AXL targeting restores PD-1 blockade sensitivity of STK11 ...
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1 UT Southwestern Medical Center, Dallas, TX, USA. 2 BerGenBio ASA, Bergen Norway. 3 The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4 Merck & Co., Inc., Kenilworth, NJ, USA. AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells Abstract Mutations in the tumor suppressor STK11/LKB1 are associated with negative predictive and prognostic impact in non-small cell lung cancer patients receiving immune checkpoint blockade in several published cohorts, although there have been some conflicting reports on the association of such mutations with patient outcomes in this setting [1-9]. We found that introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in a syngeneic KPL tumor model that recapitulated the responses and tumor microenvironment of human STK11/LKB1 mutant NSCLCs. Mechanistically, KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells to respond to ICB treatment. Systemic inhibition of AXL with the small molecule inhibitor bemcentinib/BGB324 results in increased type I interferon secretion from dendritic cells that expands tumor-associated TCF1+ PD-1+ CD8 T cells, restoring therapeutic response to PD-1 ICB for KPL tumors. This effect was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. Anecdotally, 3 of 3 evaluable NSCLC patients with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that in these models AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC. STK11 Mutated Tumors Lack TCF1 CD8 T Cells Funding Resources / Acknowledgements This work was supported by: CPRIT training grant RP210041(to HL); RCN industrial PhD studentship 311397 (to AR); BerGenBio ASA and NIH grants R01 CA243577 and U54 CA210181 (to RAB); NIH SPORE P50 CA070907, U54 CA224065, and CPRIT RP160652 (to JDM); RP150072 and RP180725 (Y-XF); NIH P30 CA142543 (RAB, JDM, Y-XF). We also thank the ARC, Whole Brain Microscopy Facility and Flow Cytometry Facility cores at UTSW for assistance and we acknowledge NIH P01 HD087150 for cord blood collection. Huiyu Li 1 , Zhida Liu 1 , Longchao Liu 1 , Hongyi Zhang 1 , Chuanhui Han 1 , Luc Girard 1 , Hyunsil Park 1 , Anli Zhang 1 , Chunbo Dong 1 , Jianfeng Ye 1 , Austin Rayford 2 , Michael Peyton 1 , Xiaoguang Li 1 , Kimberley Avila 1 , Xuezhi Cao 1 , Shuiqing Hu 1 , Md Maksudul Alam 1 , Esra Akbay 1 , Luisa M. Solis 3 , Carmen Behrens 3 , Sharia Hemandez-Ruiz 3 , Lu Wei 3 , Ignacio Wistuba 3 , John. V. Heymach 3 , Michael Chisamore 4 , David Micklem 2 , Hani Gabra 2 , Gro Gausdal 2 , James B. Lorens 2 , Bo Li 1 , Yang-Xin Fu 1 , John D. Minna 1 , and Rolf A. Brekken 1 Conclusion / Summary Lack of TCF1-expressing CD8 T cells prevents ICB efficacy in KPL tumors. Systemic inhibition of AXL increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+ PD-1+ CD8 T cells and restored anti-PD-1 efficacy in STK11/LKB1 mutant tumors. Anecdotally, NSCLC patients with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. These results show that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC. Therapeutic Effects in NSCLC Xenografts & Patients 0 10 20 30 40 0 1000 2000 3000 Days After Treatment Tumor Volume (mm 3 ) Ctrl Pembrolizumab BGB324 Combined **** Treat w/ BGB324 0 10 20 30 40 0 1000 2000 3000 Days After Treatment Tumor Volume (mm 3 ) Treat w/ BGB324 *** Ctrl BGB324 Pembrolizumab Combined 0 50 100 150 #TCF1 + PD-1 + CD8 + Cells/mm 3 of tumor ns ns **** Ctrl BGB324 Pembrolizumab Combined 0 50 100 150 #TCF1 + PD-1 + CD8 + Cells/mm 3 of tumor ns ns ** A549 A549 H2122 H2122 Terminal Exhausted T Inhibitory T Proliferating T Central Memory T 0 50 100 Percentage KP KPL KP KPL 0 50 100 150 200 #TCF1 + PD-1 + CD8 + Cells/mm 3 of tumor ** MDACC NSCLC Patients TCF1 CD8 T Cells T Cells TME from scRNAseq CD8 T Cells from scRNAseq Allografts ICB Responses Axl Inhibition in Dendritic Cells Restores TCF1 CD8 T Cells STK11 wt STK11 mut 0 20 40 60 No. of patients None Medium High * AXL Expression in Immune Cells from MDACC NSCLC Patients Axl Expression in Allografts from scRNAseq 0 5 10 15 20 0 500 1000 1500 Days After Treatment Tumor Volume (mm 3 ) Axl -/- - Ctrl Axl -/- - anti-PD-1 **** WT Axl -/- 0 50 100 150 200 #TCF1 + PD-1 + CD8 + Cells/mm 3 of tumor * KPL Allografts in Axl -/- mice TCF1 CD8 T Cells Axl Expression in KPL Tumor Myeloid Cells from scRNAseq 0 5 10 15 20 0 500 1000 1500 2000 Days After Treatment Tumor Volume (mm 3 ) Liposome Ctrl- Combined Liposome- Ctrl Liposome- Combined **** Liposome Ctrl- Ctrl 0 5 10 15 20 0 500 1000 1500 2000 Days After Treatment Tumor Volume (mm 3 ) WT- Ctrl WT- Combined Baft3 -/- - Ctrl Baft3 -/- - Combined **** Responses in KPL Tumor with Macrophages Depletion Responses in KPL Tumor with CD103 + DCs Depletion Ctrl- WT Ctrl- Axl -/- anti-IFNαR- Axl -/- 0 5000 10000 15000 20000 MFI (a.u.) ** ** ns Ctrl BGB324 anti-IFNαR-Ctrl anti-IFNαR-BGB324 0 5000 10000 15000 20000 25000 MFI (a.u.) **** ns ns ns TCF1 Expression in CD8 T Cells Co-cultured with BMDCs IgG- Ctrl IgG- BGB324 anti-IFN a R- BGB324 0 200 400 600 800 #TCF1 + PD-1 + CD8 + Cells/mm 3 of tumor ns **** **** 0 5 10 15 20 0 500 1000 1500 2000 Days After Treatment Tumor Volume (mm 3 ) IgG- Ctrl IgG- Combined anti-IFNaR - Ctrl anti-IFNaR - Combined **** Responses in KPL Tumors with Type I Interferon Receptor Blockade TCF1 CD8 T Cells Ctrl IFNα 0 5000 10000 15000 20000 MFI (a.u.) *** Bemcentinib Sensitizes STK11 Mutant tumors to ICB Therapy KPL Allografts TCF1 CD8 T Cells 0 10 20 30 0 500 1000 1500 2000 Days After Treatment Tumor Volume (mm 3 ) Cd8a wt Tcf7 fl / fl - Ctrl Cd8a wt Tcf7 fl / fl - Combined Cd8a Cre Tcf7 fl / fl - Ctrl Cd8a Cre Tcf7 fl / fl - Combined **** References: 1 Gu M, Xu T, et al. Ther Adv Med Oncol. 2021;13:17588359211006950. 2 Cho BC, et al. Cancer Res. 2020;80(16 Supplement):CT084. 3 Aredo JV, et al. Lung Cancer. 2019;133:144-150. 4 Kwack WG, et al. Oncol Targets Ther. 2020;13:8901–8905. 5 Shire NJ, et al. PLoS One. 2020;15(9):e0238358. 6 Skoulidis F, et al. Cancer Discov. 2018;8(7):822-835. 7 Wang H, et al. 2020;84:106574. 8 Kitajima S, et al. Cancer Discov. 2019;9(1):34-45. 9 Mograbi B, et al. Diagnostics (Basel). 2021;11(2):196 Table 1: NCT03184571, BerGenBio ASA and Merck & Co., Inc. Age/Gender 79 / Male 73 / Male 51 / Male Previous therapy Carboplatin / Paclitaxel Pembrolizumab Atezolizumab STK11 mutation Moderate LD140PY Moderate D115V High S271fs KRAS mutation Not detected Not detected Not detected TP53 mutation High (multiple variants) Moderate R337L High R110P PD-L1 TPS 0 15 0 AXL Expression Tumor and Immune weak pos. Immune strong pos. Immune pos. Target Lesions 1 Lung, 1 Adrenal 1 lymph node, 1 chest wall Sum Longest Diam. 79 mm 85 mm 129 mm PFS on study 10.1 months 3.5 months 6.2 months Overall survival >33 months (ongoing) 10 months 10 months Best response Partial Response Stable Disease Stable Disease Graphic Abstract
Transcript of AXL targeting restores PD-1 blockade sensitivity of STK11 ...
1UT Southwestern Medical Center, Dallas, TX, USA. 2BerGenBio ASA, Bergen Norway. 3The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4Merck & Co., Inc., Kenilworth, NJ, USA.
AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells
AbstractMutations in the tumor suppressor STK11/LKB1 are associated with negativepredictive and prognostic impact in non-small cell lung cancer patients receivingimmune checkpoint blockade in several published cohorts, although there havebeen some conflicting reports on the association of such mutations with patientoutcomes in this setting [1-9]. We found that introduction of a Stk11/Lkb1 (L)mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss(KP) resulted in a syngeneic KPL tumor model that recapitulated the responses andtumor microenvironment of human STK11/LKB1 mutant NSCLCs. Mechanistically,KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells to respond to ICB treatment.Systemic inhibition of AXL with the small molecule inhibitor bemcentinib/BGB324results in increased type I interferon secretion from dendritic cells that expandstumor-associated TCF1+ PD-1+ CD8 T cells, restoring therapeutic response to PD-1ICB for KPL tumors. This effect was observed in syngeneic immunocompetent mousemodels and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumorxenografts. Anecdotally, 3 of 3 evaluable NSCLC patients with identified STK11/LKB1mutations receiving bemcentinib and pembrolizumab demonstrated objectiveclinical response to combination therapy. We conclude that in these models AXL is acritical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.
STK11 Mutated Tumors Lack TCF1 CD8 T Cells
Funding Resources / Acknowledgements This work was supported by: CPRIT training grant RP210041(to HL); RCN industrial PhD studentship 311397(to AR); BerGenBio ASA and NIH grants R01 CA243577 and U54 CA210181 (to RAB); NIH SPORE P50CA070907, U54 CA224065, and CPRIT RP160652 (to JDM); RP150072 and RP180725 (Y-XF); NIH P30CA142543 (RAB, JDM, Y-XF). We also thank the ARC, Whole Brain Microscopy Facility and Flow CytometryFacility cores at UTSW for assistance and we acknowledge NIH P01 HD087150 for cord blood collection.
Huiyu Li1, Zhida Liu1, Longchao Liu1, Hongyi Zhang1, Chuanhui Han1, Luc Girard1, Hyunsil Park1, Anli Zhang1, Chunbo Dong1, Jianfeng Ye1, Austin Rayford2, Michael Peyton1, Xiaoguang Li1, Kimberley Avila1, Xuezhi Cao1, Shuiqing Hu1, Md Maksudul Alam1, Esra Akbay1, Luisa M. Solis3, Carmen Behrens3, Sharia Hemandez-Ruiz3, Lu Wei3, Ignacio Wistuba3, John. V. Heymach3, Michael Chisamore4, David Micklem2, Hani Gabra2, Gro Gausdal2, James B. Lorens2, Bo Li1, Yang-Xin Fu1, John D. Minna1, and Rolf A. Brekken1
Conclusion / SummaryLack of TCF1-expressing CD8 T cells prevents ICB efficacy in KPL tumors. Systemic inhibition of AXL increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+ PD-1+ CD8 T cells and restored anti-PD-1 efficacy in STK11/LKB1 mutant tumors. Anecdotally, NSCLC patients with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. These results show that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.
Therapeutic Effects in NSCLC Xenografts & Patients
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Axl Inhibition in Dendritic Cells Restores TCF1 CD8 T Cells
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AXL Expression in Immune Cells from MDACC NSCLC Patients
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References: 1Gu M, Xu T, et al. Ther Adv Med Oncol. 2021;13:17588359211006950. 2Cho BC, et al. Cancer Res. 2020;80(16 Supplement):CT084. 3Aredo JV, et al. Lung Cancer. 2019;133:144-150. 4Kwack WG, et al. Oncol Targets Ther. 2020;13:8901–8905. 5Shire NJ, et al. PLoS One. 2020;15(9):e0238358. 6Skoulidis F, et al. Cancer Discov.2018;8(7):822-835. 7Wang H, et al. 2020;84:106574. 8Kitajima S, et al. Cancer Discov. 2019;9(1):34-45. 9 Mograbi B, et al. Diagnostics (Basel). 2021;11(2):196
Table 1: NCT03184571, BerGenBio ASA and Merck & Co., Inc.Age/Gender 79 / Male 73 / Male 51 / MalePrevious therapy Carboplatin / Paclitaxel Pembrolizumab AtezolizumabSTK11 mutation Moderate LD140PY Moderate D115V High S271fsKRAS mutation Not detected Not detected Not detectedTP53 mutation High (multiple variants) Moderate R337L High R110PPD-L1 TPS 0 15 0AXL Expression Tumor and Immune weak pos. Immune strong pos. Immune pos.Target Lesions 1 Lung, 1 Adrenal 1 lymph node, 1 chest wallSum Longest Diam. 79 mm 85 mm 129 mmPFS on study 10.1 months 3.5 months 6.2 monthsOverall survival >33 months (ongoing) 10 months 10 monthsBest response Partial Response Stable Disease Stable Disease
Graphic Abstract
![interoperability.blob.core.windows.netinteroperability.blob.core.windows.net/files/MS-AXL/[MS … · Web view[MS-AXL]: Access Application Transfer Protocol Structure. Intellectual](https://static.fdocuments.in/doc/165x107/5a78b88c7f8b9ae91b8e8101/ms-web-viewms-axl-access-application-transfer-protocol-structure-intellectual.jpg)