PTPRZ1-targeting RNA CAR T cells exert antigen-specific and bystander antitumor activity in glioblastoma

Article Article scientifique Article PTPRZ1-targeting RNA CAR T cells exert antigen-specific and bystander antitumor activity in glioblastoma eng 2024-09-13 author Martinez Bedoya Darel 0000-0002-1603-5801 University of Geneva, Geneva, Switzerland. 932040 Département de médecine (DEMED) author Marinari Eliana 0000-0001-6526-5155 University of Geneva, Geneva, Switzerland. 841772 Département de médecine (DEMED) author Davanture Suzel 0009-0007-3185-4956 University of Geneva, Geneva, Switzerland. 982947 Département de médecine (DEMED) author Castillo Cantero Luis 0009-0007-1704-6354 University of Geneva, Geneva, Switzerland. 983983 Département de médecine (DEMED) author Erraiss Sarah 0009-0003-5524-8919 University of Geneva, Geneva, Switzerland. 412814 author Dockerill Millicent 0000-0003-4657-1637 University of Geneva, Geneva, Geneva, Switzerland. 949778 Département de chimie organique (CHIOR) author Barluenga Badiola Sofia 0000-0003-3830-1178 University of Geneva, Geneva, Geneva, Switzerland. 810177 Département de chimie organique (CHIOR) author Winssinger Nicolas 0000-0003-1636-7766 University of Geneva, Geneva, Geneva, Switzerland. 769664 Département de chimie organique (CHIOR) author Schaller Karl Lothard 0009-0001-8477-5553 Geneva University Hospital, Geneva, Switzerland. 658606 Département des neurosciences cliniques (OTONO) author Bijlenga Philippe Alexandre Pierre 0000-0002-3586-2757 University Hospital of Geneva, Geneva, Switzerland. 104899 Département des neurosciences cliniques (OTONO) author Momjian Shahan Marc 0000-0002-3886-0159 University Hospital of Geneva, Geneva, Switzerland. 84022 Département des neurosciences cliniques (OTONO) author Voize Christel 0009-0008-9349-1465 University Hospital of Lausanne, Lausanne, Switzerland. author Tissot Stéphanie R 0000-0003-3080-4598 Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. author Kandalaft Lana E 0000-0002-1575-6674 CHUV, UNIL, Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Hammel Philippe 0009-0003-9292-3477 University of Geneva, CMU, Geneva 4, Switzerland. 541089 Services communs de la faculté de médecine (SCMU) author Cosson Pierre 0000-0002-4881-0358 University of Geneva, Geneva, Switzerland. 119596 Département de physiologie cellulaire et métabolisme (PHYME) author Walker Paul Richard 0000-0001-8999-6366 University of Geneva, Geneva 4, Switzerland. 104900 Département de médecine (DEMED) author Dutoit Vallotton Valérie 0000-0002-3469-4237 University of Geneva, Geneva, Switzerland. 668630 Département de médecine (DEMED) author Migliorini Denis 0000-0003-0151-3222 University Hospital of Geneva, Geneva, Switzerland. 838158 Département de médecine (DEMED) 10.1158/2326-6066.CIR-23-1094 39269445 2326-6066 https://aacrjournals.org/cancerimmunolres/article/doi/10.1158/2326-6066.CIR-23-1094/748449/PTPRZ1-targeting-RNA-CAR-T-cells-exert-antigen The great success of chimeric antigen receptor (CAR) T-cell therapy in the treatment of patients with B-cell malignancies has prompted its translation to solid tumors. In the case of glioblastoma (GBM), clinical trials have shown modest efficacy, but efforts to develop more effective anti-GBM CAR T cells are ongoing. In this study, we selected PTPRZ1 as a target for GBM treatment. We isolated six anti-human PTPRZ1 scFv from a human phage display library and produced 2nd generation CAR T cells in an RNA format. Patient-derived GBM PTPRZ1-knock-in cell lines were used to select the CAR construct that showed high cytotoxicity while consistently displaying high CAR expression (471_28z). CAR T cells incorporating 471_28z were able to release IFN-?, IL-2, TNF-a, Granzyme B, IL-17A, IL-6, and soluble FasL, and displayed low tonic signaling. Additionally, they maintained an effector memory phenotype after in vitro killing. In addition, 471_28z CAR T cells displayed strong bystander killing against PTPRZ1-negative cell lines after pre-activation by PTPRZ1-positive tumor cells but did not kill antigen-negative non-tumor cells. In an orthotopic xenograft tumor model using NSG mice, a single dose of anti-PTPRZ1 CAR T cells significantly delayed tumor growth. Taken together, these results validate PTPRZ1 as a GBM target and prompt the clinical translation of anti-PTPRZ1 CAR T cells. Dewey 540 Dewey 616.8 Dewey 616 56 Département de médecine 221 61 Département des neurosciences cliniques 226 36 Département de chimie organique 141 false 1310 Tumeurs cérébrales 1016 401 Immunobiologie des tumeurs du cerveau 669 Cancer immunology research 8ffcf891-8dd6-41a0-80f3-058d7fc6e429 Article (Accepted version) Public cir-23-1094.pdf 6551368 application/pdf 3c28db2fd7ba8948b2b4a6f9ba532861427ed04bbd3957ebc9927cc505df72c0 04b7fb9f-fd74-47fb-b193-bcbf1a86e282 Supplemental data Public cir-23-1094_table_s1_suppst1.docx 18155 application/vnd.openxmlformats-officedocument.wordprocessingml.document Table S1: Primer pairs for CAR-T cell phenotyping by qPCR 70cbeb62f588f987159f8994dcb44e0147e16a48298e70a375aad3b0707de96a 40dfeed3-a19f-4f00-80e3-389db5fbc048 Appendix Public cir-23-1094_figure_s1_supps1.docx 523760 application/vnd.openxmlformats-officedocument.wordprocessingml.document Figure S1 9f73ded09c83ce782676a8385f89f5078654e58f4fa972f617b6ef9f149883ed d26c08b9-1c5a-42e2-862c-edb341c9820f Appendix Public cir-23-1094_figure_s2_supps2.docx 334388 application/vnd.openxmlformats-officedocument.wordprocessingml.document Figure S2 dc013431195624514b4b13c33fd688df7b287dbc405f8856d29817284d1c75c1 bf4f3310-08b0-46fb-81f9-698beee292af Appendix Public cir-23-1094_figure_s3_supps3.docx 805666 application/vnd.openxmlformats-officedocument.wordprocessingml.document Figure S3 4990005fab63b092dbba8d854e5e06afba7af966747440fb5d339cef73f8ff37 4925658c-4a23-4dff-abd5-cd173390592a Appendix Public cir-23-1094_figure_s4_supps4.docx 312997 application/vnd.openxmlformats-officedocument.wordprocessingml.document Figure S4 8897d6accdaf40adadcc9813ad067ae9c4b08417c44b4940561809c6c3447f36 0fc0318e-8f9c-418e-867d-05741fbf52f9 Appendix Public cir-23-1094_figure_s5_supps5.docx 235729 application/vnd.openxmlformats-officedocument.wordprocessingml.document Figure S5 c224d925872034eb1dbd7f788f2c6a3e40b4bd3c1877a721d2f84317014f3816 af365092-cd37-4d99-9a21-e1bfc5c4c460 Appendix Public cir-23-1094_figure_s6_supps6.docx 561095 application/vnd.openxmlformats-officedocument.wordprocessingml.document Figure S6 f59810a7a9dcadfb12d167c4e1a997e96111f168dd5cf501b1b162713819cba4 d6c19d88-f6a0-4113-8fdf-ad3266cb78e5 Appendix Public cir-23-1094_figure_s7_supps7.docx 1423938 application/vnd.openxmlformats-officedocument.wordprocessingml.document Figure S7 07e0bddc6761d6319e01da8021a1bdb1aec05a30bfc95eebb659b050b6ca9c82 84592a4b-6449-4396-a6eb-94a67d7e0ef9 Article (Published version) Restricted cir-23-10941.pdf 13455464 application/pdf a5400eb23645dd0725e6d1e9d8b7f2313ab38a233ea181b1261a3fc8191722a2 openAccess Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine clinique / Département des neurosciences cliniques Faculté des sciences / Section de chimie et biochimie / Département de chimie organique

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PTPRZ1-targeting RNA CAR T cells exert antigen-specific and bystander antitumor activity in glioblastoma	Cancer immunology research	2024	305	337
PTPRZ1-targeting RNA CAR-T cells exert antigen-specific and bystander antitumor activity in glioblastoma		2023	247	760

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