bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of palbociclib in recurrent RB-positive anaplastic oligodendroglioma: A Spanish group for research in neurooncology (GEINO) trial.
Authors: Sepulveda-Sanchez Juan Manuel , Gil Gil Miguel J. , Alonso Miriam , Vaz Salgado María Ángeles , Vicente Elena , Mesia Barroso Carlos , Rodriguez Sanchez Angel , Durán Gema , De Las Penas Ramon , Muñoz-Langa José , de Velasco Guillermo , Hernandez-Lain Aurelio , Hilario Amaya , Navarro L Miguel , Benavides Manuel , Oleaga Laura , Cantero Diana , Ruano Yolanda , Sanchez-Gomez Pilar , Pineda Estela
Published: May 2019

2038

Background: The pRB-dependent cell cycle checkpoint is altered in the vast majority of anaplastic oligodendrogliomas (AO), either by homozygous deletion or by hypermethylation of CDKN2A and/or CDKN2B, or by amplification and/or overexpression of CDK4. Palbociclib is an oral inhibitor of CDK4 and 6 that has already been shown to be highly active in breast cancer. Methods: We conducted a multicenter, open-label, phase II trial evaluating efficacy and safety of Palbociclib in patients with AO that progressed to radiotherapy and more than one chemotherapy regimen containing Temozolomide and/or Lomustine. Inclusion criteria included: histologically and molecularly confirmed grade III oligodendroglioma (WHO 2016 classification, IDH1/2 mutation and 1p/19 codeletion were mandatory), recurrence after radiotherapy and 1 or 2 chemotherapy regimens and conserved RB protein expression by immunohistochemistry (IHC). Patients were treated with Palbociclib 125 mg/daily 3 weeks on/1off. The primary objective of the study was progression-free survival at 6 months (6M-PFS). Results: Between October 2015 and September 2018, 34 patients were enrolled across ten hospitals. The study was stopped early secondary to lack of efficacy, with 74% of evaluable patients progressing within 6 months. Number of patients alive and free from progression at 6 months after the enrollment was 9 (26%) out of the first 34 patients, below the minimum number required (18 out of 40) to consider Palbociclib as an active drug in this population. With a median follow-up of 11.2 months, the median PFS was 3 months (95% CI: 2.5-3.5 months). Median overall survival (OS) was 23.1 months (95% CI: 17.2-25 months). There were no partial or complete responses and only 11 patients (32%) achieved stable disease as best response. Palbociclib was well tolerated with neutropenia (Grade 3 or 4: 40%) and thrombocytopenia (Grade 3 or 4: 15%) as the most common adverse effects (AEs). Both AEs had no significant impact since there were no episodes of febrile neutropenia or bleeding. Conclusions: Despite the good tolerance and drug exposure, Palbociclib monotherapy did not show favorable activity in recurrent AO. Clinical trial information: NCT02530320.
The timing of chemoradiotherapy after surgical resection and its impact on overall survival in glioblastoma.
Authors: Press Robert H. , Shafer Sarah L. , Jiang Renjian , Buchwald Zachary S. , Abugideiri Mustafa , Tian Sibo , Morgan Tiffany , Behera Madhusmita , Sengupta Soma , Voloschin Alfredo Daniel , Olson Jeffrey J. , Curran Walter John , Eaton Bree Ruppert , Shu Hui-Kuo George , Zhong Jim
Published: May 2019

2051

Background: Prior studies examining time to initiate chemoradiotherapy (CRT) after surgical resection (S) in glioblastoma (GBM) have not provided clear consensus on its clinical impact. We sought to evaluate the effect that differential timing of adjuvant therapy may have on overall survival (OS). Methods: With the National Cancer Database (NCDB), patients (pts) with GBM who underwent S and adjuvant CRT from 2004-2013 were analyzed. Analysis was performed for the entire cohort as well as by Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classes (i.e. I, II, and III). Time from S to CRT was grouped weekly (i.e. 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, and > 8 weeks). Pts were excluded if they died within the first 8 weeks to account for immortal time bias. Kaplan-Meier analysis, log-rank testing, and multivariate (MVA) Cox proportional hazards regression were performed with OS as the primary outcome. Results: A total of 30,414 pts were included for analysis. RPA class I, II, and III contained 903, 4,347, and 25,164 pts, respectively. The most common time to initiate CRT was week 4-5 (n = 7389), and this group served as reference for survival analysis. On MVA, weeks 0-1 (hazard ratio [HR] 1.18, 95% confidence interval [CI] 1.02-1.35), 1-2 (HR 1.24, CI 1.17-1.32), and 2-3 (HR 1.11, CI 1.07-1.15) demonstrated worse OS (all p < 0.03). For RPA class I pts, week 1-2 (HR 2.07, CI 1.08-3.95) was associated with worse OS (p = 0.028). For RPA class II pts, weeks 1-2 (HR 1.34, CI 1.14-1.57), 2-3 (HR 1.18, CI 1.07-1.31), and 3-4 (HR 1.10, CI 1.0-1.21) were associated with worse OS (all p < 0.05). For RPA class III pts, weeks 0-1 (HR 1.18, CI 1.02-1.38), 1-2 (HR 1.22, CI 1.14-1.3), and 2-3 (HR 1.09, CI 1.05-1.14) were associated with worse OS (all p < 0.03). No time point after week 5 was associated with change in OS for the overall cohort or any RPA class subgroup. Conclusions: These data provide insight into the optimal timing of CRT in GBM and describe RPA-class specific outcomes. In general, OS was negatively impacted if CRT started less than 3 weeks from S. Waiting up to 8 weeks, however, was not detrimental to OS and suggests delaying CRT beyond week 4-5 should be considered if clinically indicated without undue concern.
Efficacy of re-irradiation with carbon ions (RiCi) in patients with recurrent high-grade glioma (rHGG) compared to the standard re-irradiation with photons (RiP): The reference multicenter cohort of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Authors: Knoll Maximilian , Waltenberger Maria , Bougatf Nina , Bernhardt Denise , Adeberg Sebastian , Budach Volker , Baumann Michael , Stuschke Martin , Fokas Emmanouil , Grosu Anca , Zips Daniel , Belka Claus , Combs Stephanie E , von Deimling Andreas , Bendszus Martin , Wick Wolfgang , Unterberg Andreas , Rieken Stefan , Debus Juergen , Abdollahi Amir
Published: May 2019

2057

Background: Local recurrence after surgery and radio(chemo)therapy remains a major obstacle in curative treatment of patients with HGG. Eradication of radioresistant glioma subpopulations (hypoxic- and stem cell like cells) together with formation of an antiangiogenic and immuno-permissive glioma niche are among beneficial radiobiological effects recently attributed to carbon ion irradiation in preclinical models. The impact of this novel therapy in management of rHGG patients remains elusive. Methods: 197 patients with rHGG (grade III: 71, IV: 126) received RiCi between Nov 2009 and Feb 2018 at HIT with a median dose of 42GyRBE in 14 fractions. In DKTK-ROG multicenter cohort n:565 rHGG patients (grade III: 63, IV: 479) underwent RiP between 1997-2016 with a median dose of 36 Gy in 14 fractions. Median follow up was 34.2 months (M) for RiCi and 7.1 M for RiP (DKTK) cohort. All three prognostic scores validated in DKTK-ROG cohort were evaluated and re-irradiation risk score (RRRS) considering initial grade, Karnofsky Performance Score and age at re-irradiation was utilized for stratification and matched comparisons. Results: Median PFS was 5.08 [4.26-5.87] M (grade III: 6.79, grade IV: 3.64) after RiCi, data was not available for RiP. Median OS was 10.52 [9.28-12.66] M (grade III: 28.2, grade IV: 8.53) after RiCi compared to 7.93 [7.15-8.79] M (grade III: 10.89, grade IV: 7.93) after RiP. Among the three prognostic scores evaluated, RRRS most robustly correlated with OS. RiCi was associated with HR of 0.52 ([0.49-0.72], p = 0.0000002), and HR 0.66 ([0.51-0.85], p = 0.001) for RRRS matched analysis. Conclusions: Carbon ions demonstrated activity in rHGG. This effect is most prominent in grade III while grade IV patients may further benefit from innovative multimodal strategies. Based on these encouraging results prospective randomized trials utilizing RRRS for stratification are recommended.
Functional profile and clinical significance of major tumor infiltrating lymphocyte subsets in lung cancer-associated brain metastases.
Authors: Lu Benjamin Y. , Gupta Richa , Stewart Tyler , Kluger Harriet M. , Jilaveanu Lucia , Schalper Kurt A. , Goldberg Sarah B.
Published: May 2019

2066

Background: Despite the biological and clinical implications, the immune composition and functional characteristics of adaptive immune cells in brain metastases (BrM) are poorly understood. Using multiplexed quantitative immunofluorescence (QIF), this study evaluates the level and functional profile of major T-cell subsets in primary lung tumors, BrM, and extracranial metastases (ECM) from lung cancers. Methods: A tissue microarray was constructed from formalin-fixed, paraffin-embedded tumor samples of 94 lung cancer patients treated at Yale Cancer Center between 2002-2013. Multiplexed QIF was used to evaluate the cases with a panel containing phenotype markers for major T-cell subsets (CD3, CD4, CD8 and FOXP3), and cell-localized activation and proliferation (granzyme-B and Ki-67). Signal for each marker was measured in marker-selected tissue compartments using the Automated Quantitative Analysis (AQUA) platform. Associations between markers and major clinicopathologic variables were studied. Results: In total, 40 primary lung tumors, 63 BrM, and 15 ECM were analyzed, including paired samples from 22 patients. Lung cancer histology included adenocarcinoma 62.5%, squamous cell carcinoma 11.5%, small cell 9.4%, and other non-small cell 16.7%. BrM had both significantly lower levels of CD3+ T-cells ( p< 0.0001) and T-cell granzyme B ( p= 0.0188) compared with primary lung tumors. No significant differences were observed in T-cell Ki-67 levels across tissues. FOXP3 measured in CD4+ T-cells were significantly lower in BrM compared with primary malignancies ( p= 0.0002) and ECM ( p= 0.0404). Among patients with BrM, higher levels of CD3+ T-cells in BrM were associated with longer overall survival. Conclusions: Lung cancer-associated BrM have lower T-cell infiltration, cytolytic function, and regulatory T-cells than primary lesions. These results indicate lower adaptive anti-tumor responses in BrM and suggest the presence of a tolerogenic microenvironment in the brain. Overcoming this could be used to design optimal treatment strategies.
Immunobiology, preliminary safety, and efficacy of CPI-006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced cancers.
Authors: Luke Jason J. , Powderly John D. , Merchan Jaime R. , Barve Minal A. , Hotson Andrew N. , Mobasher Mehrdad , Kwei Long , Luciano Gabriel , Buggy Joseph J. , Piccione Emily , Miller Richard A.
Published: May 2019

2505

Background: CPI-006 inhibits CD73, a nucelotidase that converts AMP to adenosine and functions as a lymphocyte adhesion molecule. CPI-006 is a humanized IgG1 FcγR binding-deficient antibody that binds to CD73+ T and B lymphocytes leading to activation of B cells and expression of CD69. This study investigates the immunobiology, safety, and efficacy of CPI-006 monotherapy and in combination with CPI-444, an adenosine A2A receptor (A2AR) antagonist (NCT03454451). Methods: Patients with relapsed solid tumors were treated in a 3 + 3 escalation study with 1, 3, 6 or 12 mg/kg CPI-006 (Q3w IV infusion) monotherapy or in combination with CPI-444 (100 mg, PO, BID). Flow cytometry was performed on blood samples for lymphocyte subset analysis and receptor occupancy. Results: 17 patients were enrolled; 11 monotherapy and 6 combination. CPI-006 was associated with Grade 1 infusion reactions occuring within 30 minutes of the first infusion and were eliminated by premedication with non-steroidals. No DLTs with monotherapy or combination therapy were seen. Receptor occupancy on peripheral lymphocytes was maintained for the full dosing interval at 12 mg/kg. Pharmacodynamic effects suggesting immune modulation were observed within 1 hr of infusion at all dose levels and included a decrease in peripheral blood CD73pos B cells (mean reduction 86%, p < 0.05), increased CD73neg CD4 T cells (mean increase 37%, p < 0.01), and decreased CD8 T cells (mean reduction 20%, p < 0.01) compared to baseline. Overall, CD4:CD8 ratios were increased. Tumor regression was observed in a prostate cancer patient after 5 cycles of monotherapy at 6 mg/kg; peripheral B cells partially returned by the second cycle and reached a new homeostatic level through subsequent cycles. No change in serum immunoglobulins were observed. Conclusions: CPI-006 induces a rapid lymphocyte redistribution, including a transient reduction of circulating CD73pos B cells suggesting redistribution to lymphoid tissues, and an increased CD4:CD8 ratio, consistent with increased TH effector/memory cells in the blood. The treatment has been well-tolerated, and there is early evidence of anti-tumor activity of CPI-006 monotherapy. Clinical trial information: NCT03454451.
Targeting MHC-linked wild type p53 with TCR mimic single chain diabody for cancer immunotherapy.
Authors: Paul Suman , Douglass Jacqueline , Schaefer Annika , Hsiue Emily Han-Chung , Pearlman Alexander , Mog Brian , Hwang Michael , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Zhou Shibin
Published: May 2019

2524

Background: Increased tumor suppressor protein p53 expression is observed in a wide range of human cancers. As a result there is intense interest in targeting p53 for cancer therapy. Intracellular p53 is inaccessible to therapeutic antibodies that bind cell surface proteins. However, intracellular proteins including p53 are degraded into peptides that are presented on cell surface in association with HLA class I molecules. Thus p53 peptide-HLA (p53-HLA) complexes can be antibody targets. Methods: Using phage display we identified a novel anti-p53-HLA single chain variable fragment (scFv) clone-43 that recognizes a wild-type p53 10-mer epitope bound to HLA-A*2402. By coupling our clone-43 scFv with an anti-CD3 scFv, we generated a single chain diabody (scDb) designed to activate T-cells against p53-expressing target cells. Results: In-vitro co-culture of clone-43 scDb with donor human T-cells and p53 expressing SIG-M5 cancer cells results in SIG-M5 cell killing and concomitant T-cell interferon gamma (IFNγ) release. In contrast, similar co-culture with SIG-M5 p53-knock out (KO) cells showed no cell killing and minimal IFNγ release demonstrating specificity of clone-43 to p53 expressing cells. Additionally, in-vivo growth of p53 expressing SW480 cancer cell xenografts in NSG mice was completely terminated by clone-43 scDb injections. A major concern for wild-type p53 epitope targeting is potential on-target off-tumor effect on non-cancerous tissue. We observed significant in-vitro clone-43 scDb mediated killing of human HLA-A*24:02 peripheral blood mononuclear cells. To better evaluate effect of clone-43 scDb on non-neoplastic human cells, we engrafted HLA-A*24:02 human CD34+ hematopoietic stem cells into NSG mice to generate a humanized mouse model with circulating mature human CD45+ cells. Clone-43 scDb treatment resulted in selective depletion of circulating human cells while the same cells persisted in mice treated with unrelated control scDb. Conclusions: Our observation that immune targeting of wild-type p53 epitope results in significant off-tumor hematopoietic cell death is contrary to previously published reports and carries important implications for future anti-p53 antibody and vaccine design for cancer immunotherapy.
Phase 1a/1b study of first-in-class B7-H4 antibody, FPA150, as monotherapy in patients with advanced solid tumors.
Authors: Sachdev Jasgit C. , Bauer Todd Michael , Chawla Sant P. , Pant Shubham , Patnaik Amita , Wainberg Zev A. , Inamdar Sandeep P. , Marina Neyssa , Sun Stefanie , Schmidt Maike , Xiang Hong , LoRusso Patricia
Published: May 2019

2529

Background: B7-H4, a transmembrane protein of the B7 family, is a negative regulator of T cell function, expressed at high levels on several cancers, including approximately 50% of breast, ovarian and endometrial cancers. FPA150 is a fully human antibody against B7-H4 that blocks inhibition of T cell activity and has enhanced antibody-dependent cell-mediated cytotoxicity. It is the first therapeutic molecule targeting B7-H4 to enter the clinic. We report preliminary results from an ongoing phase 1a/1b study of FPA150 in advanced solid tumors. Methods: Phase 1a included dose escalation in which B7-H4-unselected patients with advanced solid tumors were treated with FPA150 at doses between 0.01 to 20 mg/kg every three weeks (Q3W) in an accelerated titration followed by 3+3 design and a separate dose exploration cohort in which B7-H4+ (H-score≥100) patients were treated at doses of 3 or 10 mg/kg Q3W with mandatory pre- and on-treatment biopsies. Results: As of 12/31/2018, 24 patients with a median of 3 prior therapies were treated with FPA150, 6 of whom were in the B7-H4+ dose exploration cohort. Seven patients from dose escalation were also retrospectively identified as B7-H4+. Most patients received FPA150 at 3 mg/kg (n=8) or 10 mg/kg (n=6). Median number of doses was 3 (range 1-11). No dose-limiting toxicities or treatment-related serious adverse events were reported, and there were no treatment-related AEs (TRAEs) leading to discontinuation of FPA150. Most TRAEs were Grade 1-2, with diarrhea and fatigue most common (16.7%). Grade 3 TRAE hypertension occurred in 1 patient. FPA150 displayed approximately dose-proportional exposure at doses ≥0.3 mg/kg with half-life of 1-2 weeks. Conclusions: FPA150 monotherapy demonstrated a favorable safety profile and evaluation of anti-tumor activity is ongoing. 20 mg/kg Q3W was selected as the recommended dose. Phase 1b enrollment of FPA150 monotherapy in patients with B7-H4+ breast, ovarian and endometrial cancer began in February 2019. We will present updated safety, PK, and preliminary biomarker and efficacy data. Clinical trial information: NCT03514121.
Correlation of circulating EBV-targeted cytotoxic T lymphocyte precursors (EBV-CTLp) and clinical response following tabelecleucel (tab-cel) infusion in patients with EBV-driven disease.
Authors: Aftab Blake T. , Munson Daniel , Rasor Kevin , Foubert Philippe , Tsai Donald Edward , Weng Wen-Kai , Ghobadi Armin , Van Besien Koen , Sun Yan , Hiremath Minoti , Navarro Willis H. , Prockop Susan
Published: May 2019

2532

Background: EBV is implicated in a variety of diseases. Tab-cel is an investigational off-the-shelf, allogeneic T-cell immunotherapy utilizing endogenous T cell receptors targeting EBV antigens. We hypothesized the clinical activity of tab-cel is mediated by expansion and persistence of EBV-specific T cells. Therefore, we quantified circulating EBV- CTLp after tab-cel administration and examined the correlation between expansion and clinical response. Methods: Samples from 10 patients with EBV+ post-transplant lymphoproliferative disease (PTLD) and other EBV-associated diseases enrolled in an multicenter expanded access protocol (EAP) study ( NCT02822495 ) were analyzed. To evaluate CTLp frequencies, limited dilution analysis was performed on samples taken at baseline and day 34 post first tab-cel dose (end cycle 1). The day 34 persistence of circulating EBV-CTLp from best overall response to initial tab-cel product was tested using the two-tailed Mann-Whitney test. Changes in inflammatory cytokines were also measured. Results: Responders represented in this sampling (n=6; 2 PR and 4 CR) showed a median 5.8-fold increase in circulating CTLp between baseline and day 34 (range: 0.8 to 133-fold). Five of 6 responders showed an increase in EBV-CTLp at day 34 of ≥ 3.8-fold while 1 pt showed no change in CTLp (0.8-fold change). In contrast, the 4 non-responders (3 SD; 1 PD) showed a median 0.3-fold decrease in EBV-CTLp from baseline (range: 1.2 to 0.02-fold; ns). Cumulative analyses revealed a statistically significant correlation between the fold-change of circulating CTLp at day 34 and clinical response (p=0.038) which did not appear to correlate with the type of the EBV-associated disease. Inflammatory cytokines showed no meaningful change from baseline. The safety profile remains consistent with previously reported data. Conclusions: These data support the correlation of clinical activity of tab-cel with the expansion and persistence of EBV-specific T-cells at day 34 post-treatment, as well as the use of circulating CTLp as a biomarker for response in clinical studies. Clinical trial information: NCT02822495.
Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma.
Authors: Jazaeri Amir A. , Zsiros Emese , Amaria Rodabe Navroze , Artz Andrew S. , Edwards Robert P. , Wenham Robert Michael , Slomovitz Brian M. , Walther Axel , Thomas Sajeve Samuel , Chesney Jason Alan , Morris Robert , Matsuo Koji , Gaillard Stephanie , Rose Peter Graham , Donas Jesus Garcia , Tromp Jacqueline Maria , Tavakkoli Fatemeh , Li Huiling , Fardis Maria , Monk Bradley J.
Published: May 2019

2538

Background: There is a high unmet medical need for effective treatments for patients with recurrent, metastatic, or persistent cervical cancer. Most patients are young and survival rates are poor. ORR for second line therapies is between 4 and 14% for chemotherapy and recently approved immunotherapy. Adoptive cell transfer using tumor infiltrating lymphocytes (TIL) have demonstrated durable responses in some patients with recurrent cervical cancer thus offering the potential for long-term disease control. Methods: Study C-145-04 is an ongoing, open-label, multicenter Phase 2 clinical trial evaluating the safety and efficacy of LN-145 TIL therapy in patients with advanced cervical cancer who have undergone at least one prior line of chemotherapy. Prior checkpoint inhibitor therapy is an exclusion criterion. The primary endpoint is ORR per RECIST 1.1; secondary endpoints include duration of response (DOR), disease control rate (DCR), and LN-145 safety. Tumors surgically harvested at local institutions are shipped to central GMP facilities for TIL generation in a 22-day manufacturing process. Final LN-145 TIL product is cryopreserved and shipped to sites. Patients receive one week of preconditioning lymphodepletion (cyclophosphamide, fludarabine), a single LN-145 infusion, followed by up to 6 doses of IL-2 (600,000 IU/kg). Results: As of 4 Feb 2019, 27 efficacy-c patients have received Gen 2 of LN-145, with a mean age of 47 years and 2.6 mean prior lines of therapy. Preliminary efficacy results: ORR was 44% (1 CR, 9 PR, 2 uPR), DCR was 89% at 3.5-month median study follow-up with 11/12 patients maintaining their response. Improved responses were observed in 4 patients with longer follow-up. Mean TIL cells infused was 28x109. Median IL-2 doses administered was 6.0. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. Conclusions: LN-145 results in 44% ORR in previously treated cervical cancer patients with acceptable safety and efficacy profile. LN-145 offers patients a viable therapeutic option warranting further investigation. Clinical trial information: NCT03108495.
Development of a baseline prognostic cytokine signature that correlates with nivolumab (NIVO) clearance (CL): Translational pharmacokinetic/pharmacodynamic (PK/PD) analysis in patients with renal cell carcinoma (RCC).
Authors: Wang Rui , Shao Xiao , Zheng Junying , Ishii Yuko , Pak Irene , Roy Amit , Bello Akintunde , Lee Richard , Zhang Joshua , Wind-Rotolo Megan , Feng Yan
Published: May 2019

2544

Background: CL of checkpoint inhibitors has been identified as a predictive covariate of overall survival (OS) in several tumors. Determination of CL requires post-treatment samples, which negates its utility as a baseline prognostic biomarker. This study aims to identify a baseline composite cytokine signature that correlates with NIVO CL in patients with RCC using translational PK/PD analysis. Methods: Peripheral serum PK (NIVO CL) and serum biomarkers to assess PD (Myriad Rules-Based Medicine customized inflammatory cytokine panel) were analyzed from 985 patients with RCC enrolled in 3 clinical trials. CheckMate (CM) 009 (NCT01358721) and CM 025 (NCT01668784) of NIVO (n = 481) were used for model development (training dataset). CM 010 (NCT01354431) of NIVO and a cohort treated with everolimus in CM 025 were included in model application (test dataset; n = 504). PK/PD analyses were conducted using a machine learning algorithm with performance assessed by receiver operating characteristic (ROC) curve and accuracy by confusion matrix. Results: The model selected the top-10 baseline inflammatory cytokines to form a composite cytokine signature, which predicted NIVO CL (high vs low) that was significantly associated with OS (p < 0.001) across all 3 studies (training and test datasets). The same cytokine features were associated with OS of everolimus (p < 0.01), suggesting the potential prognostic nature of the composite signature. The PK/PD analysis provided a robust description of the association between selected cytokines and CL (ROC = 0.71). Identified cytokines (eg, serum C-reactive protein known to reflect immune cell modulation) have been shown individually to be associated with RCC prognosis. A multivariable approach resulting in tumor-specific composite signatures may provide more accurate prognostic value. Conclusions: The baseline composite cytokine signature could serve as a clinically useful biomarker for patients with RCC, pending further evaluation, as it may provide improved prognostic accuracy for long-term clinical outcome compared to individual cytokines.
CD4+ T-cell immunity predicts long-lasting antitumor immunity after PD-1 blockade therapy.
Authors: Kaira Kyoichi , Yamaguchi Ou , Yoshimura Kenichi , Mouri Atsuto , Shiono Ayako , Nishihara Fuyumi , Miura Yu , Shinomiya Shun , Hashimoto Kosuke , Murayama Yoshitake , Kitano Shigehisa , Kobayashi Kunihiko , Kagamu Hiroshi
Published: May 2019

2545

Background: Patients treated with programmed cell death 1 (PD-1)-blockade therapy fall into 3 distinct subgroups: non-responders presenting early disease progression, long survivors who achieve durable disease control, and the remaining short-term responders. We reported that the prediction formula comprised of the percentages of CD62L-downregulated (CD62Llow) and CD25+FOXP3+CD4+T cells in the peripheral blood predicted non-responders of non-small cell lung cancer patients (n = 50) scheduled to receive anti-PD-1-antibody (nivolumab) therapy in the 2017 ASCO meeting. In this study, we included 171 patients with NSCLC who were scheduled for nivolumab treatment after obtaining written informed consent. Peripheral blood mononuclear cells (PBMC) were examined before and after Nivolumab therapy up to 2 years to investigate the differences between long survivors and short-term responders. Methods: The patients received Nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks. Tumor response was assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, at week 8 and every 8 weeks thereafter. PBMCs were analyzed with a 18-color microfluorometer, LSR Fortessa and a masscytometer, CyTOF. Results: The responder-type patient group whose prediction formula values were greater than 192 showed significantly longer PFS ( P< 0.0001) and OS ( P< 0.0001). The long survivors who consisted of tail plateau of PFS exhibited significantly more CD62LlowCD4+T cells than the short-term responders as pre-existing immunity. The remaining responders kept significantly higher percentages of CD62LlowCD4+T cells ( P= 0.0088) and prediction formula values ( P= 0.017) than the patients with acquired resistance. Conclusions: The pre-existing CD4+T cell balance between primed effector and regulatory T cells correlated with anti-PD-1 therapy response. Further, CD62Llowcell-dominant CD4+T cell immunity was required to maintain durable antitumor reactivity induced by anti-PD-1 antibody therapy. These results have important clinical implication, as they support anti-PD-1 therapy provision to all potentially responding patients and pave the way for new treatment strategies for patients with distinct CD4+T cell immune statuses. Clinical trial information: UMIN000020719.
Severe immune-related adverse events in anti-PD-1-treated patients are clustered into distinct subtypes by peripheral blood T-cell profiles.
Authors: Kim Kyung Hwan , Cho Jinhyun , Hur Joon Young , Ku Bo Mi , Koh Jiae , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju , Shin Eui-Cheol
Published: May 2019

2564

Background: Although anti-programmed death-1 (PD-1) treatment has shown remarkable anti-tumor efficacy, immune-related adverse events (irAEs) develop with heterogeneous clinical manifestations. Immunological understanding of irAEs is currently limited. In the present study, we analyzed peripheral blood T cells obtained from cancer patients who received anti-PD-1 treatment to determine the immunological characteristics of severe irAEs. Methods: This study included 31 patients with refractorythymic epithelial tumor (TET) who were enrolled in a phase II trial of pembrolizumab (NCT02607631) and 60 patients with metastatic non-small cell lung cancer (NSCLC) who received pembrolizumab or nivolumab. T-cell profiling was performed by multi-color flow cytometry using peripheral blood obtained immediately before treatment and 7 days after the first dose of anti-PD-1 antibodies. Results: Severe irAEs (≥ grade 3) occurred in 7 TET patients (22.6%) and 6 NSCLC patients (10.0%). Patients with severe irAEs exhibited a significantly lower fold increase in the frequency of effector regulatory T (eTreg) cells after anti-PD-1 treatment, higher ratio of T helper-17 (Th17) and T helper-1 cells at baseline, and higher percentage of Ki-67+cells among PD-1+CD8+T cells post-treatment. In clustering analysis, patients with severe irAEs were grouped into four distinct subtypes: Th17-related, TNF-related,Treg-related, and CD8-related. Conclusions: Severe irAEs after anti-PD-1 treatment were clustered into four immunological subtypes, indicating that development of severe irAEs is not attributed to a single mechanism. Further investigations in larger cohorts are needed to validate our current findings.
Organ dysfunction (dys) and clinical outcomes in patients (pts) treated with immune checkpoint inhibitors (ICIs).
Authors: LIU QI , Sharon Elad , Zineh Issam , Xie Diqiong (Joan) , Baxi Shrujal S. , Liu Chao , Zhi Jizu , Torres Aracelis Z. , Gossai Anala , Sridhara Rajeshwari , Booth Brian , Blumenthal Gideon Michael , Huang Shiew-Mei , Khozin Sean
Published: May 2019

2569

Background: ICIs (anti-PD-L1/PD-1/CTLA-4) are approved in multiple cancers. The impact of organ dys on the pharmacokinetics of ICIs is known, but associated clinical outcomes are not well characterized. We compared real-world (rw) clinical outcomes in ICI-treated pts by liver and renal function. Methods: This retrospective study used longitudinal, patient-level data from community practices in the Flatiron Health electronic-health record (EHR)-derived database. We included pts diagnosed with advanced cancers (NSCLC, renal cell, melanoma, gastric/esophageal, or head and neck) on or after 1/1/2011, treated with an ICI with follow-up through 12/31/2018 and with baseline liver or renal function results in the EHR ≤30 days prior to ICI start. Organ function was stratified as normal, mild, moderate, or severe dys based on NCI CTCAE. We computed unadjusted median estimates for rw time to treatment discontinuation (rwTTD) for any reason and overall survival (OS) across baseline groups using the Kaplan-Meier method. Results: Of 15,979 pts, we identified 12,978/12,840 pts with evaluable renal/liver function, respectively; median follow-up was 5.1 mos and median age was 69.0 yrs (IQR: 61.0, 76.0) for both. Most pts had NSCLC (69.4/69.0%), were men (60.1/60.0%), white (73.5/73.6%), and diagnosed at stage IV (58.7%/58.6%). Most ICI was given in 1st-line (42.3/42.1%) (outcomes in Table). Conclusions: Pts with categorically worse baseline liver function had progressively worse on-treatment outcomes, including shorter OS, which differed from trends in renal dys. Whether baseline dys is prognostic or predictive of ICI outcomes should be further investigated in addition to reasons for discontinuation. Clinical outcomes (unadjusted median times, mos [95% CI]) by organ function. [Table: see text]
Neoadjuvant presurgical PD-1 inhibition in oral cavity squamous cell carcinoma.
Authors: Horton Joshua Dean , Knochelmann Hannah , Armeson Kent , Kaczmar John M. , Paulos Chrystal , Neskey David
Published: May 2019

2574

Background: Oral cavity squamous cell carcinoma (OCSCC) is a highly prevalent surgically-treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer, but has not been validated in the neoadjuvant presurgical setting. Methods: A Simon two stage design was used in this single-arm, Phase II clinical trial with a preplanned analysis after completion of stage one. The first stage included 9 patients with stage II-IVA OCSCC who received 3-4 biweekly doses of 3mg/kg Nivolumab (anti-programmed death 1 [PD-1]) followed by definitive surgical resection for cure. The primary endpoint was overall response rate to treatment. Secondary endpoints were safety and feasibility. Results: Presurgical Nivolumab therapy resulted in an overall response rate of 44% (95% CI: 14-79%) with four patients having >30% reduction in tumor size consistent with partial response. An additional patient had stable disease while the remaining four patients progressed through treatment. Neoadjuvant Nivolumab was not associated with delays in definitive surgical treatment. There were no grade 3-4 adverse events and no treatment interruptions. At median follow up of 10 months (2-16), there were 4 recurrences in 3 patients and one death. Objective response by RECIST 1.1 criteria on interval imaging predicated eventual pathologic response in 100% of patients. Conclusions: Neoadjuvant presurgical PD-1 blockade is associated with encouraging response rate and demonstrates feasibility and safety for OCSCC. Clinical trial information: NCT03021993.
A donor-dependent in vivo model for single agent and drug combination cytokine release syndrome safety evaluation.
Authors: Keck James G. , Cheng Mingshan , Brehm Michael , Greiner Dale , Shultz Lenny J. , Rueter Jens , Ye Chunting
Published: May 2019

2612

Background: Although antibodies and CART cells therapies have been successfully used for cancer therapy, they can have lethal adverse effects such as cytokine release syndrome (CRS). The animal models and in vitro human PBMC assays presently in use can’t reliably predict the CRS in patients. A predictive marker for identifying patients at risk for developing CRS upfront would improve the safety of immune-oncology drug development. Methods: We have developed a rapid, sensitive and reproducible in vivo humanized mouse model for quantitating CRS. The NSG mouse and its derivatives are engrafted with human PBMCs. On day 6 we induced cytokines release with pembrolizumab, avelumab, atezolizumab, ipilimumab, anti-CD28, ATG and OKT3 in single dose; as well as combination treatments involving pembrolizumab, lenalidomide, ATG and anti-CD28. Furthermore, we compared our method versus the in vitro PBMC assay. The cytokine levels were also compared to the dose response. Results: There are about 10-15% CD45+ human cells on day 5 of engraftment; and among of them, there were approximately 70% CD3 T cells and 25% CD56 NK cells. All tested cytokines, human IFN-γ, IL-2, IL-4, IL-6, IL-10 and TNF were upregulated after 2 and 6 hours of OKT3, ATG, anti-CD28, pembrolizumab, avelumab and atezolizumab drug treatment. Mouse’s rectal temperatures dropped from 37-38 °C to about 36 °C at 6 hours’ time point in the treated groups. There is various cytokines release levels, low to high response in different donors with anti-CD28 treatment. All donors showed high response to OKT3. The cytokine release levels were consistent with a dose response or variable PBMC engraftment. The cytokine levels were also higher in some drug combination studies such as pembrolizumab combined with lenalidomide or ATG; anti-CD28 combined with ATG. Our in vivo method was able to determine CRS missed in the in vitro testing method. Conclusions: We have developed a rapid, sensitive and reproducible novel in vivo PBMC humanized mouse model that is able to differentiate human PBMC donors based on individual safety response to single agent and combination therapeutics of immune checkpoint inhibitors and possibly CAR-T therapy. This assay could be employed in future drug development.
Interleukin-6 is potential target to de-couple checkpoint inhibitor-induced colitis from antitumor immunity.
Authors: Johnson Daniel H. , Hailemichael Yared , Foo Wai Chin , Hess Kenneth R. , Haymaker Cara L. , Wani Khalida M , Lazar Alexander J. , Saberian Chantal M , Bentebibel Salah E , Burton Elizabeth M. , Abu-Sbeih Hamzah , Wang Yinghong , Hwu Patrick , Diab Adi
Published: May 2019

2616

Background: A deep understanding of the immunobiology of checkpoint inhibitor (CPI) induced immune related toxicities, such as immune related enterocolitis (irEC), and how these compare to the immune signatures in tumors could lead to the development of strategies that de-couple autoimmunity from anti-tumor immunity. Methods: Total RNA from patient-matched irEC and normal colon FFPE tissue from patients [n = 12] receiving CPIs were profiled with the 770 gene NanoString nCounter PanCancer Immune Profiling Panel (NanoPCIP). The mean fold change in gene expression from normal vs. irEC inflamed colonic tissue and baseline vs. on-treatment tumor samples from patients responding or non-responding to ipilimumab based therapy were analyzed. C57BL/6 mice with B16.BL6 melanoma tumors were treated with systemic anti-IL-6 + anti-CTLA-4 vs. anti-CTLA4 alone vs. placebo and tumor size was measured. Results: In patients with irEC, the highest significantly upregulated differentially expressed gene (DEG) in inflamed colon tissue encoded for IL-6 (Fold change +24.1). None of the significant and highest upregulated DEGs in the colitis, including IL-6, were significantly upregulated in responding tumors. Interestingly, IL-6 was also the highest upregulated DEG in non-responding tumors numerically. When comparing mean fold changes across these analyses, the gene with the largest difference in upregulatation between colitis and responding tumors was IL-6; the other highest upregulated genes in colitis encoded for neutrophil and monocyte chemotactic molecules. In our mouse models, the addition of IL-6 blockade to anti-CTLA-4 therapy significantly improved tumor shrinkage compared to anti-CTLA-4 alone. Conclusions: Our data demonstrates that IL-6-mediated inflammation may be more prevalent in irEC and tumors not responding to CPIs than in tumors responding, and blocking IL-6 enhances CPI anti-melanoma activity. Targeting IL-6 may ameliorate irEC without hindering anti-tumor immunity.
Frameshift mutations (Fsindel) complement tumor mutation burden (TMB) in predicting survival after immune checkpoint inhibitors (ICI) in a pancancer analysis.
Authors: Florou Vaia , Park Wungki , Hosein Peter Joel , Wilky Breelyn A. , Trent Jonathan C. , Lopes Gilberto
Published: May 2019

2617

Background: ICI benefit certain patients (pts) with various malignancies and discovering biomarkers for response is an active research field. Recently, higher TMB (top 20% in each histology) based on nonsynonymous single nucleotide variants from MSK-IMPACT was shown to correlate with superior survival in a pancancer cohort. Fsindels may generate more immunogenic neoantigens and robust T cell infiltrates, thus predicting better responses to ICI. We previously demonstrated the clinical implication of fsindel in lung cancer pts on ICI. However, its value in other solid cancers has not been evaluated. Methods: Comprehensive genomic profiling (CGP) of the tumors was performed by FoundationOne to derive fsindel and TMB as previously described. Pts with advanced solid cancers who received ICI and had CGP available were included. We categorized pts into two groups; 0 fsindel (FS-) and more than 1 fsindel (FS+). Also, they were categorized into TMB high (top 20%) and TMB low (bottom 80%) within their own histology. Progression free survival (PFS) and overall survival (OS) were compared. Results: One hundred thirty-one pts excluding lung cancer were included. There were 11 histology groups: 14 soft tissue sarcomas, 19 GU, 23 GI, 23 skin, 10 HEENT, 10 RCC, 9 GYO, 6 pancreas, 5 mucosal melanoma, 4 breast, and 8 others. 74 pts received pembrolizumab, 25 nivolumab, 29 ipilimumab/nivolumab, and 3 atezolizumab. All pts had metastatic disease, mean age was 61 years and 55 (42%) were women. Among the 131 pts, 74 were FS- and 57 FS+. The presence of fsindel (FS+) was significantly correlated with overall response (p = 0.032) and clinical benefit rates (p = 0.025). TMB-high did not show any significant difference in PFS (p = 0.1) or OS (p = 0.28) when compared to the TMB low. However, in a combined model of TMB and fsindel, TMB high and FS+ patients had significantly better PFS compared to patients who had either TMB high or FS+ or neither (TMB low and FS-) (p = 0.021). Conclusions: Combined model of TMB high and fsindel (+) correlated with superior PFS in advanced solid cancer pts on ICI, in concordance with previous report for lung cancer. Validation in a larger cohort is underway.
Effect of subcutaneous multipeptide active antigen-specific immunotherapy at lymph nodes and tumor sites on clinical outcomes in progressive tumors.
Authors: Marquez-Manriquez Juan Pablo , Lucero-Diaz Pedro Alejandro , Matute-Briseno Jose Antonio , Camacho-Hernandez Alejandro , Gallardo-Rincon Dolores
Published: May 2019

2636

Background: The tumor and lymph nodes (LN) microenvironment clinically speaking are mainly unexplored and there are limited clinical studies of immunotherapeutic approaches manipulating those in progressive cancer patients. The tumor and LN microenvironment offers an opportunity to treat locally with multi-peptide immunotherapy in challenging clinical situations where we can have still a potential safe and effective therapeutic approach using the concept treat locally treat systemically. Methods: N = 11 patients were enrolled after the local IRB ethic committee approved the pilot clinical study number CICS/SS/0035. Previous identified targets such as FAP, b-2-microglobulin, Fascin, RCAS1/EBAG9, Bcl-2, survivin, Sox2, Ape-1, Valosin containing-protein (VCP) and EGFR were analyzed by IHC, Th1 and CD8 long-peptides were predicted, immune assays using PBMCs including tumor microenvironment were performed to detect Granzyme B by ELISPOT, naturally processed epitopes by T-cell expansion and cytokines. Patients were treated subcutaneously (S.C.) eight times in the axillary and inguinal LN area one week apart. Afterwards we treated S.C. as well but now in the areas with tumor activity according with the CT or PET every week 10 times. Initial DTH and at the end of the treatment was performed. Pathological, clinical and immunological correlations were made using multivariate analysis. Results: Despite progressive disease 100% of the patients responded to the treatment. 80% had CR and 20% pseudo-progression and then CR. 100% of the patients increased the levels of Granzyme B against Bcl-2 (p = 0.001), VCP (p = 0.0001), Ape-1 (p = 0.005) and RCAS1 (P = 0.0001) and this correlated with the scans post-treatment. The patients showed more CD8 infiltration in the DTH test at the tumor site (p = 0.002) than in the non-tumor site (p = 0.01). The number of metastatic lesions in lungs (p = 0.004) and hepatic tissue (p = 0.001) disappeared and correlated with increased levels of IL-12 production in vivo. Conclusions: Treating immunologically the LN and the microenvironment of the areas with tumor activity is a feasible and safe approach to limit systemic toxicity and improve the clinical outcomes in patients with progressive cancer including bone sarcoma, epithelial ovarian cancer, PDAC, pediatric sarcomas and TNBC.
Immunogenicity and tolerability of personalized mRNA vaccine mRNA-4650 encoding defined neoantigens expressed by the autologous cancer.
Authors: Cafri Gal , Gartner Jared J. , Hopson Kristen , Meehan Robert S. , Zaks Tal Z. , Robbins Paul , Rosenberg Steven A.
Published: May 2019

2643

Background: Therapeutic vaccination against cancer has proven very challenging with little clinical benefit. Vaccines against non-viral tumors have mainly targeted differentiation antigens, cancer testis antigens, and over-expressed antigens. However, negative selection in the thymus against these normal non-mutated antigens severely limits the ability to generate high avidity anti-cancer T-cells. The importance of neoantigens to each patient’s unique cancer as targets for immunotherapy has been extensively studied, by our group and others. It is now clear that neoantigen-specific T-cells are present in most cancers and these neoantigens derived from somatic mutations offer a specific and highly immunogenic target for personalized vaccination. We developed a process to identify immunogenic T-cell epitopes derived from tumor-specific mutations using tumor-infiltrating lymphocytes. Methods: We combined, for the first time, validated defined neoantigens, predicted neoepitopes and mutations in driver genes into a single mRNA concatemer (mRNA-4650) to vaccinate patients with metastatic common epithelial cancers. We are conducting a phase I/II trial in patients with metastatic melanoma, gastrointestinal, or genitourinary cancers with at least one lesion that is resectable. Patients must have an ECOG status of ≤1 with adequate organ and bone marrow function. Patients are vaccinated intramuscularly at two-week intervals for four cycles, and dosing may be repeated for a second course of vaccination. Key primary endpoints are safety, tolerability and the development of T-cell reactivity as well as objective response rate. Results: mRNA-4650 is safe at all dose levels studied to date with no reported DLTs or drug related SAEs. Neoantigen specific CD8 and CD4 T cells responses against neoepitopes included in the vaccine have been observed and no tumor regressions were seen. Conclusions: Our data show that such a personalized mRNA vaccination is feasible and can elicit neoantigen specific T cell responses. Combination of vaccines with checkpoint inhibitors or adoptive T cell therapy can open the possibility to develop effective immunotherapies for patients with the common epithelial cancers. Clinical trial information: NCT03480152.