Journal of Immunotherapy for Cancer最新文献

{"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":null,"pages":null},"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}

{"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":null,"pages":null},"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}

{"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":null,"pages":null},"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}

{"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":null,"pages":null},"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}

{"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":null,"pages":null},"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}

{"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":null,"pages":null},"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}

{"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":null,"pages":null},"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}