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Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity

Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including thos...

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Published in:Molecular therapy 2021-07, Vol.29 (7), p.2335-2349
Main Authors: Murad, John P., Tilakawardane, Dileshni, Park, Anthony K., Lopez, Lupita S., Young, Cari A., Gibson, Jackson, Yamaguchi, Yukiko, Lee, Hee Jun, Kennewick, Kelly T., Gittins, Brenna J., Chang, Wen-Chung, Tran, Chau P., Martinez, Catalina, Wu, Anna M., Reiter, Robert E., Dorff, Tanya B., Forman, Stephen J., Priceman, Saul J.
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cited_by cdi_FETCH-LOGICAL-c459t-f729117eeaf1c4094bafa3b27991b8284590d7c6d06dec66776dfc1b5d8f05263
cites cdi_FETCH-LOGICAL-c459t-f729117eeaf1c4094bafa3b27991b8284590d7c6d06dec66776dfc1b5d8f05263
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container_title Molecular therapy
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creator Murad, John P.
Tilakawardane, Dileshni
Park, Anthony K.
Lopez, Lupita S.
Young, Cari A.
Gibson, Jackson
Yamaguchi, Yukiko
Lee, Hee Jun
Kennewick, Kelly T.
Gittins, Brenna J.
Chang, Wen-Chung
Tran, Chau P.
Martinez, Catalina
Wu, Anna M.
Reiter, Robert E.
Dorff, Tanya B.
Forman, Stephen J.
Priceman, Saul J.
description Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity. [Display omitted] Priceman, Murad, and colleagues describe an immunocompetent model that demonstrates the safety and efficacy of CAR T cells for the treatment of PSCA+ solid tumors. Importantly, CAR T cell treatment with cyclophosphamide pre-conditioning provides pro-inflammatory immune modulation resulting in reversion of local T cell exclusion and promotion of protective anti-tumor immunity.
doi_str_mv 10.1016/j.ymthe.2021.02.024
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While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity. [Display omitted] Priceman, Murad, and colleagues describe an immunocompetent model that demonstrates the safety and efficacy of CAR T cells for the treatment of PSCA+ solid tumors. 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Published by Elsevier Inc. All rights reserved.</rights><rights>2021 The Author(s) 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-f729117eeaf1c4094bafa3b27991b8284590d7c6d06dec66776dfc1b5d8f05263</citedby><cites>FETCH-LOGICAL-c459t-f729117eeaf1c4094bafa3b27991b8284590d7c6d06dec66776dfc1b5d8f05263</cites><orcidid>0000-0003-0637-2414</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261088/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261088/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33647456$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Murad, John P.</creatorcontrib><creatorcontrib>Tilakawardane, Dileshni</creatorcontrib><creatorcontrib>Park, Anthony K.</creatorcontrib><creatorcontrib>Lopez, Lupita S.</creatorcontrib><creatorcontrib>Young, Cari A.</creatorcontrib><creatorcontrib>Gibson, Jackson</creatorcontrib><creatorcontrib>Yamaguchi, Yukiko</creatorcontrib><creatorcontrib>Lee, Hee Jun</creatorcontrib><creatorcontrib>Kennewick, Kelly T.</creatorcontrib><creatorcontrib>Gittins, Brenna J.</creatorcontrib><creatorcontrib>Chang, Wen-Chung</creatorcontrib><creatorcontrib>Tran, Chau P.</creatorcontrib><creatorcontrib>Martinez, Catalina</creatorcontrib><creatorcontrib>Wu, Anna M.</creatorcontrib><creatorcontrib>Reiter, Robert E.</creatorcontrib><creatorcontrib>Dorff, Tanya B.</creatorcontrib><creatorcontrib>Forman, Stephen J.</creatorcontrib><creatorcontrib>Priceman, Saul J.</creatorcontrib><title>Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. 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This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity. [Display omitted] Priceman, Murad, and colleagues describe an immunocompetent model that demonstrates the safety and efficacy of CAR T cells for the treatment of PSCA+ solid tumors. 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source Open Access: PubMed Central
subjects adoptive cellular immunotherapy
Animals
Antigens, Neoplasm - genetics
Apoptosis
Cell Proliferation
chimeric antigen receptor
cyclophosphamide
Cyclophosphamide - pharmacology
GPI-Linked Proteins - antagonists & inhibitors
GPI-Linked Proteins - genetics
Humans
immunosuppression
Immunotherapy, Adoptive - methods
Male
Mice
Mice, Inbred C57BL
Myeloablative Agonists - pharmacology
Neoplasm Proteins - antagonists & inhibitors
Neoplasm Proteins - genetics
Original
pancreatic cancer
Pancreatic Neoplasms - immunology
Pancreatic Neoplasms - pathology
Pancreatic Neoplasms - therapy
pre-conditioning
prostate cancer
prostate stem cell antigen
Prostatic Neoplasms - immunology
Prostatic Neoplasms - pathology
Prostatic Neoplasms - therapy
Tumor Cells, Cultured
Tumor Microenvironment
Xenograft Model Antitumor Assays
title Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity
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