bluuebunny/crossref_metadata_2025 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 .
Using autoantibody signatures to predict immunotherapy discontinuation in melanoma patients.
Authors: Osman Iman , Giles Keith M. , Qian Yingzhi , Wind-Rotolo Megan , Loffredo John , Hulett Tyler , Weber Jeffrey S. , Zhong Hua
Published: May 2020

3069

Background: Immune checkpoint inhibitors (ICIs), e.g., ipilimumab (IPI) and/or nivolumab (NIVO), produce durable survival benefit in a substantial proportion of melanoma patients but can also induce severe immune-related adverse events (irAEs) requiring treatment discontinuation. There is no biomarker to predict irAEs in ICI-treated melanoma patients. Given the similar clinical manifestation between irAEs and autoimmune disorders, we hypothesized that a subset of patients possess a subclinical baseline predisposition to developing irAEs that is characterized by specific autoantibodies (autoAbs). Methods: Pre-treatment melanoma patient sera from the CheckMate-238 Phase III trial of adjuvant IPI vs. NIVO were used for autoAb profiling with HuProt proteomic arrays (CDI Labs). The outcome of interest is to predict toxicity events that caused treatment discontinuation. For each treatment arm, we allocated patients to training and testing datasets in a 3:1 ratio. We calculated the area under the curve (AUC) of the receiver operating characteristic curve to select a probability threshold, which was applied to the testing dataset to assess accuracy, sensitivity, and specificity. Functional enrichment among autoAb protein targets was assessed using Metascape. Results: There were 707 irAEs among 597 patients (IPI = 423, NIVO = 174), of which 355 required treatment discontinuation (IPI = 287, NIVO = 68). In the training sets, we identified a 170 autoAbs signature consisting of 102 autoAbs for IPI treatment and 68 autoAbs for NIVO treatment. In the independent testing set, the signatures showed AUC of 0.85 (0.78, 0.92), 82% sensitivity, 78% specificity, and overall accuracy of 81% to predict IPI discontinuation, and AUC of 0.87 (0.74, 0.99), 75% sensitivity, 97% specificity, and overall accuracy of 88% to predict NIVO discontinuation. Enrichment of nuclear lumen-associated protein targets was identified among autoAb signatures that predict IPI or NIVO discontinuation. Conclusions: The identified signature within a large Phase III trial cohort highlights the potential utility of pre-treatment autoAbs for prediction of patients at high risk of developing irAEs in the adjuvant setting necessitating treatment termination. We are currently validating and refining toxicity-associated autoAb signatures with the goal of developing a Clinical Laboratory Improvement Amendments (CLIA)-certified assay to enable clinicians to optimize immunotherapy delivery and patient selection.
Influence of antibiotic therapy (ATB) on oncological outcomes of metastatic non-small cell lung cancer (mNSCLC) patients treated with chemo-immunotherapy (CIT).
Authors: Clark James , Ricciuti Biagio , Bolina Anita , Venkatraman Deepti , Newsom-Davis Thomas , Ottaviani Diego , Lee Karla , Awad Mark M. , Pinato David James
Published: May 2020

3080

Background: ATB exposure is proven to worsen response and survival in immunotherapy recipients. However, its influence on outcomes from CIT is currently undefined. Methods: We conducted a retrospective, multi-centre observational study including 77 mNSCLC patients who received pembrolizumab, pemetrexed and carboplatin CIT as first-line therapy for mNSCLC, between December 1, 2018 and January 1, 2020 in 3 academic referral centres in Europe and in the United States. We documented ATB exposure in the 30 days prior to CIT commencement (pATB) or concurrently (cATB) until CIT cessation. Outcome measures included overall (OS) and progression-free survival (PFS) calculated from commencement of CIT, and overall response rates (ORR) defined by Response Evaluation Criteria in Solid Tumors (v1.1). Results: We enrolled 77 patients, 41 of whom were female (n = 53%) with adenocarcinoma (n = 73, 95%), performance status (PS) 0-1 (n = 69, 90%) PD-L1 Tumour Proportion Score < 50 (n = 57, 74%). Median OS was 16.4 months (95%CI 8.4-24.4), median PFS was 6.7 months (95%CI 5.7-7.6). ORR was 48% including 1 complete (1%) and 36 partial responses (47%). Eleven patients (14%) received pATB, with penicillin/cephalosporins (p/c, n = 7, 63%) for <7 days (n = 10, 90%). Thirty-five patients (45%) received cATB with p/c (n = 11, 40%) for <7 days (n = 28, 80%). Most common indication for ATB was peri-procedure prophylaxis in pATB (n = 7, 63%) and suspected febrile neutropenia in cATB (n = 14, 40%). pATB (p = 0.004) but not cATB (p = 0.85) predicted for worse OS (19.6 vs 6.5 months, Hazard Ratio [HR] 2.9 95%CI 1.3-6.3). Neither pATB nor cATB predicted for PFS or ORR (p > 0.05). Multivariable analyses confirmed pATB (HR 2.3 95%CI 1.1-5.5, p = 0.05) to predict for OS independent of PD-L1 status, PS and cATB. pATB+/- groups were balanced with regards to age, gender, PS nor PD-L1 status (p > 0.05). Conclusions: Whilst cATB does not compromise outcome from CIT, this study reproduces the detrimental effects observed for pATB exposure in immunotherapy recipients. Mechanistic verification of the immune-biologic foundations underlying this association is urgently warranted.
Targeting HER2 in combination with anti-PD-1 and chemotherapy confers a significant tumor shrinkage of gastric cancer: A multi-institutional phase Ib/II trial of first-line triplet regimen (pembrolizumab, trastuzumab, chemotherapy) for HER2-positive advanced gastric cancer (AGC).
Authors: Rha Sun Young , Lee Choong-Kun , Kim Hyo Song , Kang Beodeul , Jung Minkyu , Bae Woo Kyun , Koo Dong-Hoe , Shin Su-Jin , Jeung Hei-Cheul , Zang Dae Young , Chung Hyun Cheol
Published: May 2020

3081

Background: Combining anti-PD-1 agent and trastuzumab has shown synergy in HER2 positive preclinical cancer models. We first report the result of a multi-institutional phase Ib/II trial of triple combination (pembrolizumab, trastuzumab, and chempotherapy) as first line therapy for HER2 positive AGC. (PANTHERA trial; NCT02901301). Methods: Pembrolizumab 200mg IV D1, Trastuzumab 6mg/kg (after 8mg/kg load) D1, Capecitabine 1000mg/m2 bid D1-14, and Cisplatin 80mg/m2 D1 every 3 weeks was selected as recommended phase II dose. The primary endpoint for phase II was ORR per RECIST v1.1. Secondary endpoints included PFS, OS, DoR, safety, and molecular analysis by targeted NGS. Results: Total of 43 patients were treated with median follow up of 16.1 months, and 11 pts remained on the treatment (treatment duration range: 1.4 to 24 months). There was significant tumor shrinkage of 95.3% with 54.6% median depth of response, with 76.7% ORR (CR 16.3%, PR 60.5%, conversion surgery 4.6%), and 97.7% DCR. Median PFS was 8.6 months (95% CI 7.2-22.0) and median OS was 18.4 months (95% CI 17.9-NA). Subsequent chemotherapy was given to 83.3% of 30 progressed pts. There were no MSI-H/dMMR or EBV-positive pts. PD-L1 status (57.1% of pts ≥ CPS 1 and 14.3% of pts ≥ CPS 10 among 35 pts), metastatic organ or baseline tumor burden was not related to the survival. Treatment-related AE (≥G3) occurred in 32 pts (74.4%) including 17 pts (39.5%) with neutropenia G3-4. Immune-related AEs (≥G3) occurred in 4 pts (10%). Ninety-six tumor tissues from 32 pts (paired tumor tissues from 25 pts) were analyzed with targeted NGS. TMB (median 12.7 mut/MB with range of 9.45-16.71) was not related to the PD-L1 expression or survival. Conclusions: First-line triplet regimen (Pembrolizumab, Trastuzumab, and Chemotherapy) confers a significant tumor shrinkage for HER2 positive AGC, regardless of PD-L1 status. Phase III Keynote-811 study (NCT03615326) is ongoing based on the protocol of this study. Clinical trial information: NCT02901301 . [Table: see text]
The spatial localization of CD163+ tumor-associated macrophages predicts prognosis and response to therapy in inflammatory breast cancer.
Authors: Van Berckelaer Christophe , Rypens Charlotte , Van Laere Steven , Marien Koen , Van Dam Pieter-Jan , Vermeulen Peter B. , Colpaert Cecile , Dirix Luc Yves , Kockx Mark , Van Dam Peter
Published: May 2020

3086

Background: The mechanisms contributing to the aggressive biology of inflammatory breast cancer (IBC) are under investigation. A specific immune response seems to be an important driver, but the functional role of infiltrating immune cells in IBC remains unclear. Tumor-associated macrophages (TAMs) are associated with worse outcome, while CD8+ cytotoxic T cells demonstrate anti-tumor properties in breast cancer. In this study, we assessed spatial associations between CD163+ TAMs, CD8+ cells and cancer cells in IBC, using deep-learning and ecological statistics. Methods: We collected clinicopathological variables, evaluated PDL1-positivity (SP142, Ventana) and scored TILs according to the TIL working group guidelines on H&E slides for 144 IBC patients. Immunostainings for CD8 and CD163 (Hematoxylin-DAB) were done according to validated protocols. All slides were digitized, underwent virtual multiplexing and were evaluated in Visiopharm to quantify the number of DAB+ immune cells. Each immune cell was located using XY coordinates and spatial interactions were examined using a Morisita Horn Index (MHI). Tumor cell coordinates were collected using a deep-learning algorithm applied to the CD8-stained slide. This algorithm was trained in 18 images with more than 150.000 iterations (Deeplabv3+). Results: Complete pathological response (pCR) after neo-adjuvant chemotherapy was achieved by 30.6% (n= 30/98) of the patients with initially localized disease. Besides PDL1-postivity ( P= .03), infiltration with CD8+ T cells ( P= .02) and TAMs ( P= .01) also predicted pCR. However, a likelihood ratio test showed no difference between a model using CD8+ cells, TAMs or TILs. Interestingly, the colocalization of CD163+ and CD8+ cells (MHI >0.83) was associated with pCR (P= .01) and remained significant in a multivariate model (OR: 3.18; 95% CI: 1.04 – 10.6; P= .05) including TIL score, PDL1-positivity and hormone receptor (HR) status. Furthermore, a shorter disease-free survival (DFS) was associated with HR- status, no pCR and the colocalization of TAMs near tumor cells (HR: 3.3; 95% CI: 1.6 – 7.1; P= .002) in a multivariate model. The density of TAMs was not associated with outcome. Conclusions: The impact of TAMs on clinical outcome appears to depend on the spatial arrangement. The number of TAMs solely was not associated with outcome, but patients with more TAMs in proximity of the tumor cells had a worse DFS. Surprisingly, the clustering of TAMs near CD8+ cells was associated with pCR independent of the number of TAMs or TILs.
MR1 in combination with tumor mutational burden and PD-1/PD-L1 expression as a potentially novel clinical predictor for T cell exhaustion and immune checkpoint inhibitor response.
Authors: Farha Mark , Jairath Neil , El Naqa Issam , Spratt Daniel Eidelberg , Lawrence Theodore
Published: May 2020

3109

Background: Immune checkpoint inhibitors (ICIs) restore T cell function by reversing T cell exhaustion. Variable response to ICIs warrants the development of precise predictive biomarkers, which is challenging due to difficulty in capturing the interplay of factors involved with tumor cell immune recognition. High intratumoral expression of MR1, the MHC-I related protein basally expressed on cancer cells, may drive T cell exhaustion through presentation of cancer-specific antigens. Here, we construct a database to study the relationship between MR1, tumor mutational burden (TMB), the PD-1/PD-L1 axis and T cell exhaustion across 8,975 sequenced tumors and 27 cancer types. Methods: RNA Seq by expectation maximization (RSEM) values from the TCGA were collected and normalized along with expression data for markers of interest (Table). TMB was defined as the number of non-synonymous somatic mutations per sample. For each cancer, 5 cohorts were created based on ascending mean expression levels of MR1, PD-1, PD-L1, and increasing TMB. For each cancer, an “immunogenicity score” for these factors was computed, and its relationship with T cell exhaustion signatures was assessed via linear regression. Data is presented as adjusted R2 and p-value. Results: While PD-1 and T cell exhaustion marker expression were correlated across cancers, the “immunogenicity score” (IS) correlated with exhaustion markers specifically in cancers with FDA-approved ICIs. Excluding MR1 from the score weakened the correlation with EOMES and TBET expression (Table). Each component of the score analyzed independently failed to show a statistically significant correlation for both EOMES and TBET expression. Conclusions: In this cross-cancer analysis, we support the hypothesis that presentation of metabolic intermediates in cancer cells via MR1 may drive T cell exhaustion. Also, the novel “immunogenicity score”, which incorporates MR1 into standard biomarkers for response to ICIs may convey the global picture of cancer cell recognition by the immune system and warrants further investigation as a tool for predicting clinical response. [Table: see text]
Association between immune and tumor gene signatures with response or resistance to tislelizumab monotherapy or in combination with chemotherapy in gastroesophageal adenocarcinoma.
Authors: Xu Jianming , Liu Tianshu , Lee Jong-Seok , Bai Yuxian , Chao Yee , Yang Silu , Zhang Yun , Ma Xiaopeng , Zhang Pei , Zheng Jianfei , Li Yanyan , Wang Jin , Shen Lin
Published: May 2020

3115

Background: Tislelizumab, an anti-PD-1 monoclonal antibody, has demonstrated clinical benefit as a single agent and in combination with chemotherapy for patients (pts) with gastroesophageal adenocarcinoma (GEA), including gastric, gastroesophageal junction (G/GEJ), and esophageal adenocarcinoma (EAC). Immune- and tumor-transcriptomic features of response and resistance to tislelizumab were assessed from data collected in two monotherapy studies (NCT02407990, CTR20160872) and one tislelizumab plus chemotherapy study (NCT03469557). Methods: Gene expression profiling (GEP), using the 1392-gene HTG EdgeSeq panel, was performed on baseline tumor samples from 103 pts with GEA receiving monotherapy and 13 receiving combination therapy. Signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures (GS). Differential gene signature (DEG) analysis was performed between responders and nonresponders (NRs) using Wilcoxon rank-sum test; GS associated with survival were evaluated using Cox proportional hazards model. Results: Of the 76 pts with available GEP data, 64 (n=51 G/GEJ; n=13 EAC) had evaluable responses. Across these pts with GEA, tislelizumab demonstrated antitumor activity (Table). In pts treated with monotherapy, DEG showed IFNγ GS ( IFNG, CXCL9, CXCL10, HLA-DRA, IDO1, STAT1) scores were positively correlated with response ( P=0.03) as well as progression-free (HR=0.5, 95% CI: 0.27–0.93) and overall survival (HR=0.44, 95% CI: 0.21–0.89). Monotherapy NRs could be clustered into distinct GEP subgroups. Compared with responders, two NR subgroups had lower IFNγ GS ( P=0.002, 0.047) along with either higher epithelial-mesenchymal transition (EMT; P=0.027), and angiogenesis ( P=0.002) or cell cycle (CC; P=0.097) GS expression. A third NR subgroup showed higher CC GS scores compared with responders ( P=0.015), despite high IFNγ GS levels. Unlike tislelizumab monotherapy, responders to combination therapy showed higher CC GS expression versus NRs ( P=0.089). Conclusions: While higher IFNγ GS was associated with clinical benefit with monotherapy, elevated EMT/angiogenesis and CC GS levels may indicate resistance. The effects of these signatures in pts treated with combination therapy may vary. Both immune- and tumor-intrinsic factors may be considered for validation in a phase 3 study (NCT03777657). [Table: see text]
Validation of an immunomodulatory gene signature algorithm to predict response to neoadjuvant immunochemotherapy in patients with primary triple-negative breast cancer.
Authors: Iwase Toshiaki , Pusztai Lajos , Blenman Kim , Li Xiaotong , Seitz Robert , Nielsen Tyler J , Schweitzer Brock L , Hout David Richard , Bailey Dan B , Zhang Xiang , Shen Yichao , Ueno Naoto T.
Published: May 2020

3117

Background: A 101-gene algorithm established as a molecular subtyping method for triple-negative breast cancer (TNBC) includes assignment of an immunomodulatory (IM) subtype based on genes active in immune cell processes. Recently, we isolated the IM concept to an independent 27-gene algorithm and its predictive ability for immunotherapy response was demonstrated in lung cancer. The objective of this study was to validate the predictive accuracy of the IM subtype as determined by the 27-gene algorithm for pathological complete response (pCR) compared with PD-L1 immunohistochemistry (IHC) staining in TNBC. Methods: We obtained RNA sequencing data from pretreatment core needle biopsies in 55 patients with stage I-III primary TNBC who received neoadjuvant immunotherapy (durvalumab with weekly nab-paclitaxel followed by ddAC) in phase I/II trial (NCT02489448). The 27-gene algorithm was used to determine IM positivity using a cutoff point previously validated from 71 lung cancer biopsy patients treated with immunotherapy. Results from the algorithm and PD-L1 IHC (antibody, SP263) were compared with pCR. Predictive accuracy of both methods was determined by diagnostic indicators. In cases positive for the IM subtype and pCR, we analyzed the immune microenvironment by deconvoluting the immune infiltration using a computational algorithm. Results: Of the 55 patients, 25 (45%) had pCR. Compared with previous subtyping methods, the 27-gene algorithm showed stronger predictive value (odds ratio, 4.125; 95% CI, 1.36-13.47; P < 0.015). For PD-L1 IHC, the odds ratio was 2.63 (95% CI, 0.82-9.21; P = 0.11). The positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for PD-L1 IHC were 0.55, 0.68, 1.43, and 0.54, respectively. For the 27-gene algorithm, these metrics were 0.65, 0.69, 2.09, and 0.51, indicating its superior accuracy for predicting pCR. The computational algorithm showed that the IM subtype and pCR were negatively associated with a macrophage-enriched microenvironment. CD4+ T cells and dendritic cells were significantly increased among the baseline immune cell population in IM-positive patients. Conclusions: We conclude that 27-gene algorithm is a clinically applicable and a possible predictive marker for response to neoadjuvant immunochemotherapy for patients with primary TNBC. Our immune microenvironment results suggest that antigen-presenting immune cells have a crucial role in immunochemotherapy response.
Significance of meflin-positive cancer-associated fibroblasts in predicting response to immune checkpoint inhibitors in non-small cell lung cancer.
Authors: Miyai Yuki , Enomoto Atsushi , Ando Yuichi , Takahashi Masahide
Published: May 2020

3118

Background: Tumor immunity is regulated by complex interactions between cancer and immune cells, which also involves other components of the tumor microenvironment (TME). Recently, cancer-associated fibroblasts (CAFs), a major constituent of the TME, have emerged as important regulators of tumor immunity. Specifically, for example, α-smooth muscle actin or leucine-rich repeat containing 15-positive CAFs have been shown to be crucial for the suppression of tumor immunity. However, a comprehensive picture of how other CAF subset(s) are involved in tumor immunity is still lacking. Here, we show the involvement of a CAF subset highly expressing Meflin, which was recently identified as a marker of cancer-restraining CAFs in pancreatic cancer (Mizutani et al., Cancer Res, 2019), in the response of non-small cell lung cancer (NSCLC) patients to immune checkpoint inhibitors (ICIs). Methods: A sample cohort of 122 subjects with NSCLC who had received ICI monotherapy with nivolumab, pembrolizumab, or atezolizumab was identified at the Department of Respiratory Medicine at Nagoya University Hospital. We selected 92 eligible patients, collected formalin-fixed paraffin-embedded tumor tissues, and prepared 4–µm-thick slides for the analysis of Meflin expression by RNA-in situ hybridization assay, followed by the evaluation of treatment response of 88 patients using the iRECIST criteria. We assessed the number of Meflin-positive CAFs and divided the patients into Meflin-High (20% and more CAFs express Meflin) and -Low groups. The cut-off value was obtained by the ROC analysis. Primarily, objective response rate (ORR) was compared between Meflin-High and –Low groups. Overall survival (OS), and progression free survival (PFS) were also assessed. Results: Patients who started to receive ICIs till the end of March 2019 were enrolled and followed-up until the end of 2019. Analysis of the tumor tissues revealed that 24 (40.7%) of 59 Meflin-High patients responded to the ICI monotherapy. In contrast, none (0%) of 29 Meflin-Low patients showed any significant response (p-value: 0.0000174). Meflin-High groups showed statistically significant prolongations in both OS and PFS with the hazard ratios of 0.3114 [0.1591-0.6094] and 0.3997 [0.2290-0.6976], respectively. Conclusions: This retrospective observation indicated that the high infiltration of Meflin-positive CAFs may shape tumor-suppressive immune response and increase the sensitivity to ICIs, which differs from those of other CAF subsets.
Machine learning-based identification of predictive features of the tumor micro-environment and vasculature in NSCLC patients using the IMpower150 study.
Authors: Taylor-Weiner Amaro , Beck Andrew , Cowan James Donovan , Elliott Hunter , Fridlyand Jane , Glass Benjamin , Guardino Ellie , Hegde Priti , Kerner Jennifer K , Khosla Aditya , Lee Mark , Liu Yi , McCleland Mark , Montalto Michael , Schulze Katja , Shames David S. , Srinivasan Ramprakash , Zou Wei , Wapinski Ilan , Giltnane Jennifer Margaret
Published: May 2020

3130

Background: IMpower150 is a phase 3 study measuring the effect of carboplatin and paclitaxel (CP) combined with atezolizumab (A) and/or bevacizumab (B) in patients with advanced nonsquamous NSCLC, testing the hypothesis that anti-PD-L1 therapy may be enhanced by the blockade of VEGF. Here, we apply a machine-learning based approach to quantify the tumor micro-environment (TME) and vasculature and identify associations with clinical outcome in IMpower150. Methods: Digitized H&E images were registered onto the PathAI research platform (n=1027). Over 200K annotations from 90 pathologists were used to train convolutional neural networks (CNNs) that classify human-interpretable features (HIFs) of cells and tissue structures from images. Blood vessel compression (BVC) indices were calculated using the long versus short axes for each predicted blood vessel. HIFs were clustered to reduce redundancy, and selected features were associated with progression free survival (PFS) within each arm (ABCP, ACP, and BCP) using Cox proportional hazard models. Results: We used the trained CNNs to generate 4,534 features summarizing each patient’s histopathology and TME. After association with survival and correction for multiple comparisons we identified clusters that were significantly associated with survival in at least one arm. Among patients receiving treatments that target PD-L1 (ABCP and ACP), high lymphocyte to fibroblast ratio (LFR) was associated with improved PFS (HR=0.64 (0.51, 0.81), p < 0.001) and showed no significant association with PFS among patients treated with BCP alone (HR=1.13 (0.85, 1.51), p=0.4). Among BCP treated patients, a higher average BVC within the tumor tissue was associated with improved PFS (HR=0.67 (0.50,0.90), p=0.01) and worse PFS among patients treated with ACP (HR=1.50 (1.10,2.06), p=0.009). Conclusions: We developed a deep learning-based assay for quantifying pathology features of the TME and vasculature from H&E images. Application of this system to Impower150 identified an association between high LFR and improved PFS among patients receiving PD-L1 targeting therapy, and between low BVC and improved PFS among patients receiving BCP. These findings support the importance of the TME and vasculature in determining response to PD-L1 and VEGF-targeting therapies.