BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial

Bockorny, Bruno; Semenisty, Valerya; Macarulla, Teresa; Borazanci, Erkut; Wolpin, Brian M.; Stemmer, Salomon M.; Golan, Talia; Geva, Ravit; Borad, Mitesh J.; Pedersen, Katrina; Park, Joon Oh; Ramirez, Robert A.; Abad, David Gutiérrez; Feliú, Jaime; Muñoz, Andrés; Ponz-Sarvisé, Mariano; Peled, Amnon; Lustig, Tzipora M; Bohana‐Kashtan, Osnat; Shaw, Stephen M.; Sorani, Ella; Chaney, Marya; Kadosh, Shaul; Haras, Abi Vainstein; Hoff, Daniel D. Von; Hidalgo, Manuel

doi:10.1038/s41591-020-0880-x

Cited by 340 publications

(294 citation statements)

References 25 publications

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“…interactions between CAFs and CD8 + T-cells ( Figure 2B), which has been linked to inhibition of T-cell migration to the TME (118). Moreover, CXCR4 inhibition improves PDAC sensitivity to anti-PD-1/PD-L1 immunotherapy (119,120). Thus, modulating this axis may further improve clinical outcomes associated with neoadjuvant CRT.…”

Section: Treatment-associated Contractile Phenotype In Cancer-associamentioning

confidence: 99%

Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

Hwang

Jagadeesh

Guo

et al. 2020

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory disease. Characterizing PDAC by mRNA profiling remains particularly challenging. Previously identified bulk expression subtypes were influenced by contaminating stroma and have not yet informed clinical management, whereas single cell RNA-seq (scRNA-seq) of fresh tumors under-represented key cell types. Here, we developed a robust single-nucleus RNA-seq (snRNA-seq) technique for frozen archival PDAC specimens and used it to study both untreated tumors and those that received neoadjuvant chemotherapy and radiotherapy (CRT). Gene expression programs learned across untreated malignant cell and fibroblast profiles uncovered a clinically relevant molecular taxonomy with improved prognostic stratification compared to prior classifications. Moreover, in the increasingly-adopted neoadjuvant treatment context, there was a depletion of classical-like phenotypes in malignant cells in favor of basal-like phenotypes associated with TNF-NFkB and interferon signaling as well as the presence of novel acinar and neuroendocrine classical-like states, which may be more resilient to cytotoxic treatment. Spatially-resolved transcriptomics revealed an association between malignant cells expressing these basal-like programs and higher immune infiltration with increased lymphocytic content, whereas those exhibiting classical-like programs were linked to sparser macrophage-predominant microniches, perhaps pointing to susceptibility to distinct therapeutic strategies. Our refined molecular taxonomy and spatial resolution can help advance precision oncology in PDAC through informative stratification in clinical trials and insights into differential therapeutic targeting leveraging the immune system.

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Section: Treatment-associated Contractile Phenotype In Cancer-associamentioning

confidence: 99%

Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

Hwang

Jagadeesh

Guo

et al. 2020

Preprint

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“…The primary endpoint was objective response rate. 22 patients received triple combination of motixafortide, pembrolizumab with chemotherapy, with an overall response rate of 32% and median duration of response of 7.8 months [41]. These results need further evaluation in larger randomized clinical trial.…”

Section: Pancreatic Adenocarcinomamentioning

confidence: 99%

Role of Immune Checkpoint Inhibitors in Gastrointestinal Malignancies

Mazloom

Ghalehsari

Gazivoda

et al. 2020

JCM

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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several solid and hematological malignancies. ICIs are not only able to produce long and durable responses, but also very well tolerated by patients. There are several approved indications of use of ICIs in treatment of metastatic gastrointestinal malignancies including gastric, esophageal, colorectal and hepatocellular carcinoma. In addition, ICIs can be used in microsatellite instability-high (MSI-H) and high tumor mutational burden (TMB) tumors in chemotherapy-resistant setting. Despite having good efficacy and superior safety profile, ICIs are clinically active in small subset of patients, therefore, there is a huge unmet need to enhance their efficacy and discover new predictive biomarkers. There are several ongoing clinical trials that are exploring the role of ICIs in various gastrointestinal cancers either as single agent or in combination with chemotherapy, radiation therapy, targeted agents or other immunotherapeutic agents. In this review, we discuss the published and ongoing trials for ICIs in gastrointestinal malignancies, including esophageal, gastric cancer, pancreatic, hepatocellular, biliary tract, colorectal and anal cancers. Specifically, we focus on the use of ICIs in each line of therapy and discuss the future directions of these agents in each type of gastrointestinal cancer.

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“…For example, the chemokine CXCL12 secreted by CAFs and the chemokine receptor CXCR4 found on T cells appear to drive immunosuppression in the TME by increasing populations of MDSCs [132,133]. CXC12 inhibition combined with checkpoint blockade showed improved T cell infiltration and halted tumor growth in mouse models [133] and the phase II COMBAT trial of combination CXCR4 blockade with BL-8040 plus pembrolizumab recently reported a DCR of 34.5% in an ITT of 29 patients and mOS of 7.5 months as a second-line therapy in patients with advanced PDAC [134]. Supportively, the corresponding translational analyses indicated that BL-8040 reduced MDSC and Treg populations and increased tumor infiltration with CTLs [134].…”

Section: Combination Checkpoint Blockade and Stromal Targeting Agentsmentioning

confidence: 99%

“…CXC12 inhibition combined with checkpoint blockade showed improved T cell infiltration and halted tumor growth in mouse models [133] and the phase II COMBAT trial of combination CXCR4 blockade with BL-8040 plus pembrolizumab recently reported a DCR of 34.5% in an ITT of 29 patients and mOS of 7.5 months as a second-line therapy in patients with advanced PDAC [134]. Supportively, the corresponding translational analyses indicated that BL-8040 reduced MDSC and Treg populations and increased tumor infiltration with CTLs [134]. These exciting results are likely to lead onto confirmatory phase III studies.…”

Section: Combination Checkpoint Blockade and Stromal Targeting Agentsmentioning

confidence: 99%

Targeting the immune milieu in gastrointestinal cancers

2020

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Gastrointestinal (GI) cancers are among the most common and lethal solid tumors worldwide. Unlike in malignancies such as lung, renal and skin cancers, the activity of immunotherapeutic agents in GI cancers has, on the whole, been much less remarkable and do not apply to the majority. Furthermore, while incremental progress has been made and approvals for use of immune checkpoint inhibitors (ICIs) in specific subsets of patients with GI cancers are coming through, in a population of ‘all-comers’, it is frequently unclear as to who may benefit most due to the relative lack of reliable predictive biomarkers. For most patients with newly diagnosed advanced or metastatic GI cancer, the mainstay of treatment still involves chemotherapy and/or a targeted agent however, beyond the second-line this paradigm confers minimal patient benefit. Thus, current research efforts are concentrating on broadening the applicability of ICIs in GI cancers by combining them with agents designed to beneficially remodel the tumor microenvironment (TME) for more effective anti-cancer immunity with intention of improving patient outcomes. This review will discuss the currently approved ICIs available for the treatment of GI cancers, the strategies underway focusing on combining ICIs with agents that target the TME and touch on recent progress toward identification of predictors of sensitivity to immune checkpoint blockade in GI cancers.

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BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial

Cited by 340 publications

References 25 publications

Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

Role of Immune Checkpoint Inhibitors in Gastrointestinal Malignancies

Targeting the immune milieu in gastrointestinal cancers

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