R. Shapira-Frommer, M. V. Dongen, K. Dobrenkov, E. Chartash, Fang Liu, Claire H. Li, R. Wnek, M. Patel
Background MK-5890 is a humanized agonist monoclonal antibody that binds to CD27 to provide a costimulatory signal that enhances T-cell–mediated responses. This first-in-human phase 1 study of MK-5890 evaluated the safety and efficacy of escalating doses of MK-5890 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. Methods Key eligibility criteria included histologically or cytologically confirmed advanced solid tumor, measurable disease by RECIST v1.1, and ECOG PS ≤1. MK-5890 was tested alone (dose range, 2-700 mg) or with pembrolizumab (fixed dose, 200 mg). Patients with disease progression following MK-5890 monotherapy were eligible to cross over to combination treatment. The primary objective was safety and tolerability. Objective response rate by investigator per RECIST v1.1 was also evaluated. The database cutoff for this analysis was May 30, 2019. Results Of 44 patients enrolled, 25 received MK-5890 and 19 received MK-5890 plus pembrolizumab; their median age was 59.0 years, 61.4% were female, 47.7% had ECOG PS 1, and 13.6% previously received immune checkpoint inhibitor therapy. In the initial phase, dose-limiting toxicities (DLTs) were reported in 3 patients receiving MK-5890 and 1 patient receiving MK-5890 plus pembrolizumab; all DLTs were associated with infusion-related adverse events. Maximum tolerated dose was defined. Treatment-related adverse events (TRAEs) were reported in 40 patients (90.9%): 22 patients (88.0%) receiving MK-5890 and 18 patients (94.7%) receiving MK-5890 plus pembrolizumab. The most common TRAEs were fatigue (28.0%) and infusion-related reactions (28.0%) with MK-5890 and fatigue (36.8%) and pruritus (31.6%) with MK-5809 plus pembrolizumab. Grade 3-4 TRAEs were reported in 10 patients (22.7%): 6 patients (24.0%) receiving MK-5890 and 4 patients (21.1%) receiving MK-5890 plus pembrolizumab; no grade 5 events were observed. One patient (4.0%) achieved a partial response (PR) with MK-5890 and 1 patient (5.3%) achieved a PR with MK-5890 plus pembrolizumab. Fourteen patients entered the crossover phase to receive MK-5890 plus pembrolizumab. In the crossover phase, no DLTs were reported. TRAEs were reported in 12 patients (85.7%); the most common were pruritus (21.4%), rash (21.4%), and headache (14.3%). One patient (7.1%) reported grade 3-4 TRAEs of increased amylase and increased lipase; no grade 5 events were observed. Two patients (14.3%) achieved a complete response and 2 patients (14.3%) achieved a PR. Conclusions Treatment with MK-5890, alone and in combination with pembrolizumab, demonstrated an acceptable safety profile. Early antitumor activity was observed in patients with advanced solid tumors in both monotherapy and combination therapy arms.
{"title":"O83 Phase 1 study of an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors","authors":"R. Shapira-Frommer, M. V. Dongen, K. Dobrenkov, E. Chartash, Fang Liu, Claire H. Li, R. Wnek, M. Patel","doi":"10.1136/LBA2019.3","DOIUrl":"https://doi.org/10.1136/LBA2019.3","url":null,"abstract":"Background MK-5890 is a humanized agonist monoclonal antibody that binds to CD27 to provide a costimulatory signal that enhances T-cell–mediated responses. This first-in-human phase 1 study of MK-5890 evaluated the safety and efficacy of escalating doses of MK-5890 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. Methods Key eligibility criteria included histologically or cytologically confirmed advanced solid tumor, measurable disease by RECIST v1.1, and ECOG PS ≤1. MK-5890 was tested alone (dose range, 2-700 mg) or with pembrolizumab (fixed dose, 200 mg). Patients with disease progression following MK-5890 monotherapy were eligible to cross over to combination treatment. The primary objective was safety and tolerability. Objective response rate by investigator per RECIST v1.1 was also evaluated. The database cutoff for this analysis was May 30, 2019. Results Of 44 patients enrolled, 25 received MK-5890 and 19 received MK-5890 plus pembrolizumab; their median age was 59.0 years, 61.4% were female, 47.7% had ECOG PS 1, and 13.6% previously received immune checkpoint inhibitor therapy. In the initial phase, dose-limiting toxicities (DLTs) were reported in 3 patients receiving MK-5890 and 1 patient receiving MK-5890 plus pembrolizumab; all DLTs were associated with infusion-related adverse events. Maximum tolerated dose was defined. Treatment-related adverse events (TRAEs) were reported in 40 patients (90.9%): 22 patients (88.0%) receiving MK-5890 and 18 patients (94.7%) receiving MK-5890 plus pembrolizumab. The most common TRAEs were fatigue (28.0%) and infusion-related reactions (28.0%) with MK-5890 and fatigue (36.8%) and pruritus (31.6%) with MK-5809 plus pembrolizumab. Grade 3-4 TRAEs were reported in 10 patients (22.7%): 6 patients (24.0%) receiving MK-5890 and 4 patients (21.1%) receiving MK-5890 plus pembrolizumab; no grade 5 events were observed. One patient (4.0%) achieved a partial response (PR) with MK-5890 and 1 patient (5.3%) achieved a PR with MK-5890 plus pembrolizumab. Fourteen patients entered the crossover phase to receive MK-5890 plus pembrolizumab. In the crossover phase, no DLTs were reported. TRAEs were reported in 12 patients (85.7%); the most common were pruritus (21.4%), rash (21.4%), and headache (14.3%). One patient (7.1%) reported grade 3-4 TRAEs of increased amylase and increased lipase; no grade 5 events were observed. Two patients (14.3%) achieved a complete response and 2 patients (14.3%) achieved a PR. Conclusions Treatment with MK-5890, alone and in combination with pembrolizumab, demonstrated an acceptable safety profile. Early antitumor activity was observed in patients with advanced solid tumors in both monotherapy and combination therapy arms.","PeriodicalId":16067,"journal":{"name":"Journal of Immunotherapy for Cancer","volume":"25 1","pages":"A2 - A2"},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74455010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Piha-Paul, J. Bendell, A. Tolcher, S. Hurvitz, A. Patnaik, R. Shroff, P. Pohlmann, M. Zettl, N. Hahn, A. Krishnamurthy, M. Duerr, J. Mei, K. Aviano, R. Yusuf, L. Matis, S. Olwill, I. Bruns, G. Ku
Background Anticalin® proteins are recombinantly engineered human proteins based on lipocalins. PRS-343 is a first-in-class bispecific antibody-Anticalin fusion protein targeting the oncogenic tumor antigen HER2 and the costimulatory immune receptor 4-1BB on T and other immune cells. Here, we report the results of a phase 1 single-agent dose escalation trial in patients with HER2+ solid tumors. Methods PRS-343 has been evaluated in sequential dose cohorts from 0.0005 to 8 mg/kg i.v. Doses were administered Q3W and the 8 mg/kg dose was also given Q2W. An accelerated titration design was utilized for the initial dose escalation followed by a modified 3+3 design and the option to back-fill cohorts. Dose-limiting toxicities (DLTs) were reported during the first cycle of each schedule. The primary study objectives include the safety profile and RP2D of PRS-343. Secondary objectives include ORR and DCR, PD biomarker response and PK profile. PD response was assessed in tumor biopsies (CD8+ T cell IHC) pre- and post- PRS-343 treatment. Results 51 patients (median age 61.2 years, 61% female, 82% caucasian, 57% with more than three lines of prior therapy) with a variety of solid tumor indications [gastric/GEJ (n=19); BC (n=12); gynecological cancer (n=6); CRC (n=5); BTC (n=4); UC (n=2); melanoma, pancreatic and salivary duct (n=1 each)] have been treated with PRS-343. Based on pharmacokinetic analyses and observed kinetics of the CD8+ T cell expansion post-treatment, the low end of the active dose range is considered 2.5 mg/kg. 19 patients treated at active dose levels before the data cut-off on 09-06-2019 were evaluable for response [DCR 58% (11% confirmed PR) as per RECIST 1.1]. At the active doses, we observed significant and pronounced post-treatment expansion of CD8+ T cells particularly in the tumor nests, consistent with the MoA of PRS-343, while there was no increase in the doses below 2.5 mg/kg. The post-treatment expansion of CD8+ T cells was more pronounced in patients with a confirmed PR or prolonged SD. PRS-343 was very well tolerated, with no SAEs reported. The most frequent TRAEs were fatigue (9%), chills (6%) and diarrhea (5%) of mild to moderate severity. None qualified as a DLT. Conclusions PRS-343 is the first molecule of its kind to demonstrate encouraging evidence of safety and clinical benefit with a correlative PD effect in a heavily pre-treated population. These initial data suggest that PRS-343, the first 4-1BB bispecific to enter clinical development, merits further investigation in clinical trials. Trial Registration NCT03330561
{"title":"O82 A phase 1 dose escalation study of PRS-343, a HER2/4–1BB bispecific molecule, in patients with HER2-positive malignancies","authors":"S. Piha-Paul, J. Bendell, A. Tolcher, S. Hurvitz, A. Patnaik, R. Shroff, P. Pohlmann, M. Zettl, N. Hahn, A. Krishnamurthy, M. Duerr, J. Mei, K. Aviano, R. Yusuf, L. Matis, S. Olwill, I. Bruns, G. Ku","doi":"10.1136/LBA2019.2","DOIUrl":"https://doi.org/10.1136/LBA2019.2","url":null,"abstract":"Background Anticalin® proteins are recombinantly engineered human proteins based on lipocalins. PRS-343 is a first-in-class bispecific antibody-Anticalin fusion protein targeting the oncogenic tumor antigen HER2 and the costimulatory immune receptor 4-1BB on T and other immune cells. Here, we report the results of a phase 1 single-agent dose escalation trial in patients with HER2+ solid tumors. Methods PRS-343 has been evaluated in sequential dose cohorts from 0.0005 to 8 mg/kg i.v. Doses were administered Q3W and the 8 mg/kg dose was also given Q2W. An accelerated titration design was utilized for the initial dose escalation followed by a modified 3+3 design and the option to back-fill cohorts. Dose-limiting toxicities (DLTs) were reported during the first cycle of each schedule. The primary study objectives include the safety profile and RP2D of PRS-343. Secondary objectives include ORR and DCR, PD biomarker response and PK profile. PD response was assessed in tumor biopsies (CD8+ T cell IHC) pre- and post- PRS-343 treatment. Results 51 patients (median age 61.2 years, 61% female, 82% caucasian, 57% with more than three lines of prior therapy) with a variety of solid tumor indications [gastric/GEJ (n=19); BC (n=12); gynecological cancer (n=6); CRC (n=5); BTC (n=4); UC (n=2); melanoma, pancreatic and salivary duct (n=1 each)] have been treated with PRS-343. Based on pharmacokinetic analyses and observed kinetics of the CD8+ T cell expansion post-treatment, the low end of the active dose range is considered 2.5 mg/kg. 19 patients treated at active dose levels before the data cut-off on 09-06-2019 were evaluable for response [DCR 58% (11% confirmed PR) as per RECIST 1.1]. At the active doses, we observed significant and pronounced post-treatment expansion of CD8+ T cells particularly in the tumor nests, consistent with the MoA of PRS-343, while there was no increase in the doses below 2.5 mg/kg. The post-treatment expansion of CD8+ T cells was more pronounced in patients with a confirmed PR or prolonged SD. PRS-343 was very well tolerated, with no SAEs reported. The most frequent TRAEs were fatigue (9%), chills (6%) and diarrhea (5%) of mild to moderate severity. None qualified as a DLT. Conclusions PRS-343 is the first molecule of its kind to demonstrate encouraging evidence of safety and clinical benefit with a correlative PD effect in a heavily pre-treated population. These initial data suggest that PRS-343, the first 4-1BB bispecific to enter clinical development, merits further investigation in clinical trials. Trial Registration NCT03330561","PeriodicalId":16067,"journal":{"name":"Journal of Immunotherapy for Cancer","volume":"46 1","pages":"A1 - A2"},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81298488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michele Maio, Matteo Carlino, Anthony Joshua, Elaine McWhirter, Antoni Ribas, P. Ascierto, Wilson Miller, Marcus Butler, Pier Ferrucci, Robert Zielinski, Michele Del Vecchio, E. Gasal, R. Ghori, S. Diede, E. Croydon, Omid Hamid
Background Pembrolizumab+dabrafenib+trametinib demonstrated promising antitumor activity and acceptable tolerability in BRAF-mutant melanoma in phase 1/2 KEYNOTE-022 parts 1 and 2 (NCT02130466). Pembrolizumab+dabrafenib+trametinib numerically prolonged PFS and DOR versus placebo+dabrafenib+trametinib but had a higher grade 3-5 TRAE rate in part 3. KEYNOTE-022 parts 4 and 5 evaluated pembrolizumab+trametinib. Methods In part 4 (open-label, 3+3 dose-finding) patients with advanced solid tumors (irrespective of BRAF status) or unresectable/metastatic BRAF wild-type melanoma received pembrolizumab 200 mg Q3W with trametinib as concurrent (2 or 4 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD]) or intermittent dosing (2 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD; 1 week off/2 weeks on]). Interim MTDs identified in part 4 were confirmed in part 5 using a modified toxicity probability interval design. The primary objectives were safety, tolerability, and ORR by investigator assessment per RECIST v1.1 of the maximum administered or tolerated dose (MAD/MTD) of pembrolizumab+trametinib. Safety was analyzed for all patients who received ≥1 dose of study drug; patients treated during the trametinib run-in who discontinued study before receiving pembrolizumab were included; patients who did not complete trametinib run-in or receive ≥66% of planned doses during the 6-week dose-limiting toxicity (DLT) evaluable period were not included for DLT evaluation. AEs were graded per NCI CTCAE v4. Results Of 42 enrolled patients, most were female (61.9%); median age was 55.0 years; 57.1% had received ≥2 prior lines of therapy. At database cutoff (June 26, 2019), median follow-up was 9.0 months (range, 1.4-25.6 months). Of 38 DLT-evaluable patients, 10 had DLTs (table 1). Dosing regimens were selected for confirmation in part 5 based on safety data. Any-grade TRAEs occurred in 39 (92.9%) patients; grade 3-4 TRAEs occurred in 19 (45.2%), none were grade 5. TRAEs led to discontinuation in 8 (19.0%) patients. Immune-mediated AEs occurred in 12 (28.6%) patients, most commonly severe skin reactions (n=6; 14.3%), pneumonitis (n=3; 7.1%), hypothyroidism (n=2; 4.8%). The MTD of concurrent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg with 2 weeks of trametinib run-in (ORR, 0/16; 0%) and the MTD of intermittent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 2 mg with 2 weeks of run-in (ORR, 4/15; 26.7%). Abstract P863 Table 1 DLT, TRAE, and ORR in KEYNOTE-022 parts 4 and 5 Conclusions Both concurrent or intermittent pembrolizumab+trametinib dosing were feasible and the combination showed antitumor activity in patients with advanced solid tumors or advanced BRAF wild-type melanoma.
{"title":"P863 KEYNOTE-022 parts 4 and 5: pembrolizumab plus trametinib for patients with solid tumors or BRAF wild-type melanoma","authors":"Michele Maio, Matteo Carlino, Anthony Joshua, Elaine McWhirter, Antoni Ribas, P. Ascierto, Wilson Miller, Marcus Butler, Pier Ferrucci, Robert Zielinski, Michele Del Vecchio, E. Gasal, R. Ghori, S. Diede, E. Croydon, Omid Hamid","doi":"10.1136/LBA2019.16","DOIUrl":"https://doi.org/10.1136/LBA2019.16","url":null,"abstract":"Background Pembrolizumab+dabrafenib+trametinib demonstrated promising antitumor activity and acceptable tolerability in BRAF-mutant melanoma in phase 1/2 KEYNOTE-022 parts 1 and 2 (NCT02130466). Pembrolizumab+dabrafenib+trametinib numerically prolonged PFS and DOR versus placebo+dabrafenib+trametinib but had a higher grade 3-5 TRAE rate in part 3. KEYNOTE-022 parts 4 and 5 evaluated pembrolizumab+trametinib. Methods In part 4 (open-label, 3+3 dose-finding) patients with advanced solid tumors (irrespective of BRAF status) or unresectable/metastatic BRAF wild-type melanoma received pembrolizumab 200 mg Q3W with trametinib as concurrent (2 or 4 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD]) or intermittent dosing (2 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD; 1 week off/2 weeks on]). Interim MTDs identified in part 4 were confirmed in part 5 using a modified toxicity probability interval design. The primary objectives were safety, tolerability, and ORR by investigator assessment per RECIST v1.1 of the maximum administered or tolerated dose (MAD/MTD) of pembrolizumab+trametinib. Safety was analyzed for all patients who received ≥1 dose of study drug; patients treated during the trametinib run-in who discontinued study before receiving pembrolizumab were included; patients who did not complete trametinib run-in or receive ≥66% of planned doses during the 6-week dose-limiting toxicity (DLT) evaluable period were not included for DLT evaluation. AEs were graded per NCI CTCAE v4. Results Of 42 enrolled patients, most were female (61.9%); median age was 55.0 years; 57.1% had received ≥2 prior lines of therapy. At database cutoff (June 26, 2019), median follow-up was 9.0 months (range, 1.4-25.6 months). Of 38 DLT-evaluable patients, 10 had DLTs (table 1). Dosing regimens were selected for confirmation in part 5 based on safety data. Any-grade TRAEs occurred in 39 (92.9%) patients; grade 3-4 TRAEs occurred in 19 (45.2%), none were grade 5. TRAEs led to discontinuation in 8 (19.0%) patients. Immune-mediated AEs occurred in 12 (28.6%) patients, most commonly severe skin reactions (n=6; 14.3%), pneumonitis (n=3; 7.1%), hypothyroidism (n=2; 4.8%). The MTD of concurrent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg with 2 weeks of trametinib run-in (ORR, 0/16; 0%) and the MTD of intermittent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 2 mg with 2 weeks of run-in (ORR, 4/15; 26.7%). Abstract P863 Table 1 DLT, TRAE, and ORR in KEYNOTE-022 parts 4 and 5 Conclusions Both concurrent or intermittent pembrolizumab+trametinib dosing were feasible and the combination showed antitumor activity in patients with advanced solid tumors or advanced BRAF wild-type melanoma.","PeriodicalId":16067,"journal":{"name":"Journal of Immunotherapy for Cancer","volume":"48 1 1","pages":"A10 - A11"},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89206780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Skolnik, D. Reardon, S. Brem, A. Desai, S. Bagley, Sylvia C. Kurz, M. I. Fuente, S. Nagpal, M. Welch, B. Sacchetta, Sarah K Bartra, A. Bredlau, I. Lowy, K. Kraynyak, M. Morrow, T. McMullan, J. Boyer
Background GBM is one of the most deadly cancers and treatment is surgery, followed by radiation (RT) and temozolomide (TMZ) daily during RT followed by cycles of TMZ for select patients.1 New immunotherapies, such as checkpoint inhibition, may benefit patients with GBM. T cell-enabling therapies, in combination with checkpoint inhibition, may improve overall survival (OS). In this study, a novel antigen-specific T cell-generating therapy, INO-5401 (synthetic DNA plasmids encoding for human telomerase [hTERT], Wilms Tumor-1 [WT-1] and prostate specific membrane antigen [PSMA]), plus INO-9012 (synthetic DNA plasmid encoding for IL-12), with the PD-1 checkpoint inhibitor, cemiplimab, was given to patients with newly-diagnosed GBM to evaluate tolerability, immunogenicity and clinical efficacy of the combination. Methods Phase I/II, single arm, two cohort study (A: MGMT Promoter Unmethylated, B: MGMT Promoter Methylated). The primary objective is to evaluate the safety of INO-5401 and INO-9012 followed by EP with CELLECTRA® 2000 in combination with cemiplimab. Secondary objectives include the evaluation of preliminary clinical efficacy and immunogenicity. Treatment is with 9 mg INO-5401 with 1 mg INO-9012 every three weeks (Q3W) for four doses, then Q9W; and cemiplimab (350 mg IV Q3W). RT is given as 40 Gy over three weeks; TMZ is given concurrent with radiation (Cohorts A and B), followed by maintenance TMZ (Cohort B). Results 52 patients were enrolled onto this study; 32 in Cohort A and 20 in Cohort B. 18 were women (35%) and 47 were white (90%). The median age was 60 years (range 19-78 years). The most common Grade ≥3 adverse events were elevations in alanine or aspartate aminotransferase (ALT/AST; 5 patients), and tumor inflammation/edema (5 patients); there was one Grade 5 unrelated event of urosepsis. The only related SAE reported in more than one patient was pyrexia. 22 patients (42%) reported immune-related AEs, with the most common being elevations in ALT or AST (8 patients), and were reported most commonly within the first nine weeks of treatment. The safety profile was consistent with that of patients with GBM and of checkpoint inhibitors. ELISpot assessments performed to date demonstrated the majority of patients have T cell responses to INO-5401. PFS6 was 75% (95% CI 56.6, 88.5) in Cohort A (preliminary; Cohort B pending). Conclusions INO-5401 + INO-9012 with cemiplimab has an acceptable safety profile, is immunogenic and is potentially efficacious in patients with newly-diagnosed GBM. This combination is promising; survival results will be updated next year. Trial Registration NCT03491683. Ethics Approval This study was approved by New York University institution’s Ethics Board; approval number i17-00764. References Stupp R, et al. (2009). Lancet Oncology 10(5): 459–466.
GBM是最致命的癌症之一，治疗方法是手术，然后是放疗(RT)和替莫唑胺(TMZ)，在放疗期间每天，然后选择患者进行TMZ周期治疗新的免疫疗法，如检查点抑制，可能使GBM患者受益。T细胞激活疗法，结合检查点抑制，可能提高总生存率(OS)。本研究采用新型抗原特异性T细胞生成疗法INO-5401(编码人类端粒酶[hTERT]、Wilms Tumor-1 [WT-1]和前列腺特异性膜抗原[PSMA]的合成DNA质粒)和INO-9012(编码IL-12的合成DNA质粒)联合PD-1检查点抑制剂cemiplimab，对新诊断的GBM患者进行耐受性、免疫原性和临床疗效评价。方法I/II期，单臂，双队列研究(A: MGMT启动子未甲基化，B: MGMT启动子甲基化)。主要目的是评估INO-5401和INO-9012的安全性，随后是EP与CELLECTRA®2000联合用药。次要目的包括初步临床疗效和免疫原性评价。治疗方法是每三周使用9mg INO-5401和1mg INO-9012 (Q3W)，共四次，然后是Q9W;和西米单抗(350mg IV Q3W)。三周内给予40 Gy的RT;TMZ与放疗同时给予(队列A和B)，随后给予维持TMZ(队列B)。结果52例患者纳入本研究;A组32例，b组20例，女性18例(35%)，白人47例(90%)。中位年龄为60岁(范围19-78岁)。最常见的≥3级不良事件是丙氨酸或天冬氨酸转氨酶(ALT/AST;肿瘤炎症/水肿(5例);有1例5级尿脓毒症无关事件。在一个以上的患者中报告的唯一相关SAE是发热。22名患者(42%)报告了免疫相关的不良反应，最常见的是ALT或AST升高(8名患者)，最常见于治疗的前9周。安全性与GBM患者和检查点抑制剂一致。迄今为止进行的ELISpot评估显示，大多数患者对INO-5401有T细胞应答。队列A中PFS6为75% (95% CI 56.6, 88.5)(初步;B队列待定)。结论INO-5401 + INO-9012联合头孢米单抗具有可接受的安全性，具有免疫原性，对新诊断的GBM患者可能有效。这种组合是有希望的;生存结果将于明年更新。试验注册编号NCT03491683。本研究经纽约大学伦理委员会批准;批准号i17-00764。参考文献Stupp R等(2009)。中华医学杂志，10(5):459-466。
{"title":"P858 An open-label, multi-center trial of INO-5401 and INO-9012 delivered by electroporation (EP) in combination with cemiplimab in subjects with newly-diagnosed glioblastoma (GBM)","authors":"J. Skolnik, D. Reardon, S. Brem, A. Desai, S. Bagley, Sylvia C. Kurz, M. I. Fuente, S. Nagpal, M. Welch, B. Sacchetta, Sarah K Bartra, A. Bredlau, I. Lowy, K. Kraynyak, M. Morrow, T. McMullan, J. Boyer","doi":"10.1136/LBA2019.12","DOIUrl":"https://doi.org/10.1136/LBA2019.12","url":null,"abstract":"Background GBM is one of the most deadly cancers and treatment is surgery, followed by radiation (RT) and temozolomide (TMZ) daily during RT followed by cycles of TMZ for select patients.1 New immunotherapies, such as checkpoint inhibition, may benefit patients with GBM. T cell-enabling therapies, in combination with checkpoint inhibition, may improve overall survival (OS). In this study, a novel antigen-specific T cell-generating therapy, INO-5401 (synthetic DNA plasmids encoding for human telomerase [hTERT], Wilms Tumor-1 [WT-1] and prostate specific membrane antigen [PSMA]), plus INO-9012 (synthetic DNA plasmid encoding for IL-12), with the PD-1 checkpoint inhibitor, cemiplimab, was given to patients with newly-diagnosed GBM to evaluate tolerability, immunogenicity and clinical efficacy of the combination. Methods Phase I/II, single arm, two cohort study (A: MGMT Promoter Unmethylated, B: MGMT Promoter Methylated). The primary objective is to evaluate the safety of INO-5401 and INO-9012 followed by EP with CELLECTRA® 2000 in combination with cemiplimab. Secondary objectives include the evaluation of preliminary clinical efficacy and immunogenicity. Treatment is with 9 mg INO-5401 with 1 mg INO-9012 every three weeks (Q3W) for four doses, then Q9W; and cemiplimab (350 mg IV Q3W). RT is given as 40 Gy over three weeks; TMZ is given concurrent with radiation (Cohorts A and B), followed by maintenance TMZ (Cohort B). Results 52 patients were enrolled onto this study; 32 in Cohort A and 20 in Cohort B. 18 were women (35%) and 47 were white (90%). The median age was 60 years (range 19-78 years). The most common Grade ≥3 adverse events were elevations in alanine or aspartate aminotransferase (ALT/AST; 5 patients), and tumor inflammation/edema (5 patients); there was one Grade 5 unrelated event of urosepsis. The only related SAE reported in more than one patient was pyrexia. 22 patients (42%) reported immune-related AEs, with the most common being elevations in ALT or AST (8 patients), and were reported most commonly within the first nine weeks of treatment. The safety profile was consistent with that of patients with GBM and of checkpoint inhibitors. ELISpot assessments performed to date demonstrated the majority of patients have T cell responses to INO-5401. PFS6 was 75% (95% CI 56.6, 88.5) in Cohort A (preliminary; Cohort B pending). Conclusions INO-5401 + INO-9012 with cemiplimab has an acceptable safety profile, is immunogenic and is potentially efficacious in patients with newly-diagnosed GBM. This combination is promising; survival results will be updated next year. Trial Registration NCT03491683. Ethics Approval This study was approved by New York University institution’s Ethics Board; approval number i17-00764. References Stupp R, et al. (2009). Lancet Oncology 10(5): 459–466.","PeriodicalId":16067,"journal":{"name":"Journal of Immunotherapy for Cancer","volume":"19 1","pages":"A8 - A8"},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82949557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Cameron, B. Richardson, J. Golden, Lukas Pfannensttiel, M. Cartwright, Yousef Moustafa, Samjhana Thapaliya, G. Roversi, Y. Phoon, M. Cameron, B. Gastman
Background Coexpression of the immune checkpoint receptors PD-1 and TIM-3 is associated with dysfunction of tumor infiltrating lymphocytes in melanoma (MEL) and squamous cell carcinoma (SCC). To identify the mechanisms underlying this dysfunctional phenotype and to identify targets to rescue immune function, we performed transcriptional profiling of PD-1+TIM-3+CD8+ TILs sorted directly from MEL and SCC tumors in conjunction with immunologic phenotyping. We identified a number of novel dysregulated pathways and associated gene signatures in the PD-1+TIM-3+ subset that have not previously been reported in TILs, including bile acid metabolism, and demonstrated that these pathways are highly correlated not only to immune checkpoint receptor expression but also to MTOR pathway activation. Methods Surgically excised melanoma tumors were dissociated and mononuclear cells were isolated by Ficoll gradient separation and cryopreserved. For sorting based on immune checkpoint receptor expression, a cocktail of monoclonal antibodies to the following targets, including viability dye was used: CD3, CD4, CD8, CD45RA, CD27, CCR7 PE, CD14, CD19, Live/Dead, BTLA, TIM-3, PD-1, CTLA-4, TIGIT and LAG-3. RNA was purified from 10,000 sorted cells using RNeasy Mini Kits (Qiagen), followed by RNASeq library generation using TruSeq Stranded Total RNA HT Kits (Illumina). Gene set variation analysis (GSVA) was used for pathway analysis, as well as linear regression modelling using limma (Bioconductor). Results Transcriptomic analysis of CD8+ TILs revealed 4,228 genes (P<0.05, t-test) as differentially expressed in TILs vs. functional peripheral CD8 T cells. Using a nonlinear dimensionality-reduction technique, we found that there were several unique clusters of cell surface marker expression that were present at significantly different frequencies in the TILs. We used pathway enrichment analysis and linear regression modeling to identify gene signatures that correlate with the progressive and coordinate expression of PD-1, TIM-3, and additional checkpoint receptors thereby driving progressive dysfunction on in TILs. The peroxisome and bile acid metabolism pathways were significantly enriched in the TIL transcriptome. Moreover, higher frequencies of events in dysfunctional clusters were strongly correlated with positive enrichment of the bile acid metabolism pathway and enhanced MTOR signaling. Conclusions Transcriptomic analysis of PD-1+TIM-3+ CD8+ TILs identified novel candidate mechanisms of immune dysfunction in CD8+ TILs from patients with metastatic melanoma who fail immunotherapy. Our study identifies the bile acid and MTOR metabolic pathways as a potential novel therapeutic targets for complementary therapy to restore immune function in melanoma and SCC patients. Ethics Approval This study was performed under an IRB approved protocol.
免疫检查点受体PD-1和TIM-3的共表达与黑色素瘤(MEL)和鳞状细胞癌(SCC)中肿瘤浸润淋巴细胞功能障碍有关。为了确定这种功能失调表型的机制并确定拯救免疫功能的靶点，我们对直接从MEL和SCC肿瘤中分选的PD-1+TIM-3+CD8+ TILs进行了转录分析，并结合免疫表型。我们在PD-1+TIM-3+亚群中发现了一些新的失调通路和相关基因特征，这些通路在TILs中以前没有报道过，包括胆汁酸代谢，并证明这些通路不仅与免疫检查点受体表达高度相关，而且与MTOR通路激活高度相关。方法将手术切除的黑色素瘤游离，采用Ficoll梯度分离法分离单个核细胞并冷冻保存。根据免疫检查点受体的表达进行分选，使用以下靶点的单克隆抗体鸡尾酒，包括活力染料:CD3、CD4、CD8、CD45RA、CD27、CCR7 PE、CD14、CD19、Live/Dead、BTLA、TIM-3、PD-1、CTLA-4、TIGIT和LAG-3。使用RNeasy Mini kit (Qiagen)从10,000个分选细胞中纯化RNA，然后使用TruSeq strand Total RNA HT kit (Illumina)生成RNASeq文库。基因集变异分析(GSVA)用于途径分析，并使用limma (Bioconductor)进行线性回归建模。结果CD8+ TILs的转录组学分析显示，有4228个基因在TILs与功能性外周CD8 T细胞中表达差异(P<0.05, T检验)。使用非线性降维技术，我们发现在TILs中有几个独特的细胞表面标记表达簇，它们以显着不同的频率存在。我们使用途径富集分析和线性回归模型来识别与PD-1、TIM-3和其他检查点受体的进行性和协调表达相关的基因特征，从而驱动TILs的进行性功能障碍。过氧化物酶体和胆汁酸代谢途径在TIL转录组中显著富集。此外，在功能失调的群集中，较高的事件频率与胆汁酸代谢途径的正富集和MTOR信号的增强密切相关。结论PD-1+TIM-3+ CD8+ TILs的转录组学分析发现了免疫治疗失败的转移性黑色素瘤患者CD8+ TILs免疫功能障碍的新候选机制。我们的研究确定了胆汁酸和MTOR代谢途径作为补充治疗的潜在新治疗靶点，以恢复黑色素瘤和鳞状细胞癌患者的免疫功能。伦理批准本研究按照IRB批准的方案进行。
{"title":"P852 Transcriptomic analysis of dysfunctional CD8+ TILs in melanoma identifies bile acid and MTOR pathways as novel potential immunotherapy targets","authors":"C. Cameron, B. Richardson, J. Golden, Lukas Pfannensttiel, M. Cartwright, Yousef Moustafa, Samjhana Thapaliya, G. Roversi, Y. Phoon, M. Cameron, B. Gastman","doi":"10.1136/LBA2019.6","DOIUrl":"https://doi.org/10.1136/LBA2019.6","url":null,"abstract":"Background Coexpression of the immune checkpoint receptors PD-1 and TIM-3 is associated with dysfunction of tumor infiltrating lymphocytes in melanoma (MEL) and squamous cell carcinoma (SCC). To identify the mechanisms underlying this dysfunctional phenotype and to identify targets to rescue immune function, we performed transcriptional profiling of PD-1+TIM-3+CD8+ TILs sorted directly from MEL and SCC tumors in conjunction with immunologic phenotyping. We identified a number of novel dysregulated pathways and associated gene signatures in the PD-1+TIM-3+ subset that have not previously been reported in TILs, including bile acid metabolism, and demonstrated that these pathways are highly correlated not only to immune checkpoint receptor expression but also to MTOR pathway activation. Methods Surgically excised melanoma tumors were dissociated and mononuclear cells were isolated by Ficoll gradient separation and cryopreserved. For sorting based on immune checkpoint receptor expression, a cocktail of monoclonal antibodies to the following targets, including viability dye was used: CD3, CD4, CD8, CD45RA, CD27, CCR7 PE, CD14, CD19, Live/Dead, BTLA, TIM-3, PD-1, CTLA-4, TIGIT and LAG-3. RNA was purified from 10,000 sorted cells using RNeasy Mini Kits (Qiagen), followed by RNASeq library generation using TruSeq Stranded Total RNA HT Kits (Illumina). Gene set variation analysis (GSVA) was used for pathway analysis, as well as linear regression modelling using limma (Bioconductor). Results Transcriptomic analysis of CD8+ TILs revealed 4,228 genes (P<0.05, t-test) as differentially expressed in TILs vs. functional peripheral CD8 T cells. Using a nonlinear dimensionality-reduction technique, we found that there were several unique clusters of cell surface marker expression that were present at significantly different frequencies in the TILs. We used pathway enrichment analysis and linear regression modeling to identify gene signatures that correlate with the progressive and coordinate expression of PD-1, TIM-3, and additional checkpoint receptors thereby driving progressive dysfunction on in TILs. The peroxisome and bile acid metabolism pathways were significantly enriched in the TIL transcriptome. Moreover, higher frequencies of events in dysfunctional clusters were strongly correlated with positive enrichment of the bile acid metabolism pathway and enhanced MTOR signaling. Conclusions Transcriptomic analysis of PD-1+TIM-3+ CD8+ TILs identified novel candidate mechanisms of immune dysfunction in CD8+ TILs from patients with metastatic melanoma who fail immunotherapy. Our study identifies the bile acid and MTOR metabolic pathways as a potential novel therapeutic targets for complementary therapy to restore immune function in melanoma and SCC patients. Ethics Approval This study was performed under an IRB approved protocol.","PeriodicalId":16067,"journal":{"name":"Journal of Immunotherapy for Cancer","volume":"348 18","pages":"A4 - A5"},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91419163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Sarnaik, N. Khushalani, J. Chesney, H. Kluger, B. Curti, K. Lewis, T. Medina, Sajev Thomas, A. Pavlick, E. Whitman, S. Algarra, P. Corrie, O. Hamid, J. Lutzky, J. Oláh, J. Weber, J. Larkin, W. Shi, Kelly DiTrapani, Harry Qin, Mariam Mirgoli, R. Wu, T. Takamura, M. Fardis, J. Kirkwood
Background Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented. Methods C-144-01 is a global Phase 2 open-label, multicenter study of the safety and efficacy of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 66) patients with Stage IIIC/IV unresectable melanoma who received lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. All responses were assessed by RECIST 1.1. Results 66 patients had the following baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), relatively high tumor burden (106 mm mean target lesion sum of diameters), 44% with liver and/or brain lesions, median LDH 244 U/L. Objective Response Rate (ORR) by investigator was 36.4% (2 CR, 22 PR, 1 previously confirmed PR is now changed to SD) and Disease Control Rate (DCR) of 80.3%. At a median follow up of 9.7 months, median Duration of Response (DOR) has not been reached. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. The ORR per IRC was 34.8% (2 CR, 21 PR) and DCR was 72.7%. At a median follow up of 6.9 months, the median IRC DOR has not been reached. Overall concordance rate of investigator and IRC read of response was 89.4%. The concordance compares favorably with literature reports in a metastatic disease.1 Conclusions Lifileucel treatment resulted in a 36.4% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who had received prior anti-PD1 and BRAF/MEK inhibitors, if tumor BRAF mutated. The high concordance of 89.4% between investigator and IRC confirms the original assessment of lifileucel efficacy in metastatic melanoma.2 Acknowledgements The authors would like to thank the patients and their families for participation in the study. The authors would also like to acknowledge the support and dedication of all investigators and site team members from all participating clinical trial institutions. Trial Registration ClinicalTrials. gov Identifier: NCT02360579 Ethics Approval Ethics Approval This trial was approved by Western Institutional Review Board - IRB Tracking Number: 20160198
{"title":"P865 Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update","authors":"A. Sarnaik, N. Khushalani, J. Chesney, H. Kluger, B. Curti, K. Lewis, T. Medina, Sajev Thomas, A. Pavlick, E. Whitman, S. Algarra, P. Corrie, O. Hamid, J. Lutzky, J. Oláh, J. Weber, J. Larkin, W. Shi, Kelly DiTrapani, Harry Qin, Mariam Mirgoli, R. Wu, T. Takamura, M. Fardis, J. Kirkwood","doi":"10.1136/LBA2019.18","DOIUrl":"https://doi.org/10.1136/LBA2019.18","url":null,"abstract":"Background Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented. Methods C-144-01 is a global Phase 2 open-label, multicenter study of the safety and efficacy of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 66) patients with Stage IIIC/IV unresectable melanoma who received lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. All responses were assessed by RECIST 1.1. Results 66 patients had the following baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), relatively high tumor burden (106 mm mean target lesion sum of diameters), 44% with liver and/or brain lesions, median LDH 244 U/L. Objective Response Rate (ORR) by investigator was 36.4% (2 CR, 22 PR, 1 previously confirmed PR is now changed to SD) and Disease Control Rate (DCR) of 80.3%. At a median follow up of 9.7 months, median Duration of Response (DOR) has not been reached. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. The ORR per IRC was 34.8% (2 CR, 21 PR) and DCR was 72.7%. At a median follow up of 6.9 months, the median IRC DOR has not been reached. Overall concordance rate of investigator and IRC read of response was 89.4%. The concordance compares favorably with literature reports in a metastatic disease.1 Conclusions Lifileucel treatment resulted in a 36.4% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who had received prior anti-PD1 and BRAF/MEK inhibitors, if tumor BRAF mutated. The high concordance of 89.4% between investigator and IRC confirms the original assessment of lifileucel efficacy in metastatic melanoma.2 Acknowledgements The authors would like to thank the patients and their families for participation in the study. The authors would also like to acknowledge the support and dedication of all investigators and site team members from all participating clinical trial institutions. Trial Registration ClinicalTrials. gov Identifier: NCT02360579 Ethics Approval Ethics Approval This trial was approved by Western Institutional Review Board - IRB Tracking Number: 20160198","PeriodicalId":16067,"journal":{"name":"Journal of Immunotherapy for Cancer","volume":"7 1","pages":"A12 - A12"},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90312261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N. Ottoson, N. Bose, Anissa S. H. Chan, Xiaohong X. Qiu, B. Harrison, R. Walsh, P. Mattson, M. Gargano, J. Cox, M. Chisamore, M. Uhlik, J. Graff
Background Checkpoint inhibitor (CPI) monotherapies, including pembrolizumab (KEYTRUDA®, pembro), avelumab and atezolizumab have demonstrated modest clinical benefit in chemotherapy-relapsed/refractory TNBC patients (pts) with ~5-10% response rate, median overall survival (mOS) of 7-9 months, and 1 year OS ~37-40%. TNBC, although more immunogenic relative to the other breast cancer subtypes, is also the most heterogenous, resulting in substantial variability in immune responses. There is a dire need for immunotherapeutic agents that could consistently induce anti-cancer immune responses. Methods The primary analyses of our Phase 2 study (NCT02981303; collaboration with Merck & Co., Inc.) in 44 (intent-to-treat) chemotherapy-refractory/relapsed TNBC pts treated with Imprime PGG (Imprime), a novel yeast derived, Dectin-1 agonist β-glucan PAMP in combination with pembro has shown enhanced disease control rate (25%, N= 11;1 CR, 6 PR and 4 SD>24 weeks), 12-month OS rate (57.3%) and increased mOS (16.6 months) vs the respective endpoints in Keynote086 pts treated with pembro alone. As part of exploratory translational objectives, peripheral blood from pts receiving the combination in 3-week cycles were collected at various time points. Results from serum and cellular immunopharacodynamic (IPD) evaluations from 41 pts are presented. Results Peak levels of serum circulating immune complexes (~3 to 22-fold) and complement protein SC5b-9 (~1.4 to 41-fold) in stage 1 pts provided evidence for Imprime-anti beta glucan antibody immune complex formation. A significant increase in the frequency of HLA-DR+ myeloid cells was observed in the overall population (up to 7.4-fold). In pts showing disease control (N=11), a significant increase in complement function (CH50, ~0.8-4 fold range), select chemokines such as MCP-1 production (up to 1000-fold), CD86 expression on monocyte (~0.5-6-fold) and DC subsets (~0.8-11-fold), and increased frequency of Ki-67+, HLA-DR/PD-1+ CD8 T cells (~0.4-14-fold) was observed. Some IPD responses were associated with the 12-month landmark OS analyses. Additionally, enhanced mPFS (HR 0.51; p=0.03) and mOS (HR 0.13; p=0.0013) was observed in 18 pts with >1.25-fold increase in CD86 expression on classical monocytes. Greater than 2-fold increase in the frequency of Ki-67+, HLA-DR/PD-1+ CD8 T cells in 16 pts was also associated with enhanced mPFS (HR 0.395; p=0.01) and mOS (HR 0.183; p=0.008). Additionally, the gene expression profile of these IPD-responders were similar to the RECIST responders with >2-fold upregulation of several genes including IFNg, CD83, GZMA, GZMK, and CD3. Conclusions Overall, the strong association of the innate/adaptive IPD responses to the clinical responses are suggestive of interplay between the therapeutic mechanisms of Imprime and pembro combination. Ethics Approval The study was approved by central and local ethics committees depending on site requirements. The central IRB for the study is Western Institutio
{"title":"P859 Association of immunopharmacodynamic responses of imprime PGG plus pembrolizumab with clinical benefit in metastatic triple negative breast cancer (TNBC) subjects failing front-line chemotherapy","authors":"N. Ottoson, N. Bose, Anissa S. H. Chan, Xiaohong X. Qiu, B. Harrison, R. Walsh, P. Mattson, M. Gargano, J. Cox, M. Chisamore, M. Uhlik, J. Graff","doi":"10.1136/LBA2019.13","DOIUrl":"https://doi.org/10.1136/LBA2019.13","url":null,"abstract":"Background Checkpoint inhibitor (CPI) monotherapies, including pembrolizumab (KEYTRUDA®, pembro), avelumab and atezolizumab have demonstrated modest clinical benefit in chemotherapy-relapsed/refractory TNBC patients (pts) with ~5-10% response rate, median overall survival (mOS) of 7-9 months, and 1 year OS ~37-40%. TNBC, although more immunogenic relative to the other breast cancer subtypes, is also the most heterogenous, resulting in substantial variability in immune responses. There is a dire need for immunotherapeutic agents that could consistently induce anti-cancer immune responses. Methods The primary analyses of our Phase 2 study (NCT02981303; collaboration with Merck & Co., Inc.) in 44 (intent-to-treat) chemotherapy-refractory/relapsed TNBC pts treated with Imprime PGG (Imprime), a novel yeast derived, Dectin-1 agonist β-glucan PAMP in combination with pembro has shown enhanced disease control rate (25%, N= 11;1 CR, 6 PR and 4 SD>24 weeks), 12-month OS rate (57.3%) and increased mOS (16.6 months) vs the respective endpoints in Keynote086 pts treated with pembro alone. As part of exploratory translational objectives, peripheral blood from pts receiving the combination in 3-week cycles were collected at various time points. Results from serum and cellular immunopharacodynamic (IPD) evaluations from 41 pts are presented. Results Peak levels of serum circulating immune complexes (~3 to 22-fold) and complement protein SC5b-9 (~1.4 to 41-fold) in stage 1 pts provided evidence for Imprime-anti beta glucan antibody immune complex formation. A significant increase in the frequency of HLA-DR+ myeloid cells was observed in the overall population (up to 7.4-fold). In pts showing disease control (N=11), a significant increase in complement function (CH50, ~0.8-4 fold range), select chemokines such as MCP-1 production (up to 1000-fold), CD86 expression on monocyte (~0.5-6-fold) and DC subsets (~0.8-11-fold), and increased frequency of Ki-67+, HLA-DR/PD-1+ CD8 T cells (~0.4-14-fold) was observed. Some IPD responses were associated with the 12-month landmark OS analyses. Additionally, enhanced mPFS (HR 0.51; p=0.03) and mOS (HR 0.13; p=0.0013) was observed in 18 pts with >1.25-fold increase in CD86 expression on classical monocytes. Greater than 2-fold increase in the frequency of Ki-67+, HLA-DR/PD-1+ CD8 T cells in 16 pts was also associated with enhanced mPFS (HR 0.395; p=0.01) and mOS (HR 0.183; p=0.008). Additionally, the gene expression profile of these IPD-responders were similar to the RECIST responders with >2-fold upregulation of several genes including IFNg, CD83, GZMA, GZMK, and CD3. Conclusions Overall, the strong association of the innate/adaptive IPD responses to the clinical responses are suggestive of interplay between the therapeutic mechanisms of Imprime and pembro combination. Ethics Approval The study was approved by central and local ethics committees depending on site requirements. The central IRB for the study is Western Institutio","PeriodicalId":16067,"journal":{"name":"Journal of Immunotherapy for Cancer","volume":"44 1","pages":"A8 - A9"},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79449573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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