentrations when antigens that are captured by the nanoneedles follow Poisson statistics, the number of antigens can be quantitated by counting the presence or absence of color changes of individual nanoneedles in a binary fashion. As the protein concentrations increase, the binding events increase accordingly and achieve saturation when all nanoneedles capture more than one protein. Above the digital saturation concentration, an adjacent section of analog nanoneedles perform quantitative analysis based on the level of color change, thus providing a wider dynamic range up to 1ug/ml. Each single analyte area, including both digital and analog sensors, is less than 500um. Therefore, high level multiplex can be achieved by duplicating the detection sensor in a microarray format without loss of sensitivity and dynamic range. Conclusions: The CMOS-compatible NanoMosaic technology provides the cost-effectiveness, sensitivity, dynamic range and multiplexing capacity required to fully integrate patient immune response into therapeutic development and decision making.
Generation of dendritic cells using viral lysate of tumor cells in vitro.
Authors: Kolpakov Sergey A. , Kolpakova Elena P. , Sitkovskaya Anastasia O. , Zlatnik Elena Yu. , Filippova Svetlana Yu. , Bondarenko Elena S. , Kolesnikov Vladimir E. , Oganyan Nairi B. , Pavlov Vladislav K. , Karasev Timofey S. , Kit Oleg I.
Published: May 2020

e15202

Background: The purpose of the study was to investigate the effect of a new unclassified rotavirus on the effectiveness of maturation of dendritic cells (DC) and their activation of lymphocytes in vitro. Methods: Strain No.100 of the RVK virus was isolated by S.A. Kolpakov and characterized as rotavirus. U87MG cell lysate (glioblastoma) was obtained by incubation with 108 RVK particles in the DMEM medium with L-glutamine for 72 hours; a cytopathic effect was observed. Immature DCs were cultured for 7 days in the presence of IL-4 and GM-CSF. For antigen loading of DCs, we used the following options for 48 h: a) U87MG lysate obtained by repeated freeze-thaw cycles (TL); b) U87MG lysate obtained by co-cultivation with RVK (VTL); c) RVK. To assess the DC ability to activate autologous lymphocytes, they were co-cultured for 5 days in a 3:1 ratio. Results: The use of VTL culture for DC loading caused an increase in the expression of mature DC (mDC) markers compared to TL: the number of CD83+/CD86+ cells increased by more than 2 times, CD83+/CD80+ by 1.2 times, CD83+HLA-DR - by 5.5 times. With VTL, expression of markers of immature DCs (CD1a, CD14) was minimal. The use of RVK as an antigen induced the generation of DCs from monocytes, but their maturation was much less pronounced: a significant increase in the membrane expression of CD86, but not CD83, was determined. These DCs demonstrated a higher expression of markers of immature DCs, compared to stimulation with cell lysates (both TL and VTL): CD1a and CD14; CD80+/CD86+ level was the highest among all options. Analysis of the DC effect on co-cultivated lymphocytes showed that DCs loaded with RVK, both alone and as part of VTL, stimulated predominantly the NKT subpopulation. The same samples contained more T lymphocytes, activated CD4+ and CD8+ compared to samples stimulated by TL. However, the samples co-cultivated with VTL contained the maximal amount of CD4+/CD25+/CD127dim phenotypically corresponding to Tregs. Conclusions: The antigen loading of immature DCs with RVK alone causes their activation, but not maturation, which is not realized in typical terms of the DC generation from blood monocytes. The presence of RVK, including in VTL, has a stimulating effect on NKT lymphocytes suggesting the possible generation of specific highly active cytotoxic lymphocytes.
Use of alpelisib in the treatment of hormone receptor positive metastatic breast cancer: An institutional experience.
Authors: Lama Tamang Tsering G. , Kyung Daniel , Eisenbud Lauren , Tang Tianyi , Parajuli Ritesh , Mehta Rita S.
Published: May 2020

e15216

Background: Mutations in PI3K pathway is a known mechanism of resistance to endocrine therapy in breast cancer. Alpelisib is an alpha-specific PI3K inhibitor. Alpelisib with Fulvestrant is approved for treatment (Tx) of PIK3CA mutated HR+ metastatic breast cancer (MBC) that progress on hormonal therapy. Despite its approval by the FDA, real world data on the use of Alpelisib for the management of MBC is lacking. This abstract reviews the safety and efficacy of Alpelisib in the management of patients with MBC. Methods: A retrospective review of the tumor registry database at a single institution was conducted to identify patients with HR+ MBC. Detailed clinical and pathologic data of PIK3CA mutated patients treated with Alpelisib were obtained. Genomic profiling was done with Foundation One. Results: Table highlights the characteristics of the four patients. All were treated with Alpelisib and Fulvestrant after PIK3CA mutation was demonstrated. 3 patients were heavily pretreated with systemic Tx including CDK 4/6 inhibitors. All patients responded to Alpelisib and Fulvestrant despite treatment history. Mucositis, rash, hyperglycemia and pancytopenia were the observed adverse events (A/E). All A/E were adequately managed except in one patient that required discontinuation of Tx. None has clinically progressed. Conclusions: Our data suggests that Alpelisib and Fulvestrant is tolerated and improves outcomes in patients with HR+ MBC. Alpelisib and Fulvestrant could be an effective therapy in patients who have also progressed on systemic chemotherapy including CDK 4/6 inhibitors. Although our sample size is small, we hope that our experience could guide clinicians in the management of patients with HR+ MBC who harbor the PIK3CA mutation and are being treated with Alpelisib. [Table: see text]