bluuebunny/crossref_metadata_2025_split huggingface dataset:
PROCLAIM-CX-072: Analysis of patients with advanced solid tumors receiving long-term treatment with CX-072, a PD-L1 probody therapeutic, as a single agent or in combination with ipilimumab.
Authors: Thistlethwaite Fiona , Naing Aung , Gil-Martin Marta , LoRusso Patricia , Randhawa Manreet , Eskens Ferry , Sanborn Rachel E. , Uboha Nataliya Volodymyrivna , Cho Daniel C. , Spira Alexander I. , Bondarenko Igor , Plummer Elizabeth Ruth , Garcia-Corbacho Javier , Victoria Iván , Lavernia Javier , Melero Ignacio , De Vries Elisabeth , Garner William , Arkenau Hendrik-Tobias , Bendell Johanna C. 
Published: May 2020

3005 Background: Monotherapy with immune checkpoint inhibitors (ICIs) has demonstrated efficacy in many cancers. Combining ICIs PD-L1 + CTLA-4 enhanced efficacy but worsened toxicity vs monotherapy; therefore, CTLA-4 dose modifications are often needed, despite a dose-response effect having been shown for efficacy. CX-072 is an investigational PD-L1 PROBODY therapeutic that is preferentially activated in the tumor microenvironment (TME); localized activation may reduce immune-related AEs (irAEs). PROCLAIM-CX-072-001 identified 10 mg/kg Q2W (Mono10) as the recommended monotherapy dose. Here we provide data for Mono10 and for dose escalation of CX-072 in combination with IPI (Combo), with a focus on long-term (≥6 mo) therapy. Methods: Mono10 was evaluated in multiple tumor types. Combo doses evaluated were CX-072 0.3–10 mg/kg and IPI 3–10 mg/kg Q3W. Patients (pts) with ≥6 mo treatment duration (≥6M-TD) were compared to those with < 6 mo of treatment ( < 6M-TD) as of November 30, 2019. Results: Disease control rates (DCR = CR+PR+SD) were 41% for Mono10 (n = 47 of 114; 10 PRs) and 37% for Combo (n = 10 of 27; 1CR + 4 PRs (1CR and 3PRs at 3 mg/kg IPI [IPI3]). Additional results are shown in the table. No treatment-related adverse events (TRAEs) led to death. The most common reason for discontinuation (dc) in all groups was disease progression. Conclusions: CX-072 monotherapy demonstrated durable responses consistent with activation of the PROBODY therapeutic in the TME. The safety profile supports the tolerability of CX-072 as monotherapy and when combined with IPI3. CX-072 + IPI3 demonstrated activity in heavily pretreated pts with various tumors. The safety profile of the combination of CX-072 with IPI3 compares favorably to historical data (grade ≥3 TRAEs 55% and leading to dc in 36%; Larkin J, et al. N Engl J Med. 2015;373:23-34). CX-072 + IPI3 is being explored in a phase 2 study in 2L melanoma Clinical trial information: NCT03993379 . [Table: see text]
Correlation of pathogenic POLE mutations with clinical benefit to immune checkpoint inhibitor therapy.
Authors: Garmezy Benjamin , Gheeya Jinesh S. , Thein Kyaw Zin , Pilie Patrick Glen , Wang Wanlin , Rodon Ahnert Jordi , Shaw Kenna Rael , Meric-Bernstam Funda , Yap Timothy A 
Published: May 2020

3008 Background: Mutations in DNA polymerase epsilon ( POLE) may induce DNA replication errors, increasing neoantigen load and potentially enhancing clinical benefit to immune checkpoint inhibitors (ICI). We present a clinicopathologic analysis of patients (pts) with advanced cancers harboring POLE mutations and their response to ICI therapy at MD Anderson Cancer Center. Methods: We used targeted exome sequencing via CLIA-certified next generation sequencing assays to identify pts with POLE-aberrant tumors and their co-occurring mutations. The pathogenicity of each POLE mutation was annotated utilizing InterVar and ClinVar databases. Chi-square analysis was performed. Results: Tumors from 12,947 pts were analyzed and 448 (3.5%) pts had a mutation or copy number variation in POLE (3.5%), comparable to the TCGA PanCancer Atlas (4.0%). Clinical data were available for 293 pts; the most common cancers were colorectal (14.7%), non-small cell lung (13.7%), cholangiocarcinoma (13.3%) and melanoma (10.2%). There were 267 unique co-mutations, including KRAS (23.0%), ARID1A (21.5%), BRCA2 (18.7%), ATM (18.4%), CDKN2A (17.5%), BRAF (15.3%), EGFR (15.3%), ATRX (12.6%), CREBBP (11.7%), APC (11.3%), ATR (11.0%), BRCA1 (11.0%) and CDK12 (10.4%). POLE variants were annotated in all pts: pathogenic/likely pathogenic (n = 34, 11.6%), benign/likely benign (61, 20.8%), and variant of unknown significance (198, 67.6%). 104 (35.8%) of 293 pts with POLE mutations received PD-1/L1 inhibitors as monotherapy or in combination. 93 (88.4%) of 104 pts were evaluable for response: Radiological CR 4.3% (n = 4), PR 26.9% (n = 25), SD 22.6% (n = 21), PD 46.2% (n = 43), for a clinical benefit rate (CR + PR + SD) of 53.8%. Pathogenic status of POLE mutation was associated with clinical benefit to PD-1/L1 inhibitors (p = 0.04). TMB (p = 0.44), PD-L1 (p = 0.11), and MSI (p = 0.66) status were not associated with pathogenic status. MSI-H status was not over-represented in pts with ICI clinical benefit (p = 0.36). Conclusions: Pathogenic POLE mutations were associated with clinical benefit to ICI therapy. Further studies are warranted to validate POLE mutations as a predictive biomarker. Multiple co-occurring DNA damage response mutations were found, which may contribute to ICI clinical benefit.
Tumor microenvironment associated with increased pretreatment density of activated PD-1+ LAG-3+/− TIM-3− CD8+ T cells facilitates clinical response to axicabtagene ciloleucel (axi-cel) in patients (pts) with large B-cell lymphoma.
Authors: Galon Jerome , Scholler Nathalie , Perbost Regis , Turcan Sarah , Danan Corinne , Locke Frederick Lundry , Neelapu Sattva Swarup , Miklos David Bernard , Jacobson Caron A. , Lekakis Lazaros J. , Lin Yi , Ghobadi Armin , Chou Justin , Wang Zixing , Xue Allen , Rossi John M. , Bot Adrian 
Published: May 2020

3022 Background: Axi-cel is a US and EU-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for pts with relapsed/refractory large B cell lymphoma after ≥ 2 prior therapies. In ZUMA-1 (NCT02348216), the objective response rate was 83% (58% complete response rate; Locke et al. Lancet Oncol. 2019). T cell-related biology (Immunosign 21; Immunoscore) measured pretreatment in the tumor microenvironment (TME) was associated with response to axi-cel (Rossi et al. AACR 2018. #LB-016; Rossi et al. AACR 2019. #CT153). This expanded analysis characterized the pretreatment TME immune contexture and examined associations between immune cell subsets and response. Methods: In ZUMA-1, pts received axi-cel at a target dose of 2.0 × 106 CAR T cells/kg. Archival pretreatment tumor biopsy samples were analyzed by multiplex immunohistochemistry (Brightplex). Two panels were developed and applied to assess T cell (CD3, CD8, FoxP3, PD-1, LAG-3, TIM-3) and myeloid cell (CD11b, CD14, CD15, LOX1, S100A9, CD68) subsets (n = 14 total). The association between T cell and myeloid cell subset density, prespecified immune scores (Immunosign 21; Immunoscore), and objective response was evaluated. T test values were based on Brightplex analysis. Results: Pretreatment tumor biopsy samples from 18 pts were analyzed (14 objective responders and 4 nonresponders). The pretreatment TME comprised all major myeloid and T cell subsets, with diverse distribution across samples analyzed. The median TME density of monocytes (CD11b+ CD15− CD14+; 1215 cells/mm2) and macrophages (CD68+; 530 cells/mm2) was greater than that of the total CD8+ T cell subset (312 cells/mm2). The pretreatment Immunosign 21 and Immunoscore scores associated positively with the density of all major T cell subsets and some myeloid subsets. The density of activated CD8+ T cells (PD-1+ LAG-3+/− TIM-3−) was most significantly associated with clinical response versus other T cell subsets. The density of nonactivated CD8+ T cells (PD-1− LAG-3− TIM-3−) and exhausted CD8+ T cells (PD-1+ LAG-3+ TIM-3+) were not significantly associated with response. Additional characterization of the immune contexture and correlative analysis of cell subsets will be presented. Conclusions: These results suggest that a TME associated with increased density of activated PD-1+ LAG-3+/− TIM-3− CD8+ T cells, measurable pretreatment, facilitates clinical response in pts post–axi-cel.
Ongoing, first-in-human, phase I dose escalation study of the investigational CD47-blocker TTI-622 in patients with advanced relapsed or refractory lymphoma.
Authors: Patel Krish , Maris Michael B. , Cheson Bruce D. , Zonder Jeffrey A. , Lesokhin Alexander M. , Von Keudell Gottfried , Seymour Erlene Kuizon , Lin Gloria H.Y. , Catalano Tina , Shou Yaping , Iyer Swaminathan Padmanabhan , Ramchandren Radhakrishnan 
Published: May 2020

3030 Background: CD47 is an immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Cancer cells frequently overexpress CD47 to escape immune surveillance. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. TTI-622 acts as a decoy receptor, preventing CD47 from delivering its inhibitory signal and enabling macrophage activation and anti-cancer activity via pro-phagocytic signals present on cancer cells. Unlike many CD47-blocking antibodies, TTI-622 does not bind to human erythrocytes and thus may not cause anemia in patients. Methods: In phase 1A, patients with advanced relapsed or refractory lymphoma received IV TTI-622 once per week with dose increased based on traditional 3+3 escalation. Dosing was on a mg/kg basis with the third and subsequent weekly doses approximately 2-fold higher than the first 2 doses (e.g., 0.05, 0.05, and 0.1 mg/kg for weeks 1, 2 and 3). Blood samples were obtained for PK analysis and assessment of CD47 receptor occupancy (RO) on peripheral T cells. Results: At data cut-off, 19 patients (11 M, 8 F) of median age 62 years (range, 24-86) with the following lymphomas: DLBCL 10; HL 6; and TCL, MCL and FL, 1 each, with a median of 3 prior therapies (range, 1-8) were enrolled. No DLTs have been observed in 5 dose levels (0.05 to 4.0 mg/kg). Grade ≥3 related neutropenia occurred in 2 patients; other related AEs occurring in 2 patients each included abdominal pain, fatigue, and nausea; no patients experienced a related SAE. Acute, post-dose platelet decreases occurred transiently and generally were Grade 1- 2; no related Grade ≥3 thrombocytopenia or anemia AEs have been observed. Preliminary PK data indicate a dose-proportional increase in exposure and a T1/2 of approximately 4-5 days following repeat infusions (Week 6). Preliminary biomarker data reveal approximately 60% RO at the end of the first infusion of 2 mg/kg and more sustained 24-hour RO at 1 and 2 mg/kg vs ≤ 0.8 mg/kg. To date, 1 patient with stage 4 non-GCB DLBCL (5 prior therapies) initially achieved PR by Wk 8 and CR by Wk 36, with response ongoing. Conclusions: TTI-622 is well tolerated at doses up to 4 mg/kg per week. Preliminary data indicate dose-dependent increases in PK exposure and target engagement with 1 DLBCL patient having achieved a durable, ongoing CR. Dose escalation is ongoing and additional safety, PK, biomarker and response data will be available at the time of meeting presentation. Clinical trial information: NCT03530683 .
Final results of controlled IL-12 monotherapy in adults with grade III or IV gliomas.
Authors: Chiocca E. Antonio , Lukas Rimas Vincas , Yu John , Yamini Bakhtiar , Oberheim Bush Nancy Ann , Amidei Christina , Buck Jill Yannetti , Demars Nathan A. , Hadar Nira , Miao John , Estupinan Taylor , Wang Yunxia , Loewy John W. , Gelb Arnold Bruce , Cooper Laurence JN 
Published: May 2020

3040 Background: Interleukin-12 (IL-12), a master regulator of the immune system, results in anti-tumor responses in preclinical models, but safe use requires tightly controlled production. This phase 1 trial (NCT02026271) is the first to evaluate the safety and tolerability of Ad-RTS-hIL-12 (Ad) under transcriptional control with veledimex (V) in adults with grade III or IV gliomas. Methods: Multicenter, phase 1, open-label, 3 + 3 dose escalation study of Ad (a single intratumoral injection, 2 × 1011 viral particles, Day 0) with oral V dosing (Days 0 to 14) of 10, 20, 30, and 40 mg in subjects with rGBM. Results: 38 subjects were treated (resection group: V 10 mg (n = 6); 20 mg (n = 15); 30 mg (n = 4); 40 mg (n = 6); and, stereotactic group: V 20 mg, n = 7). The adverse event profile of Ad+ V, was predictable and controllable, with the main adverse reactions (ARs) being mild to moderate. All ARs were manageable and reversible upon withholding V. We observed increased peak (mean ± SEM) serum recombinant IL-12 and downstream endogenous IFN-g: V 10mg 21.4 ± 11.7 pg/mL and 14.6 ± 7.1 pg/mL; V 20 mg 25.8 ± 7.1 pg/mL and 57.0 ± 26.5 pg/mL; V 30 mg 65.7 ± 45.5 pg/mL and 60.7 ± 50.0 pg/mL; V 40mg 108.8 ± 41.0 pg/mL and 167.5 ± 70.9 pg/mL, V 20mg (stereotactic) 25.1 ± 7.2 pg/mL and 69.8 ± 48.5 pg/mL, respectively. In the V 20 mg cohort , there was an increase in tumor-associated T cells (CD3+CD8+%) from pre-Ad (mean ± SEM) 0.6 ± 0.4 to biopsy (~5 mons) 6.3 ± 5.0 and production of IFN-g 97.2 ± 85.3 pg/g (n = 2). Median overall survival (mOS) in the V 20 mg cohort (resection, n = 15) was 12.7 mons (mean follow-up, 13.1 mons). Subjects with unifocal disease (n = 6) who received low-dose (≤ 20mg total) dexamethasone during active dosing (Days 0-14) had an mOS of 17.8 mons. Tumor response data will be presented. Conclusions: Results of Controlled IL-12 in rGBM are promising, with V-dependent and proportional increases in IL-12 and IFN-g resulting in immune activation, with a favorable safety profile and encouraging survival. The 20 mg V dose is the recommended phase 2 dose. Controlled IL-12 is being evaluated in a monotherapy substudy (n = 36, V 20 mg) and two combination studies with immune checkpoint inhibitors for rGBM. Clinical trial information: NCT02026271 .
Correlating immune toxicity, blood cell counts, and overall survival in cancer patients receiving immune therapy.
Authors: Lu Rong , Xie Donglu , Gloria-McCutchen Yvonne , Saltarski Jessica , von Itzstein Mitchell S. , Hsieh David , Watters Mary Katherine , Bleiberg Benjamin Aaron , Popat Vinita , Ahmed Murtaza , Fattah Farjana , Gerber David E. , Khan Shaheen , Park Jason , Wakeland Edward , Khan Saad A. 
Published: May 2020

3043 Background: Baseline circulating white blood cell differential counts have been proposed as possible markers of response to Immune therapy (ICI) and immune toxicity (irAE), but have not been validated for clinical practice. Methods: 214 patients with various cancers receiving ICI had clinical lab results and overall/organ specific irAE analyzed. Absolute lymphocyte (ALC), eosinophil (AEC) and neutrophil (ANC) counts <7 days of starting and 3-12 weeks after ICI were correlated with survival and development of irAE. The association between overall irAE and cell count changes was evaluated using multivariate logistic regression, adjusting for patients’ age, gender, race, and including all 3 types of cell count changes in one model. The association between overall survival and cell counts changes was tested using multivariate Cox proportional hazard model, adjusting for age, gender, race, and overall irAE (yes/no). Results: The combination of MEDIAN rise or fall in ALC, ANC and AEC after ICI combined with development of irAE was associated with altered overall survival (OS). Higher statistically significant (p=<0.05) OS was seen in patients with AEC↑/irAE+(n=94; median OS 14.9 months), ANC↓/irAE+(60; 17.9 mo), ALC↑/irAE+(65; 11.5 mo), ALC↓/irAE+(92; 12.2 mo). Lower OS was seen with ANC↑/irAE-(21; 5.4 mo), ALC↑/irAE-(9; 5.8 mo), ALC↓/irAE-(24; 6.1 mo). All these relationships were unchanged if patients were grouped into ANY rise during the 3-12 weeks rather than median. After multivariable adjustment for age/sex/race there was statistically significant association between higher baseline ALC and development of any irAE (p=0.05) and grade ≥2 irAE (p=0.02). No association was seen between overall toxicities and ANC or AEC. Organ-specific irAE’s with statistically significant associations included pneumonitis:↓AEC (p=0.05), hepatitis:↓ANC (p=0.05), hypothyroidism:↓ANC (p=0.02), colitis:↑ALC (p=0.02). Skin rash, hypophysitis and adrenalitis were not associated with any cell count changes. Conclusions: In patients with cancer receiving immune therapy, the predictive value of serial monitoring in ALC, AEC and ANC is greatly enhanced by the addition of irAE detection. irAEs appear to be a greater predictor of survival than changes in blood counts. In contrast to prior reports we found ANC/ALC/AEC in isolation were less reliable in predicting improved survival. Lack of standardized methods of assessing irAE’s confound identifying strong associations with clinical lab-derived cell counts.
Association of reinvigoration of circulating anti-telomerase CD4 Th1 response in cancer patients with anti-PD-1 response.
Authors: Orillard Emeline , Boullerot Laura , Laheurte Caroline , Martin Amandine , Jacquin Marion , Berthod Diane , Ramseyer Mélanie , Jacoulet Pascale , Lahourcade Jean , Gainet Brun Marie , Almotlak Hamadi , Puzenat Eve , Nardin Charlee , Eberst Guillaume , Guion-Dusserre Marc , Mansi Laura , Aubin Francois , Westeel Virginie , Borg Christophe , Adotevi Olivier 
Published: May 2020

3044 Background: Increasing evidence highlights the crucial roles played by CD4+ Th1 cells in cancer immunity and immunotherapy (Spitzer et al., Cell 2017, Borst et al., Nat rev Immunol 2018). Here, we investigate the relevance of circulating CD4 Th1 response against shared tumor-associated antigens (TAA) in cancer patients treated by anti-PD-1 immunotherapy. Methods: A total of 46 advanced cancer patients (pts) including 32 pts with non-small cell lung cancer (NSCLC), 14 pts with melanoma, were enrolled (ITHER trial NCT02840058). Patients were treated with anti-PD-1 therapy as standard of care (26 pts with nivolumab and 20 pts with pembrolizumab). Peripheral blood mononuclear cells were collected before and after treatment at 1 and 3 months. The presence of circulating TAA-specific Th1 response was measured by IFNy ELISPOT assay using a mixture of 15mer peptides derived from telomerase (TERT) (Laheurte et al., Oncoimmunology 2016 and Br J C 2019). Results: At the baseline, the anti-TERT Th1 response was observed in 37% of pts. After anti-PD-1 therapy, de novo induction and/or amplification of pre-existing anti-TERT Th1 response was found in 26 % of pts (12/46). Whereas, a decrease of this response was documented in 15% of pts (7/46).The presence of anti-TERT Th1 response in peripheral blood during anti-PD-1 treatment was associated with a prolonged progression free-survival (PFS) as compared to the immune non responder pts (14.4 vs 2.6 months respectively, p = 0.006, HR 0.39 [0.2;0.76]). Similar observation was made for the overall survival (OS) (22.3 vs 12.3 months respectively, p = 0.04 HR 0.45 [0.21;0.96]). Notably, de novo reinvigoration of peripheral anti-TERT Th1 response after anti-PD-1 therapy was associated with a better clinical outcome as compared to the group of pts with decreased immune response after treatment (Median OS not reached vs 5.8 months). In contrast, no association with anti-PD-1 response was observed neither with circulating anti-NY-ESO-1 or with anti-viral Th1 response, concurrently measured in these patients. Conclusions: The reinvigoration of circulating CD4 Th1 against telomerase in patients treated by anti-PD-1 is associated with a better clinical outcome. These results underline the potential interest of monitoring circulating antitumor CD4 Th1 response for immune checkpoint inhibitors management.
An open-label, phase I trial of BI 754091 alone and in combination with BI 754111 in Asian patients (pts) with advanced solid tumors.
Authors: Kang Yoon-Koo , Yamaguchi Kensei , Oh Do-Youn , Kondo Shunsuke , Kuboki Yasutoshi , Morimoto Manabu , Hara Hiroki , Rha Sun Young , Lin Chia-Chi , Tachibana Yoshifumi , Ge Miaomiao , Elgadi Mabrouk M. , Kitano Shigehisa 
Published: May 2020

3054 Background: Dual blockade of immune checkpoint molecules, PD-1 and LAG-3, may enhance the anti-tumor response versus PD-1 blockade alone. This Phase I trial investigated BI 754091, an anti-PD-1 antibody, as monotherapy and in combination with BI 754111, an anti-LAG-3 antibody, in Asian pts with advanced solid tumors. Methods: This trial comprised 3 parts. Parts 1 and 2 (dose escalation) were in pts with unresectable/metastatic solid tumors. In Part 1, pts received BI 754091 240 mg intravenously (iv), every 3 weeks (q3w); in Part 2, pts received BI 754091 240 mg in combination with BI 754111 (400 mg, 600 mg or 800 mg iv, q3w). Dose escalation was guided by a Bayesian logistic regression model, with overdose control. The primary endpoint in Parts 1 and 2 was maximum tolerated dose (MTD) of BI 754091 alone or in combination with BI 754111, based on dose-limiting toxicities (DLTs) in Cycle 1. In Part 3, BI 754091 240 mg plus BI 754111 600 mg q3w was assessed in 4 expansion cohorts. Cohorts A–C included pts with: A) gastric/esophagogastric junction cancer; B) esophageal cancer; C) hepatocellular cancer; all had received ≥1 line of prior systemic therapy and no prior anti-PD-(L)1 therapy. Cohort D included pts who had received prior anti-PD-(L)1 therapy for the tumor types in Cohorts A–C. The primary endpoint in Part 3 was objective response (confirmed complete response or partial response [PR] per RECIST 1.1). Results: In Part 1, 6 pts received BI 754091 240 mg. In Part 2, 9 pts received BI 754091 240 mg plus BI 754111 (400 mg/600 mg/800 mg; n = 3 per cohort). No DLTs were reported in Parts 1 and 2. In Part 3, 121 pts were treated (97 [80%] male, median age 61 years [range 23–80]); Cohorts A/B/C/D included 33/33/20/35 pts. All-grade adverse events (AEs) and treatment-related AEs (TRAEs) were experienced by 96 (79%) and 47 (39%) pts, respectively. The most commonly reported AEs (all/≥G3) were pyrexia (21%/0%), decreased appetite (17%/2%), anemia (11%/6%), and nausea (9%/0%). 36 (30%) pts reported immune-related AEs, most commonly hypothyroidism, in 7 (6%) pts. Confirmed PR was observed in 6 pts (5%; Cohort A/B, n = 4/2) and 35 (29%) pts had stable disease (Cohort A/B/C/D, n = 9/11/10/5). Conclusions: MTD was not reached for BI 754091 monotherapy or for BI 754091 in combination with BI 754111. The recommended dose for the combination was determined as BI 754091 240 mg plus BI 754111 600 mg q3w. Treatment was well tolerated and consistent with that observed in the global trial. Preliminary anti-tumor activity was seen. Clinical trial information: NCT03433898 .