bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]