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In preclinical work, the inflammatory cytokine IL-1β was shown to be upregulated in pancreatic cancer tumors and to contribute to activation of pancreatic stellate cells and immunosuppression (Das et al 2020). We conducted an open-label multicenter Phase Ib study evaluating gemcitabine, nab-paclitaxel, canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) mAb, and spartalizumab (PDR001), a PD-1 mAb. Eligible subjects had previously untreated metastatic PDA and RECIST measurable disease. The primary objective was to confirm recommended phase II dose by evaluating the incidence of dose limiting toxicities (DLTs) in the first 56 days of dosing in at least 6 evaluable subjects utilizing a Bayesian logistic regression model. Subjects underwent baseline and on-study tissue and blood collection for correlative translational research. Results: 10 subjects were enrolled between Nov 2020 and Mar 2021. At the primary data cut off of May 23, 2021, 6 subjects were evaluable for DLT. There were no DLTs, the recommended Phase II dose was established as: gemcitabine (1000mg/m2 IV) day 1,8,15; nab-paclitaxel (125mg/m2 IV) day 1,8,15; canakinumab (250mg SC) day 1, spartalizumab (400mg IV) day 1; of each 28 day cycle. At the time of an updated database extraction on June 1, 2022, 2 subjects remain on study. Adverse events were consistent with those typically seen with chemotherapy. The most common Grade 3/4 AEs were neutropenia (60%) and anemia (50%), with no fatal AEs. One patient discontinued spartalizumab due to grade 3 pneumonitis. In preliminary efficacy analysis (n=10), there are 3 confirmed PRs, 5 subjects with stable disease, 2 subjects with progression as best response. Individual site data estimates that the 12 month OS rate is 60%; updated RR, PFS and OS data will be reported. Activation of CD8 T cells in peripheral blood and increased serum levels of IFN-induced chemokines CXCL9/10 were observed in both responder and non-responder patients. Using an in vitro suppression assay, we showed that baseline serum from responders could induce myeloid derived suppressor cells, an effect that was abrogated with treatment. Single cell transcriptional profiling, multiplex immunofluorescence and spatial transcriptomics also revealed treatment-dependent shifts in T cell activation state and myeloid cells in the tumors of patients experiencing clinical response. Conclusions: PanCAN-SR1 established the Phase II dose of canakinumab and spartalizumab with chemotherapy in first line metastatic PDA, based upon favorable benefit-risk assessment. Based on our comprehensive analysis of 10 patients treated with combination therapy including IL-1b blockade, we hypothesize that the definitive role of anti-IL-1b in human patients with pancreatic cancer is to reduce systemic immune suppression and to reduce immunosuppressive myeloid cell activation in the tumor. The clinical utility of targeting IL-1β in pancreatic cancer is being evaluated in a randomized Phase II/III study through the Precision Promise clinical trial network. NCT04581343. Citation Format: Paul E. Oberstein, Osama Rahma, Nina Beri, Amy Stoll-D'Astice, Emily A. Kawaler, Igor Dolgalev, Gregor Werba, Victoire Cardo-Ruffino, Naïma Böllenrücher, Andressa Dias Costa, Saloney Nazeer, Matthew Squires, Jonathan Nowak, Dafna Bar-Sagi, Brian Wolpin, Diane M Simeone, Stephanie K Dougan. Primary results of PanCAN-SR1, a phase 1b study evaluating Gemcitabine, nab-Paclitaxel, Canakinumab, and Spartalizumab to target IL-1β and PD-1 in metastatic pancreatic cancer with correlative tissue and blood biomarker analysis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR005.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression. Improving our understanding of the PDAC TME and its role in response to therapy via in-depth single cell characterization will have broad clinical implications for biomarker development and therapeutic design. In this study, we performed single-cell RNA sequencing on freshly collected human PDAC samples of primary (n=16) or metastatic (n=11) origin, either before (n=20) or after (n=7) chemotherapy. We found a heterogeneous mixture of basal and classical Moffitt cancer cell subtypes in all samples, along with distinct cancer-associated fibroblast (CAF) and tumor-associated macrophage (TAM) subpopulations. We identified the major CAF subpopulations as inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs); within these subpopulations were a very few cells expressing immunogenic features which have previously been associated with antigen presenting CAFs (apCAFs). Tumor-associated macrophages (TAMs) could be categorized into two major subpopulations, C1QC+ TAMs or SPP1+ TAMs, each with distinct functional characteristics. For example, phagocytosis-associated gene sets were enriched in C1QC+ TAMs, while angiogenesis-associated gene sets were enriched in SPP1+ TAMs. Comparison of naïve and chemotherapy treated primary PDAC samples revealed that classical and basal-like cancer cells exhibited similar transcriptional responses to chemotherapy; this contrasts with some previous reports which posited a shift towards a basal-like transcriptional program among treated samples. We further noted that treated samples evinced fewer ligand-receptor interactions, particularly between TIGIT on CD8+ T cells and its ligand on cancer cells. We also identified TIGIT, not PD1, as the major inhibitory checkpoint molecule of CD8+ T cells in the PDAC TME. Altogether, our results suggest that chemotherapy impacts the PDAC TME and may further reduce response to immunotherapy. Citation Format: Daniel Weissinger, Emily A. Kawaler, Gregor Werba, Ende Zhao, Despoina Kalfakakou, Surajit Dhara, Grace Oh, Xiaohong Jing, Nina Beri, Lauren Khanna, Tamas Gonda, Paul E. Oberstein, Cristina Hajdu, Cynthia Loomis, Adriana Heguy, Mara H. Sherman, Amanda W. Lund, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos, Diane M. Simeone. Single-cell sequencing elucidates the effects of chemotherapy on cancer cell heterogeneity and the tumor microenvironment of human pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR010.

Background: Improving outcomes of PDAC with checkpoint inhibitors (CPIs) have been ineffective, underscoring the need to co-target alternative pathways. Preclinical data showed that CXCR4-SDF1 axis modulates the tumor microenvironment (TME) in PDAC and that CXCR4 inhibition enhances T cell access to the TME, increasing tumor sensitivity to CPIs. This was confirmed in the COMBAT Cohort 1 (CC1) study showing that the dual combination M+P increases activated CD8+ T cells and decreases myeloid derived suppressor cells (MDSCs) within the TME. Moreover, our pre-clinical studies showed that adding C to M+P resulted in improved efficacy vs C alone. The COMBAT Cohort 2 (CC2) aims to test the safety and efficacy of the triple combination of M+P+C in 2L mPDAC. Methods: Single arm phase 2a study in mPDAC. In cohort 2, patients with stage IV PDAC at diagnose who had progressed to 1L gemcitabine-based C received 5 days M priming, followed by M BIW + P Q3W plus C [Irinotecan liposomal injection/5-FU/LV (OFL)] Q2W. The primary endpoint was RR. Results: A total of 43 patients with stage 4 PDAC, 98% of whom were diagnosed with stage 4 disease, were enrolled. Median age was 68 (40-85) and 74.4% had liver disease. The safety profile was consistent with the individual profiles of each treatment alone. Of note, the incidence of ≥G3 neutropenia (G3Neu) was 7% and ≥G3 infection was 7%, which is lower than expected for C (OFL) alone (20% and 17%, respectively). The levels of T-cells increased during M priming and returned to normal values, which remained stable across the study despite the OFL treatment. For the evaluable patients (N=38) the ORR was 21.1% with a 13.2% confirmed ORR (defined as two consecutive assessments showing PR) and a 63.2% DCR (PR+SD). Median duration of clinical benefit was 5.6 months. Median OS and PFS were 6.5 months and 4.0 months, respectively (6.6 months and 3.8 months, respectively, for the ITT population). Conclusions: The triple combination of M+P+C is tolerable and shows encouraging results with cORR 13.2%, mPFS 4.0 months and mOS 6.5 months (compared to 7.7%, ~3 months and 4.7 months, respectively, on a historical basis for OFL alone in the stage 4 diagnosis subpopulation). SD of 42.1% and DCR of 63.2% were also higher than historical data on SoC chemotherapy used in 2L patients. The incidence of severe neutropenia and infections is lower than the historical data on C. The results from the CC2 suggest that M+P may expand the efficacy and safety benefit of OFL in PDAC, and warrants further investigation in a randomized study. Citation Format: Manuel Hidalgo, Teresa Macarulla, Valerya Semenisty, Erkut Borazanci, Jaime Feliu, Mariano Ponz-Sarvise, David Gutierrez Abad, Paul Oberstein, Angela Alistar, Andres Muñoz, Ravit Geva, Carmen Guillén-Ponce, Mercedes Salgado Fernandez, Amnon Peled, Marya Chaney, Irit Glicko-Kabir, Liron Shemesh-Darvish, Debby Ickowicz, Ella Sorani, Shaul E. Kadosh, Abi Vainstein-Haras, Bruno Bockorny. A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT177.

Quantitative metrics to objectively assess the fidelity of cancer models, such as cell lines, organoids, or patient-derived xenografts (PDXs), remain elusive, with histological criteria or the presence of specific mutations often used as driving principles. However, focusing on individual mutations inevitably ignores the effect of a large complement of additional, model-specific genetic and epigenetic events. As a result, effective model fidelity assessment is best performed a posteriori, for instance, by determining whether dependencies identified in a specific tumor model (e.g., a cell line or organoid) are recapitulated in vivo in PDXs or in patients, via pre-clinical or clinical trials. Unfortunately, such an approach is inefficient and time-consuming, creating an urgent need for methodologies capable of effectively and quantitatively assessing model fidelity a priori. This unmet need motivated us to develop and test a quantitative, molecular-level framework (OncoMatch), to assess the fidelity of a given tumor model in the context of a specific biological question, and in particular for addressing issues of drug sensitivity. We addressed this challenge by integrating two independent computational metrics to assess: (a) conservation of regulatory networks inferred from patient-derived samples in a model of interest, and; (b) overlap of master regulator (MR) proteins–i.e., proteins representing the mechanistic determinants of the transcriptional state associated with the phenotype of interest–as inferred from patient-derived and model-derived samples. We show that these molecular-level criteria can effectively identify cell lines that recapitulate patient-specific drug mechanism of action and drug sensitivity, independent of histological consideration. By leveraging gene expression profiles of drug-perturbations in primary cells and explants derived from gastroenteropancreatic-neuroendocrine tumor (GEP-NET) patients, we show that H-STS, an EBV-immortalized lymphoblastoid cell line, represents a high-fidelity model for the assessment of drug mechanism of action and drug sensitivity in these tumors. In particular, our analysis shows highly significant conservation of drug mechanism of action for 60 of 95 profiled drugs (63%, p < 10-10, Bonferroni's corrected), and higher conservation among drugs exhibiting greater bioactivity in this context. This rate is comparable and, in fact higher than what is achieved using tumor-type-matched cell line pairs representative of glioma, pancreatic and prostate carcinoma, and dramatically higher than the conservation observed between unrelated models, which we used as negative controls. Based on this systematic analysis, OncoMatch represents a valuable addition to our repertoire of tools for prioritizing cell lines, organoids and patient-derived xenograft models as high-fidelity human cancer models. We provide comprehensive prioritization of 921 cell lines as potential high-fidelity models for 10,024 human tumor samples in TCGA. This represents an actionable resource to guide selection of cell line models for specific drug mechanism of action and drug sensitivity studies. Citation Format: Mariano J. Alvarez, Yan Pengrong, Mary L. Alpaugh, Michaela Bowden, Ewa T. Sicinska, Chensheng W. Zhou, Charles Karan, Ronald B. Realubit, Prabhjot S. Mundi, Adina Grunn, Jager Dirk, John A. Chabot, Antonio T. Fojo, Paul E. Oberstein, Hanina Hibshoosh, Jeffrey W. Milsom, Matthew H. Kulke, Massimo Loda, Gabriela Chiosis, Diane L. Reidy-Lagunes, Andrea Califano. OncoMatch: Unbiased, quantitative assessment of cancer model fidelity for drug sensitivity and mechanism of action elucidation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-003.