bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic profiling of breast cancer brain metastases reveals targetable alterations.
Authors: Kabraji Sheheryar Kairas , Spurr Liam F. , Hughes Melissa E , Li Yvonne Y. , Leone Jose Pablo , Garrido-Castro Ana Christina , Barroso-Sousa Romualdo , Files Janet , Kirkner Gregory , Johnson Bruce E. , Winer Eric P. , Cherniack Andrew D. , Lin Nancy U.
Published: May 2020

2525

Background: Genomic characterization of breast cancer brain metastases (BCBMs) has thus far been limited. The objective of this study was to describe the landscape of genomic alterations in patients (pts) with BCBMs. Methods: Targeted next-generation DNA sequencing of > 300 cancer-related genes (OncoPanel) was prospectively performed on primary and metastatic (met) tumors in 321 pts with a diagnosis of BCBM between August 2016 and April 2019 at Dana-Farber Cancer Institute (table). Enrichment analysis of genomic alterations was performed using a two-sided Fisher exact test and differences in tumor mutation burden (TMB) between groups were assessed using two-sided Mann-Whitney U test. Multiple comparison correction was performed using the Benjamini-Hochberg procedure. Results: All subtypes were represented in BCBM (25 HR+/HER2-; 24 HR+/HER2+; 27 HR-/HER2+; 18 TNBC; 5 unknown; n = 99) and extracranial (EC) samples: (96 HR+/HER2-; 32 HR+/HER2+; 22 HR-/HER2+; 41 TNBC; 31 unknown; n = 222). BCBMs were found most commonly to have mutations or copy number alterations in TP53, ERBB2, PIK3CA, GATA3, PTEN, ESR1, CDH1, BRCA2, ARID1A, BRCA1 (>5% frequency, table). Two pts acquired ERBB2 amplification (amp) between the matched primary breast sample and brain met. In pair-wise comparisons of BCBMs to unmatched primaries or EC mets, only ERBB2 amp was significantly enriched (table, † = adjusted p < 0.05). There was no significant difference in TMB between BCBM and EC mets (median 9.12 vs 7.26, p = 0.15). In contrast, TMB was significantly higher in BCBMs compared to unmatched primaries (median 9.12 vs 7.26, p=0.005). Conclusions: BCBMs display similar mutations and copy number alterations compared to primary tumors and EC mets in pts with BCBM. These data suggest that BCBMs contain actionable genomic alterations that are most often also reflected in EC disease. Alterations in ERBB2, PIK3CA/PTEN, and BRCA1/2 represent potentially targetable alterations in pts with BCBM. [Table: see text]
A phase I clinical trial on intratumoral and intracavitary administration of ipilimumab and nivolumab in patients with recurrent glioblastoma.
Authors: Schwarze Julia Katharina , Duerinck Johnny , Dufait Ines , Awada Gil , Klein Samuel , Fischbuch Lydia , Seynaeve Laura , Vaeyens Freya , Rogiers Anne , Everaert Hendrik , Vanbinst Anne-Marie , Michotte Alex , Neyns Bart
Published: May 2020

2534

Background: Intravenous (IV) administration of ipilimumab (IPI) and nivolumab (NIVO) has low activity in recurrent glioblastoma (rGB). Intratumoral (IT) and intracavitary (IC) administration of IPI and NIVO is under evaluation in the GlITIpNi phase I clinical trial. Methods: Patients (pts) with resectable rGB were recruited to cohorts C1, C2 and C4; pts with non-resectable rGB were recruited in C3 (biopsy only). IT administration (brain tissue lining the resection cavity during surgery) of IPI (10 mg)(C1), or IPI (5 mg) plus NIVO (10 mg)(C2, C3 and C4), was followed by IC administration of NIVO at escalating doses of 1, 5 or 10 mg Q2w in both C3 and C4 (via an Ommaya reservoir). In all cohorts, pts received 10 mg NIVO IV Q2w (6x in C1/C2, and 12x in C3/C4). Corticosteroids were contraindicated. Results: Forty-six pts (31 male; median age 56y (38-74); IDH1 R132H mutation in 2 pts in C1/C2; NGS somatic mutation analysis for C3/C4 ongoing) with rGB following resection, RT and temozolomide were enrolled (3, 24, 13 and 6 pts in C1, C2, C3 and C4, respectively). All pts received IT administrations. Pts in C1/C2 received a median of 5 IV NIVO administrations. Study treatment has been completed in all pts in C1/C2, in 9 pts in C3, and in 3 pts in C4; pts received a median of 4 (0-10) and 3 (0-7) postoperative IC/IV administrations in C3 and C4, respectively. Two pts in C2 and 1 pt in C3 had an increased perilesional cerebral edema (G3) with neurological deterioration after surgery/IT-injection, that was reversible with steroids. Most frequent AE were fatigue (32 pts, 64%), fever (20 pts, 44%), and headache (25 pts, 50%). In 4 pts from C3, the Ommaya was removed because of bacterial colonization (asymptomatic). There were no G5 AE. There was no dose/AE correlation with increasing IC NIVO doses in C3/C4. Repetitive CSV analysis during therapy (C3/C4) revealed increased lymphocyte counts in 4 pts; scRNA- and TCR-sequencing is ongoing. Gene expression profiling for C1/C2, and pharmacokinetic analysis of NIVO and IPI in CSV for C3/C4 are ongoing. After a median FU of 62w (16-165) for pts in C1/C2, 16 pts have died; median OS is 71w (95% CI 8-134), 1- and 2y-OS% are respectively 51% (95% CI 31-71), and 34% (95% CI 10-59). OS compares favorably to a historical cohort of Belgian rGB pts (n = 469; Log-Rank p .001). After a median FU of 10w (1-37) for pts in C3/C4, 2 pts have died; median OS has not been reached. One pt in C3 achieved a PR that is ongoing at 12m. Conclusions: IT/IC administration of NIVO and IPI is feasible and sufficiently safe to warrant further investigation in pts with rGB. Clinical trial information: NCT03233152 .
Defining the prognostic role of MGMT methylation value by pyrosequencing assay in glioblastoma patients: A large Italian multicenter study.
Authors: Lombardi Giuseppe , Simonelli Matteo , Bellu Luisa , Villani Veronica , Rizzato Simona , Ius Tamara , Pasqualetti Francesco , Russo Marco , Franchino Federica , Rosina Amoroso , Bertorelle Roberta , Cavallin Francesco , Dipasquale Angelo , Carosi Mariantonia , Pizzolitto Stefano , Cesselli Daniela , Gardiman Marina Paola , Caccese Mario , Padovan Marta , Zagonel Vittorina
Published: May 2020

2539

Background: MGMT methylation (MGMTmet) status represents an important prognostic factor for glioblastoma (GBM) patients (PTS). Quantitative pyrosequencing approach has proven to be feasible for MGMTmet testing but its value is still unclear. We performed a large, multicentre, retrospective study to identify the association between MGMTmet values and clinical outcome. Methods: from 9 Italian neuro-oncology centres, we collected consecutive GBM PTS with assessment of MGMTmet by pyrosequencing approach evaluating CpG islands from 75 to 84. Other inclusion criteria were: histological diagnosis of GBM, ECOG PS ≤2, therapy with RT+TMZ. Kaplan-Meier method was used to estimate the survival curves, time-dependent ROC curve for defining the optimal cut-off value of mean percentage of MGMTmet in terms of 2y-OS, Cox regression for multivariable analysis, and restricted cubic spline to investigate the non-linear association between methylation values and OS. Results: 681 PTS were enrolled; median age was 60 ys; ECOG PS was 0 in 292 PTS, 1 in 306 PTS, 2 in 83 PTS; 391 PTS (58%) had a complete resection. 8% of PTS received a second surgery. IDH was mutated in 6%. 2y-OS was 31.6%, median OS was 17.4 ms. Median MGMTmet was 3.5% (IQR 0-22%). ROC curve identified a cutoff of 15% of MGMTmet in terms of 2y-OS (sens 78%, spec 57%, AUC = 0.67). 2y-OS was 19.7% and 53.7% for PTS with MGMTmet < and ≥15%, respectively (p < 0.0001). At multivariable analysis, MGMTmet < 15% was associated with impaired survival (HR 2.7, 95% CI 2.1-3.4; p < 0.00001), adjusting for age, KPS, type of surgery and second surgery. A non-linear association between MGMT methylation and survival was identified (non-linear term: p < 0.0001), with lower values of MGMT methylation associated with lower survival; indeed, estimated median OS was lowest (14 months, 2ys-OS: 17.4%) with MGMTmet of 4%, 21ms (2yr-OS: 40.9%) with MGMTmet of 20%, 27ms (2yr-OS: 40.9%) when MGMTmet was 40%, then leveled around 30ms (2yr-OS: 54.5-59.8%) when MGMTmet was > 40%. Conclusions: this study represents one of the largest trials analyzing MGMTmet by pyrosequencing approach. Lower values of MGMTmet were associated with impaired survival and the relationship was non-linear. Noteworthy, we identified a strong prognostic value of MGMTmet which could be used as stratification factor in prospective clinical trials
Superior therapy response predictions for patients with low-grade glioma (LGG) using Cellworks Singula: MyCare-009-04.
Authors: Ahluwalia Manmeet Singh , Watson Drew , Kapoor Shweta , Parashar Rajan , Ghosh Roy Kunal Ghosh , Alam Aftab , Rajagopalan Swaminathan , Tyagi Anuj , Sahu Diwyanshu , Suseela Rakhi Purushothaman , Ganesh Naga , Nair Prashant , Birajdar Shivgonda , Raju Karthik Sundara , Gopi Reshma , G Poornachandra , Gupta Neha , Lunkad Neelesh , Patil Vivek , Wen Patrick Y.
Published: May 2020

2569

Background: Despite using cytogenetic and molecular-risk stratification and precision medicine, the current overall outcome of LGG patients remains relatively poor. Therapy selection is often based on information considering only a single aberration and ignoring other patient-specific omics data which could potentially enable more effective treatments. The Cellworks Singula report predicts response for physician prescribed therapies (PPT) using the novel Cellworks Omics Biology Model (CBM) to simulate downstream molecular effects of cell signaling, drugs, and radiation on patient-specific in silico diseased cells. We test the hypothesis that Singula is a superior predictor of progression-free survival (PFS) and overall survival (OS) compared to PPT. Methods: Singula’s ability to predict response was evaluated in an independent, randomly selected, retrospective cohort of 137 LGG patients aged 14 to 73 years treated with PPT. Patient omics data was available from TCGA. Singula uses PubMed to generate protein interaction network activated and inactivated disease pathways. We simulated the PPT for each patient and calculated the quantitative drug effect on a composite LGG disease inhibition score based on specific phenotypes while blinded to clinical response. Univariate and multivariate proportional hazards (PH) regression analyses were performed to determine if Singula provides predictive information for PFS and OS, respectively, above and beyond age and PPT. Results: In univariate analyses, Singula was a significant predictor of both PFS (HR = 3.587, p < 0.0001) and OS (HR = 3.044, p = 0.0007). In multivariate PH regression analyses, Singula (HR = 3.707, p < 0.0001) remained an independent predictor of PFS after adjustment for PPT (p = 0.3821) and patient age (p = 0.0020). Singula (HR = 2.970, p = 0.0013) was also a significant independent predictor of OS after adjustment for PPT (p = 0.0540) and patient age (p < 0.0001). Results indicate that Singula is a superior predictor of both PFS and OS compared to PPT. Singula provided alternative standard of care therapy selections for all 34 disease progressors. Conclusions: Singula is a superior predictor of PFS and OS in LGG patients compared to PPT. Singula can correctly identify non-responders to PPT and provide alternative therapy selections.
Safety and efficacy results of GC027: The first-in-human, universal CAR-T cell therapy for adult relapsed/refractory T-cell acute lymphoblastic leukemia (r/r T-ALL).
Authors: Wang Xinxin , Li Shiqi , Gao Lei , Yuan Zhongtao , Wu Kun , Liu Lin , Luo Le , Liu Yao , Zhang Cheng , Liu Jia , Yang Chunhui , Li Yu , He Jiaping , Ye Xun , Li Zhimin , Tan Xu , Ge Jianning , Cao Wei , Wang Sanbin , Zhang Xi
Published: May 2020

3013

Background: Patients with r/r T-ALL usually have high relapse and mortality rates. Due to shared common surface antigen and potential contamination by malignant cells, development of autologous CAR-T therapies for r/r T-ALL has been lagged, regardless of the costly and lengthy process of autologous CAR-T production. Through targeting CD7, a common T cell antigen highly expressed in >95% T-ALL samples, universal CAR-T product GC027 has been developed using lentivirus and CRISPR/Cas9 system with demonstrated anti-leukemia ability in a murine xenograft model. Methods: Preliminary safety, anti-leukemic activity and expansion kinetics of GC027 are being evaluated in a single-arm, open-label, multi-center, prospective study for treating adult patients with r/r T-ALL. To date, a total of 5 patients (age 19-38 yrs, median 24 yrs) were enrolled with marrow tumor load 4-80.2% (median prior lines 5). All 5 pts have received a 6-day enhanced preconditioning chemotherapy followed by a single infusion of GC027. No patient was bridged to HSCT. Adverse events, disease response, and expansion kinetics were evaluated in this study. Results: As of Feb. 6, 2020, 5 pts had received a single dose of GC027, including 1 at 0.6x107/kg, 3 at 1x107/kg, 1 at 1.5x107/kg. 3 pts achieved MRD negative complete responses (MRD- CR) at D28 evaluation and remained MRD- at follow-up re-evaluations (161, D118, 61, respectively) without bridging to HSCT. 1 pt just achieved D28 MRD- CR at time of submission. 1 pt achieved MRD+ CR at D14, but his disease progressed at D29 and deceased due to relapse. In all 4 pts with MRD- CR, peak expansions of GC027 in peripheral blood were observed between week 1-2, analyzed by flow cytometry and Q-PCR. Grade 3 cytokine release syndrome (CRS) occurred in 4 pts and Grade 4 CRS occurred in 1 pt (ASBMT Consensus Grading). CRS symptoms were manageable and resolved after treatment and supportive care. None developed neurotoxicity or GvHD. One had prolonged cytopenia due to fungal infection and required anti-fungal therapy. Conclusions: With a single infusion of GC027, 80% of the patients had robust CAR-T cell expansion and achieved persistent MRD- CR without using any biologics as part of the preconditioning therapy or bridging to HSCT. The first-in-human, universal CAR-T therapy for r/r T-ALL, GC027 has demonstrated superior clinical efficacy and induced deep response in patients with acceptable safety profile. The trial enrollment is ongoing and updated data will be presented at the meeting. Clinical trial information: ChiCTR1900025311 .
Impact of radiotherapy on risk of adverse events in patients receiving immunotherapy: A U.S. Food and Drug Administration pooled analysis.
Authors: Anscher Mitchell Steven , Arora Shaily , Weinstock Chana , Lubitz Rachael , Amatya Anup , Fiero Mallorie , Tang Shenghui , Bandaru Pradeep , Sanchez Jacquelyn , Girvin Andrew , Tang Chad , Amiri-Kordestani Laleh , Theoret Marc Robert , Pazdur Richard , Beaver Julia A.
Published: May 2020

3018

Background: Immune checkpoint inhibitors (ICIs) are widely used in the treatment of multiple advanced malignancies. Radiotherapy (RT) has been used in combination with ICIs to activate tumor-specific T cell responses, and RT also promotes non-specific acute and chronic inflammatory responses both locally and systemically. More than 50% of patients receive RT at some point during their course of cancer therapy, and relatively little information is available pertaining to the impact of RT, if any, on the risk of adverse events (AEs) in patients receiving ICIs. Methods: Pooled data from prospective trials of ICIs submitted to the FDA in initial or supplemental BLAs or NDAs through 12/2019 were included (N=66). Trials from applications that were withdrawn or not approved were not included. Patients were subdivided by whether or not radiotherapy was administered at any time during the course of their cancer treatment. AEs common to both ICI treatment and RT were identified to focus on the following reactions: neutropenia, thrombocytopenia, colitis, hepatitis, pneumonitis, and myocarditis. Descriptive statistics were used to examine AEs associated with the use of radiation and ICIs. Results: A total of 25,836 patients were identified, of which 9087 (35%) received RT and 16,749 (65%) did not. Radiation was associated with similar rates of AEs overall with numerically higher hematologic toxicities and pneumonitis and numerically lower colitis, hepatitis and myocarditis (Table). Patients receiving RT were more likely to experience Grade 3-5 hematologic toxicities compared to those not receiving RT. Conclusions: To our knowledge, this is the largest report of AE risk associated with the use of radiation and ICIs. Our results show that the incidence of hematologic toxicity and pneumonitis in patients receiving RT may be slightly higher. Analysis to determine comparability of baseline demographic characteristics, comprehensive AE profile, and timing of RT is underway. [Table: see text]
Product characteristics and pharmacological profile of KTE-X19 in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) in the phase II registrational ZUMA-2 trial.
Authors: Wang Michael , Rossi John M. , Munoz Javier , Goy Andre , Locke Frederick Lundry , Reagan Patrick Michael , Jacobson Caron A. , Hill Brian T , Holmes Houston , Jaglowski Samantha Mary , Peng Weimin , Zheng Lianqing , Fang Xiang , Xue Allen , Rao Arati V. , Bot Adrian
Published: May 2020

3023

Background: ZUMA-2 is a Phase 2 study evaluating KTE-X19, an autologous anti-CD19 CAR T cell therapy, in pts with R/R MCL (1 – 5 prior therapies, including a BTK inhibitor). In the primary efficacy analysis of ZUMA-2 (N = 60), the objective response rate was 93% (67% complete responses) and was generally comparable among high risk pts (Wang et al. ASH 2019 #754). CAR T cell levels in blood were associated with objective response (including minimal residual disease [MRD] negativity) and toxicity. Here, we describe a comparative analysis of KTE-X19 pharmacology profile in higher vs lower risk pts in ZUMA-2. Methods: Product attributes, CAR T cell and serum cytokine levels in blood, and their associations with clinical outcomes, were analyzed using previously described methods (Locke et al. Mol Ther 2017). MRD (10−5 sensitivity) was assessed by next-generation sequencing. Pharmacology data are reported for all 68 pts treated with KTE-X19 (2 × 106 cells/kg). Results: Manufactured KTE-X19 products showed a slight bias to CD8 and effector memory/effector phenotype. Median CD4/CD8 ratio was 0.7 (range, 0.04 – 3.7); T cell phenotypes included naive (median, 24.5%; range, 0.3 – 80.7), central memory (median, 12.8%; range, 2.3 – 51.6), effector memory (median, 24.5% (range, 0.8 – 70.3) and effector (median, 28.7%; range, 2.8 – 65.2). MRD negative (n = 24/29) vs positive pts (n = 5/29) at 1 mo post KTE-X19 had increased median cytokine levels, including IL-15, IL-2, IFN-γ, IL-10, and IL-6, peaking in serum within 7 days post treatment. Pts who were MRD negative by 1 mo post treatment also had increased median peak levels of Granzyme B and soluble PD-L1. Six pts developed Grade 4 neurologic events (NE), including 1 cerebral edema case; 3 had concurrent Grade 4 cytokine release syndrome. These pts had higher peak cytokine levels vs pts without Grade 4 NE, with lack of reversion to baseline by Day 28 of serum IL-6 and sVCAM-1. Peak CAR T cell in blood and serum cytokine levels were generally comparable in higher vs lower risk pts defined as TP53 mutated (n = 6/36) vs unmutated (n = 30/36), or high vs low Ki-67 proliferation index (PI; ≥ 30% [n = 40/49] and < 30% [n = 9/49]), consistent with the comparable clinical efficacy of KTE-X19 in these subgroups. Conclusions: PD profile of KTE-X19 associated with efficacy (MRD status at 1 mo) and treatment-related NE. In contrast to approved therapies, KTE-X19 showed comparable pharmacology and clinical outcomes in pts with higher vs lower risk MCL defined by TP53 mutation or Ki-67 PI. Clinical trial information: NCT02601313 .
Breast cancer grade and clinical benefit in patients with advanced breast cancer treated with an engineered whole tumor cell-targeted immunotherapy alone or in combination with checkpoint inhibition.
Authors: Williams William , Dakhil Shaker R. , Calfa Carmen Julia , Holmes Jarrod P. , Bhattacharya Saveri , Lukas Jason Jerome , Tan-Chiu Elizabeth , Peoples George Earl , Sunkari Vivekananda , Lacher Markus , Wiseman Charles L.
Published: May 2020

3033

Background: SV-BR-1 is a breast cancer cell line derived from a grade II (moderately differentiated) tumor. SV-BR-1 was transfected with the CSF2 gene (encoding GM-CSF) to form SV-BR-1-GM. SV-BR-1-GM expresses HLA class I & II antigens and has functional antigen-presenting cell activity, directly stimulating CD4+ T cells in an HLA-DR restricted fashion. The SV-BR-1-GM regimen consists of low-dose cyclophosphamide (300 mg/m2) to reduce immune suppression, intradermal inoculation with irradiated SV-BR-1-GM (20x106 cells divided into 4 sites) and interferon-α2b (10,000 IU into each inoculation site ~2 & 4 days later) to boost the response. Here, we evaluate the impact of tumor grade on clinical benefit following treatment with the SV-BR-1-GM regimen. Methods: Patients with advanced breast cancer were treated with either the SV-BR-1-GM regimen alone or with the SV-BR-1-GM regimen with pembrolizumab. For the SV-BR-1-GM regimen alone, cycles were administered every 2 weeks x 3 and then monthly, while combination with pembrolizumab (200 mg IV 1-5 days following SV-BR-1-GM inoculation) administered cycles every 3 weeks. Tumor restaging was every 6-12 weeks. Results: 33 patients were enrolled. The treatment was generally safe with inoculation site pruritis, erythema and induration the most common adverse events. 23 patients had grade III (poorly differentiated) tumors, 9 had grade II tumors and one had a grade I (well differentiated) tumor. None of the patients with grade III tumors exhibited clinical benefit. 7 patients with grade I/II tumors received the SV-BR-1-GM regimen alone, 2 received the SV-BR-1-GM regimen with pembrolizumab and 1 received both regimens. As noted in the Table, 7 patients experienced clinical benefit including all 3 patients treated in combination with pembrolizumab. This included 6 patients with stable disease and one with a partial response. Conclusions: The SV-BR-1-GM regimen with or without pembrolizumab appears safe and able to induce clinical benefit even in very heavily pre-treated patients with low or intermediate grade advanced breast cancer. Clinical trial information: NCT03328026 . [Table: see text]
A randomized phase I/IIa study to evaluate the safety and efficacy of SNK01 (non-genetically modified autologous natural killer cells with enhanced cytotoxicity) plus pembrolizumab in patients with stage IV non-small cell lung cancer.
Authors: Kim Eo Jin , Ko Dae-Hyun , Ji Wonjun , Rho Jin Kyung , Lee Jae Cheol , Song Paul Y. , Choi Chang-Min
Published: May 2020

3037

Background: Despite the increased promise of checkpoint inhibitors in the treatment of lung cancer, the overall response rate is approximately 30% with up to 30% moderate to severe side effects. Natural killer (NK) cells have recently been implicated in antitumor response to immune checkpoint inhibitors. SNK01 is a novel non-genetically modified autologous natural killer cell therapy with enhanced cytotoxicity which has been found to have tumoricidal effects against several lung cancer cell lines. Methods: 18 patients with Stage IV NSCLC (PD-L1+, EGFR-, ALK-) who all failed prior frontline platinum-based therapy were randomized 2:1 to Pembrolizumab every three weeks +/- 6 weekly infusions of SNK01 at either 2 x 109 or 4 x 109 cells per infusion. Primary endpoint is safety and secondary endpoints are objective response rate (ORR), progression-free survival (PFS), overall survival (OS), time to progression (TPP), and quality of life (QoL). Results: 14 patients have been enrolled up to date and 9 have completed treatment. Median age is 69 (52-73). Two patients discontinued treatment prior to receiving their first dose of SNK01 due to Grade 3 toxicity to Pembrolizumab. Three patients have completed therapy with Pembrolizumab alone and all had progressive disease. Three patients have completed Pembrolizumab with 2 x 109 SNK01 and three patients have completed Pembrolizumab with 4 x 109 SNK01. Of patients receiving full combination therapy, there have been no adverse events or any reported toxicity while overall QoL has been improved. The week 9 overall response rate in the combination group is 66% using iRECIST (3/6 cPR, 1/6 PR). All remaining planned patients are currently being enrolled and a full update will be presented. Conclusions: These preliminary results demonstrate that combination therapy with Pembrolizumab and SNK01 is very safe and even appears to reduce checkpoint associated toxicity while increasing overall tumor response compared to Pembrolizumab monotherapy alone in Stage IV NSCLC patients who have failed prior platinum-based treatment.
Phase I study of CRISPR-engineered CAR-T cells with PD-1 inactivation in treating mesothelin-positive solid tumors.
Authors: Wang Zhenguang , Chen Meixia , Zhang Yan , Liu Yang , Yang Qingming , Nie Jing , Shen Lianjun , Jiang Pengfei , He Jiaping , Ye Xun , Cao Wei , Wang Haoyi , Han Weidong
Published: May 2020

3038

Background: Our previous phase I study with MPTK-CAR-T (mesothelin-directed 28ζ CAR-T cells with PD-1 and TCR disruption by CRISPR-Cas9 system) demonstrated feasibility and safety of CRISPR-mediated PD-1 inactivation in CAR-T cells, and suggested the natural TCR is beneficial for the proliferation of CAR-T cells in solid tumors. Based on these observations, we initiated a pilot dose escalation study to investigate mesothelin-directed CAR-T cells with only PD-1 disruption by CRISPR (termed as GC008t) in patients with mesothelin-positive advanced solid tumors (NCT03747965). Methods: On the data cut-off date (Jan 20, 2020), nine patients (6 pancreatic cancers, 2 ovarian cancers, 1 colorectal cancer) were treated (5 received ≥12 numbers of therapy), three in cohort 1 (0.1-0.2×107/kg), four in cohort 2 (0.5-1.0×107/kg), two in cohort 3 (2.5-5×107/kg). Eight of the 9 patients received lymphodepletion regimen of cyclophosphamide and nab-paclitaxel with or without gemcitabine. Four of the 9 patients received repeat infusions of GC008t per protocol. Results: Comparable proliferation capacity was observed in vitro between the MPTK-CAR-T and the GC008t products. The mean PD-1 surface expression in cell products was 0.5% (range, 0.2%-0.9%). GC008t infusions were well tolerated with no observed on-target/off-tumor toxicity, autoimmune activity. Only two patients in cohort 3 developed grade 1 CRS with fever and rash. Circulating GC008t expanded with a peak at day 7-14 and became undetectable by qPCR beyond 1 month. The mean peak levels of circulating CAR-T cells between GC008t and MPTK-CAR-T at similar dose level were not statistically significant. Failure of GC008t engraftment after repeat infusion was observed in 2 out of 4 patients. The best response of the 7 evaluable patients was stable disease in 4 and partial response in 2 patients (dosed ≥ 1×107/kg) with PFS of 80 and 160 days. Conclusions: Phase I trial of GC008t further establishes that genetic inactivation of PD-1 in CAR-T cells by CRISPR is feasible and safe. The expansion and persistence of CAR-T cells with PD-1 disruption is not improved significantly even in the setting of natural TCR and lymphodepletion. Future endeavors are needed to improve the clinical efficacy of CAR-T therapy in the treatment of solid tumor. Clinical trial information: NCT03747965 .
Safety and efficacy of chimeric antigen receptor T cells modified to target mesothelin and express PD-1 antibodies in patients with relapsed/refractory solid cancers in a phase I trial.
Authors: Fang Juemin , Sun Yan , Guo Xianling , Xie Bailu , Wang Hui , Mao Wei , Zhu Zhongzheng , Liu Zhuqing , Hu Fei , Yuan Min , Gao Song , Lin Zhicai , Zhang Zhiwei , Li Huimei , Chu Wenqi , Pang Xinru , Qian Qijun , Qing Huanlong , Xu Qing
Published: May 2020

3039

Background: The limitations of chimeric antigen receptor T cells (CAR-T) in solid tumors are immunosuppressive tumor microenvironment and difficult infiltration to tumor. In order to reduce on-target off-tumor toxicities and circumvent the immune-suppressive tumor microenvironment(TME), we modified autologous CAR-T to be specific for mesothelin (MSLN) on cancer cells and secrete PD-1 antibodies (aPD1-MSLN-CAR T cells). Here, we report the safety and efficacy of aPD1-MSLN-CAR T cells in 10 patients with relapsed/refractory solid cancers in this single-arm, open-label, first-in-human phase I pilot study (ClinicalTrial.gov: NCT03615313). Methods: aPD1-MSLN-CAR T cells were prepared from peripheral blood mononuclear cells and engineered using PiggyBac Transposon System to target MSLN and secrete PD-1 antibodies. 10 patients with mesothelin positive relapsed/refractory solid cancers after failure to standard therapies were treated with aPD1-MSLN-CAR T cells for two or more cycles until disease progression or intolerable toxicity. The dose escalation of CAR T cells was designed to be 5×106/kg, 5×107/kg, and 1×108/kg, respectively. Adverse events were evaluated according to CTCAE-V4.03 and clinical response was assessed by RECIST 1.1. CAR expression was analyzed using quantitative real-time polymerase chain reaction. PD-1 antibodies were detected by ELISA. Serum IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α were measured using flow cytometry. Results: The most common adverse events were mild fatigue and fever. Abdominal pain was also observed in 1 patient. Grade 1 and 2 cytokine release syndromes were observed without neurologic symptoms in 10 patients. After aPD1-MSLN-mRNA-CAR T cells treatment, 2 patients (20%) achieved partial response (PR), 4 (40%) remained stable (SD), and the rest 4 (40%) patients developed disease progression (PD). The median PFS was 97 days [95% CI (13, 180)] estimated by Kaplan-Meier method. Conclusions: These findings lend support that the combination of modified CAR T cells targeting MSLN with PD1 inhibition for solid tumors is safe. Modified CAR-T cells expressing PD-1 antibodies maybe an option to improve CAR-T efficacy as a result of refined TME. Clinical trial information: NCT03615313 . [Table: see text]
Changes in lymphocyte/monocyte ratio, prognostic marker to predict overall survival in patients with advanced cancer treated with immune checkpoint inhibitor.
Authors: Patel Sandip H. , Li Mingjia , Zhao Songzhu , Wei Lai , Burkart Jarred Thomas , Husain Marium , He Kai , Bertino Erin Marie , Shields Peter G. , Carbone David Paul , Verschraegen Claire F. , Otterson Gregory Alan , Kendra Kari Lynn , Spakowicz Daniel , Presley Carolyn J , Owen Dwight Hall
Published: May 2020

3047

Background: Immunosuppressive factors within the tumor microenvironment (TME) pose a barrier to response to treatment with immune checkpoint inhibitors (ICI). Monocytes alter the TME to promote cancer progression through local immune suppression and angiogenesis. Peripheral blood lymphocyte-to-monocyte ratio (LMR) may reflect the interaction between host immunity, represented by lymphocytes, and the tumor microenvironment, represented by monocytes. A low LMR in the peripheral blood may serve as a surrogate biomarker and has been associated with poor prognosis in various cancers; however, its role has not been well defined in the era of treatment with ICI. Methods: We retrospectively evaluated 1034 patients with advanced cancer treated with ICI from 2011 to 2017. We calculated LMR as ratio of absolute lymphocyte/monocyte counts at baseline and median of 21 days after first cycle of ICI (on-treatment LMR) and considered low if < 2. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Median OS with 95% confidence intervals (CI) was estimated using the Kaplan-Meier method. Log rank test was used for group comparison. Results: 536 pts (52%) with LMR < 2 at baseline had shorted median OS compared to 498 (48%) with LMR≥2 (median OS 8.4 months vs 17.8 months, p < 0.001). Of 1034 pts with baseline LMR, 837 had follow up LMR evaluable. In patients with baseline and on-treatment LMR, those with baseline LMR < 2, who had on treatment LMR ≥2, had OS of 16.8 months (95% CI 10.3-23.5) compared to median OS 8.0 months (95% CI 6-9.4) for patients with on treatment LMR < 2 after first cycle of ICI, p < 0.001. Patients with baseline LMR≥2, who had on treatment LMR ≥ 2, had median OS of 23 months (95% CI 19.7-28.9), but median OS was 9.4 months (95% CI 7.1-11.1) for patients with on-treatment LMR < 2 after first cycle of ICI, p < 0.001. Conclusions: We observed a statistically significant association between not only baseline LMR but also change in LMR from baseline after first cycle of ICI and overall survival in cancer patients treated with ICI. The role of LMR at baseline and on-treatment LMR should be evaluated in further studies incorporating known additional prognostic factors for ICI therapy. [Table: see text]
A phase I study of ALX148, a CD47 blocker, in combination with standard anticancer antibodies and chemotherapy regimens in patients with advanced malignancy.
Authors: Chow Laura Quan Man , Gainor Justin F. , Lakhani Nehal J. , Lee Keun Wook , Chung Hyun Cheol , Lee Jeeyun , LoRusso Patricia , Bang Yung-Jue , Hodi F. Stephen , Santana-Davila Rafael , Fanning Philip , Squifflet Pierre , Jin Feng , Wan Hong , Kuo Tracy , Pons Jaume , Randolph Sophia , Messersmith Wells A.
Published: May 2020

3056

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host immune response. ALX148 (A) is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive immunoglobulin Fc region. ALX148 enhances innate and adaptive immune responses against cancer and has previously been shown to be well tolerated in combination with the checkpoint inhibitor (CPI), pembrolizumab (P), and trastuzumab (T) in a range of solid tumors (ASCO 2019 #2514). ALX148 safety and activity in combination with T or P and standard chemotherapy regimens are reported in patients (pts) including head and neck squamous cell cancer (HNSCC) and HER2 positive gastric/gastroesophageal cancer (GC). Methods: Pts with advanced malignancy were administered AP or AT. Patients with ≥2L HNSCC progressed on platinum therapy received AP, while those with untreated advanced disease received AP+5FU (FU)+platinum. Pts with ≥2L GC progressed on T+FU+platinum received AT +/- ramucirumab (ram)+paclitaxel (pac). Safety, response, pharmacokinetic and pharmacodynamic (PD) markers were assessed. Data are reported as of 21, Jan. 2020. Results: Patients received AP (n=52); AP+FU+platinum (n=1); AT (n=30); or AT+ram+pac (n=3) as of data cutoff. Eighty-two pts experienced any adverse event (AE). Fifty-seven pts administered AP or AT regimens reported mostly low grade ALX148 treatment related (TR) AEs, the most common being fatigue (18%), AST increase (11%), platelets decreased (10%), ALT increase (8.5%), anemia (8.5%), and pruritus (8.5%). Pts receiving AP+FU+platinum or AT+ram+pac reported no TRAEs as of data cutoff. Anticancer activity was observed in response-evaluable pts. AP: HNSCC CPI-naïve (n=10) 40% ORR, mPFS 4.6 [95% CI:0.5;7.5], mOS not reached with 14.4m median follow-up; AP: HNSCC CPI-experienced (n=10) 0% ORR, mPFS 2.0 [95% CI:0.9;3.6], mOS 7.4 [95% CI:3.1;NC]; and AT: GC (n=20) 20% ORR, mPFS 2.2 [95% CI:1.9;5.4], mOS 8.1 [95% CI:3.4;12.8]. Full peripheral CD47 target occupancy and increased infiltrating immune cells in tumor biopsies were seen. Exploratory analysis of biomarkers associated with response is ongoing. Conclusions: Initial data suggests ALX148 demonstrates excellent tolerability in combination with anti cancer antibodies and standard chemotherapy. Clinical activity in pts with advanced CPI naïve HNSCC (including PD-L1 negative) and GC compares favorably with historic controls. Final data from AP and AT cohorts and initial data from chemotherapy combination cohorts will be presented. Clinical trial information: NCT03013218 .
Phase Ia dose escalation of IBI318, a first-in-class bispecific anti-PD-1/PD-L1, in patients with advanced tumors.
Authors: Xu Rui-hua , Zhao Hongyun , Wei Xiao-Li , Zhang Yang , Wang Feng , Wang Zhiqiang , Wang Fenghua , Li Yu-Hong , Zou Ben-Yan , Zhu Xiaomin , Yu Wencheng , Zhou Hui
Published: May 2020

3062

Background: With the proven success of PD-1 and PD-L1 monoclonal antibodies, exploiting antibody based immune checkpoint strategies has potential to reduce disease burden and improve patient survival outcome. IBI318, as a first-in-class anti-PD-1/PD-L1 bispecific antibody, could provide more potent anti-tumor activity and more durable response. Here we report preliminary results from an ongoing phase 1a/1b study of IBI318 in advanced tumors. Methods: In the dose escalation of Phase 1a, patients with advanced and/or refractory solid tumors or hematological malignancies were enrolled to receive IBI318. Dose escalation was from 0.3 mg to 600 mg (8 cohorts) via an accelerated titration followed by a modified toxicity probability interval-2 design with a 28-day dose-limiting toxicity (DLT) observation period. Patients without DLT will receive IBI318 every two week (Q2W). Tumor assessments were performed every 6 weeks. Results: As of Jan 10, 2020, 15 pts who had failed at least one line of treatment had been enrolled (1 pt each in 0.3 mg, 1 mg, 3 mg and 10 mg; 3 pts in 30 mg; 3 pts in 100 mg, 3 pts in 300 mg and 2 pts in 600 mg) for dose escalation and received at least 1 dose of treatment. Median duration of treatment was 6.1 (range: 2.1-24.7) weeks. IBI318 had been well tolerated with no DLT from 0.3mg to 300mg group. 11 of 15 pts had treatment related AEs (TRAEs) and the most common (≥10%) TRAEs were pyrexia (20.0%, G1/2) and infusion-related reaction (20.0%, G1/2). 1 patient in 300 mg had an immune-related AE (G2 arthritis). No ≥G3 TRAE had been observed. 12 pts had at least one on-study tumor assessment. 3 of 9 pts receiving dose level ≥10mg had achieved partial response (1 confirmed, 1 pending confirmation and the other PD after the first PR scan). A total of 10 pts discontinued treatment due to disease progression (8) and AE (2, G4 lung infection and G4 upper gastrointestinal hemorrhage, both were not related to treatment). Conclusions: IBI318 has shown an acceptable safety profile. Preliminary efficacy results are promising in advanced cancer patients. The study is currently ongoing at dose level of 600 mg Q2W. Clinical trial information: NCT03875157 .
A phase Ib study of TQ-B2450 plus anlotinib in patients with advanced solid tumor.
Authors: Cheng Ying , Cui Hongxia , Wu Chunjiao , Wang Yanping , Zhang Tingting , Xin Ying , Xu Jinhua , Chen Yan , Li Zili , Wang Ying , Wei Huafang , Zhu Jing , Du Tianying
Published: May 2020

3065

Background: Anlotinib, an antiangiogenic multi-target tyrosine kinase inhibitor, significantly improved clinical outcomes in solid tumors. TQ-B2450 is an engineered anti-programmed death-ligand 1 antibody. This onging phase 1b study aimed to assess the safety and effect of TQ-B2450 plus anlotinib in advanced solid tumors. Methods: This phase 1b study, which included a dose-escalating phase and an expansion phase, enrolled patients with advanced solid tumor who failed in or had no standard treatment between June 2019 and January 2020.Eligible patients were firstly assigned into sequential dose-escalating cohorts including 10mg and 12mg anlotinib plus TQ-B2450 following the conventional 3+3 design. If the starting dose of 10mg anlotinib led to ≥2 dose-limiting toxicities (DLTs), 8mg anlotinib would be administered. After the dose-escalating phase, eligible patients were enrolled into the expansion cohort. The primary outcomes were safety and objective response rate. Results: In the dose-escalating phase, three eligible patients received 10mg anlotinib plus TQ-B2450 had no DLTs in the first cycle, neither did three patients with 12mg anlotinib plus TQ-B2450. Then the expansion phase started, sixteen patients received 12mg anlotinib plus TQ-B2450. Finally, a total of 22 patients were included ( 6 small cell lung cancers [SCLC], 8 non-small cell lung cancers [NSCLC], 2 colorectal cancers, 2 breast cancers, 2 ovarian cancers, 1 thymic carcinoma and 1 cervical cancer). Ten ≥3 grade adverse events were observed (Table). Seventeen patients underwent at least once effect evaluation. One SCLC patient with 10mg anlotinib plus TQ-B2450 had confirmed partial responses (PR). Four patients with 12mg anlotinib plus TQ-B2450 had unconfirmed PR (2 SCLC and 2 NSCLC). And 9 patients had stable disease, 3 patients had progression disease. Conclusions: 12mg anlotinib plus TQ-B2450 showed an acceptable safety profile and promising response in advanced solid tumors. Clinical trial information: NCT03897283. [Table: see text]
Circulating tumor DNA dynamics as prognostic and predictive biomarkers of response to pembrolizumab in patients with virally-related tumors (VRT) treated within the INSPIRE study.
Authors: Oliva Bernal Marc , Liu Zhihui (Amy) , Iafolla Marco Adelmo James , Spreafico Anna , Jennings Sarah , Abdul Razak Albiruni Ryan , Yang Cindy , Bratman Scott Victor , Torti Dax , Pugh Trevor John , Siu Lillian L. , Hansen Aaron Richard
Published: May 2020

3068

Background: We previously showed a correlation between circulating tumor DNA (ctDNA) dynamics and response to pembrolizumab in a cohort of mixed tumors treated in the INSPIRE study (Yang et al, ESMO 2019). We investigated the prognostic and predictive value of ctDNA dynamics in patients (pts) with VRT. Methods: Pts with VRT (HPV+ squamous cell carcinoma (SCC), EBER+ nasopharyngeal carcinoma (NPC) and MCPyV+ Merkel carcinoma (MC)) and a control cohort of non-VRT (HPV- head and neck SCC) treated with single-agent pembrolizumab were selected for the analysis. ctDNA was assayed at baseline and start of cycle 3 using a pt-specific amplicon-based NGS assay (Signatera). Samples were considered ctDNA positive if ≥2 of 16 pt-specific targets met the qualifying confidence score threshold. Whole exome sequencing (WES) performed in baseline tumor tissue; presence of HPV, EBV and MCPyV in tumor determined through bioinformatic analysis of WES data (VirusFinder, PMID23717618). Changes in tumor size (mm) and response data using RECIST 1.1 were collected. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Results: Twenty pts with VRT (HPV+ head and neck = 8, cervical = 2 and anal = 2 SCC; EBER+NPC = 2; MC = 6) and 11 pts with non-VRT were included. Median follow-up: 11 months (0,5-11). Treatment response: VRT 6 responders (CR + PR + SD > 18weeks) and 14 non-responders (SD < 18 weeks + PD); non-VRT 3 responders and 8 non-responders. Median OS and PFS for all pts were 10.61 and 3.2 months, respectively. No differences in PFS (p = 0.60) nor OS (p = 0.66) were observed among responders between VRT and non-VRT. Among non-responders, VRT had significantly higher OS but not PFS when compared to non-VRT (HR 0.30, p = 0.01 and HR 0.82 p = 0.62, respectively). VRT had quantitatively higher ctDNA at baseline vs non-VRT (Mean 7.9 vs 0.4 ng, p < 0.001). ΔctDNA (Change in ctDNA between baseline and cycle 3) strongly correlated with changes in tumor measurements and response by RECIST 1.1 (Spearman Rho = 0.75) and was associated with survival regardless of viral status (Table). Conclusions: ΔctDNA strongly correlated with changes in tumor response and survival in both VRT and non-VRT. Higher baseline ctDNA was found in VRT. Correlation with circulating viral DNA and radiomics analyses is on-going. [Table: see text]
Spatial analysis of tumor immune microenvironment (TIME) in patients treated with Bintrafusp alfa.
Authors: Abdul Sater Houssein , Robinson Jeffrey , Strauss Julius , Gatti-Mays Margaret Elena , Redman Jason , Floudas Charalampos S. , Marte Jenn , Cordes Lisa M. , Walter Rodriguez Beatriz , Wiseman Andrew , Zaki George , Karzai Fatima , Bilusic Marijo , Madan Ravi Amrit , Schlom Jeffrey , Rajan Arun , Gulley James L.
Published: May 2020

3070

Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII receptor (TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In preclinical models, bintrafusp alfa treatment promoted CD8+ T cell and NK cell activation, and both immune cell (IC) populations were required for optimal bintrafusp alfa mediated tumor control. However, the effect of bintrafusp alfa on TIME in humans has not been reported. Methods: In this unplanned interim analysis of a biomarker expansion cohort (NCT 02517398), patients (pts) with advanced non-small cell lung cancer (NSCLC) underwent paired biopsies (bx) before and on treatment with bintrafusp alfa (~ 50 days apart). The objective was to evaluate frequency and localization of tumor infiltrated ICs by IHC. Out of 12 pts, 7 had matched (Pre vs Post) tumor-containing specimens sufficient for multiplex immunofluorescence (MxIF) analysis of TIME. Four pts were excluded as Post bx histology for 3/12 [2 PR (partial response), 1 SD (stable disease)] was negative for tumor (necrosis or fibrosis) and 1/12 did not have a Post bx performed. Results: TIME study shows CD8 T cell infiltrates were increased in Post compared to Pre bx (median 161 vs 62/mm²; interquartile range [IQR] 65–396/mm² vs 31–135/mm²; p = 0·04). While M2 macrophages were also increased (median 800 vs 367/mm²; IQR 776–1131/mm² vs 171–831/mm²; p = 0·04), the ratio of M1/M2 was reversed in pts with SD (↑) compared to pts with PD (↓). Other ICs such as CD4, T-regs, NK cells and M1 macrophages were not changed. On average compared to baseline, M2 macrophages were > 2 fold closer to every other IC in pts with PD, but > 2 fold further from any IC in pts with SD. Tregs were relatively closer to other IC in PD pts. Linear Discriminant Analysis was also performed and results indicate that differential IC densities (mainly M1 macrophages and CD4 T cells) do perform as classifiers between long ( > 5 months) and short ( < 5 months) term responses. Conclusions: This study suggests that bintrafusp alfa not only can enhance intratumoral effector IC infiltrates (CD8) but also has a modulating effect on the spatial distribution of both M1/M2 macrophages within the NSCLC TIME. The differential proximity of M2 macrophages to other IC infiltrates and changes in M1/M2 ratios in association with response suggests that an M1/M2 macrophage balance is directly involved in response and/or resistance to bintrafusp alfa. Given the limited number of patients in this cohort, we intend to study effects of bintrafusp alfa in a larger cohort of patients. Clinical trial information: 02517398 .