Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

Wang, Yujue; Liu, Sixue; Yang, Zhentao; Algazi, Alain P.; Lomeli, Shirley H.; Wang, Yan; Othus, Megan; Hong, Aayoung; Wang, Xiaoyan; Randolph, Chris E.; Jones, Alexis M.; Bosenberg, Marcus W.; Byrum, Stephanie D.; Tackett, Alan J.; Lopez, Henry; Yates, Clayton; Solit, David B.; Ribas, Antoni; Piva, Marco; Moriceau, Gatien; Lo, Roger S.

doi:10.1016/j.ccell.2021.07.023

Cited by 81 publications

(68 citation statements)

References 34 publications

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“…In support of this, the Src inhibitor dasatinib was recently proposed as a pharmacological on/off switch to control CAR T cell activity transiently and reduce its lethal toxicities [ 43 ]. Additionally, a sequential versus combinatorial treatment regimen of anti-PD-1/PD-L1 lead-in before a MAPK inhibitor was shown to maximize antitumor immunity and efficacy in murine models of melanoma, colorectal, and pancreatic cancer [ 44 ]. Clinically, fulvestrant was well tolerated when previously combined with the first-generation EGFR TKIs gefitinib [ 45 ] and erlotinib [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

Almotlak

Farooqui

Soloff

et al. 2021

IJMS

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High ERβ/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

Almotlak

Farooqui

Soloff

et al. 2021

IJMS

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“…Mechanistically, BRAFi-resistant tumours are cross-resistant to ICB due to ERK reactivation and subsequently enhanced MAPK pathway transcriptional output, which establishes an immunosuppressive environment with dysfunctional dendritic cells [35]. Interestingly, preclinical studies have shown that a lead-in treatment with ICB, before MAPKi, maximizes antitumour immunity and efficacy [36,37].…”

Section: Melanoma and The Problem Of Therapy Resistancementioning

confidence: 99%

Cytoskeletal Remodelling as an Achilles’ Heel for Therapy Resistance in Melanoma

Barreno

2022

Cells

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Melanoma is an aggressive skin cancer with a poor prognosis when diagnosed late. MAPK-targeted therapies and immune checkpoint blockers benefit a subset of melanoma patients; however, acquired therapy resistance inevitably arises within a year. In addition, some patients display intrinsic (primary) resistance and never respond to therapy. There is mounting evidence that resistant cells adapt to therapy through the rewiring of cytoskeleton regulators, leading to a profound remodelling of the actomyosin cytoskeleton. Importantly, this renders therapy-resistant cells highly dependent on cytoskeletal signalling pathways for sustaining their survival under drug pressure, which becomes a vulnerability that can be exploited therapeutically. Here, we discuss the current knowledge on cytoskeletal pathways involved in mainly targeted therapy resistance and future avenues, as well as potential clinical interventions.

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“…Identifying combination strategies that may enhance the durable immunologic response will improve clinical outcomes for NSCLC patients. Recent pre-clinical studies have highlighted the potential role of MEK inhibitor combinations that affect the immune cell landscape 3 , 4 or where tumor MAPK activation drives an immune-evasive tumor microenvironment, 5 indicating a potential role for MEK inhibitors outside of the targeted agent landscape.…”

Section: Main Textmentioning

confidence: 99%

“…Recent pre-clinical work by Wang et al. 4 found that initial treatment with immunotherapy followed by MAPK inhibition optimized anti-tumor response and lead to immune cell reinvigoration. Future studies should focus on the dosing of MEKi that is necessary for CXCL10 induction and further assess which biomarkers best indicate the time point and order when immunotherapy should be given versus MEKi.…”

Section: Main Textmentioning

confidence: 99%

MEK inhibition invigorates chemoimmunotherapy by tumor mitophagy-induced CXCL10 expression

Rodriguez

Gibbons

2022

Cell Reports Medicine

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Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

Cited by 81 publications

References 34 publications

Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

Cytoskeletal Remodelling as an Achilles’ Heel for Therapy Resistance in Melanoma

MEK inhibition invigorates chemoimmunotherapy by tumor mitophagy-induced CXCL10 expression

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