Multimodal delineation of a layer of effector function among exhausted CD8 T cells in tumors
(1) Ray A (2) Bassette M (3) Hu KH (4) Pass LF (5) Courau T (6) Samad B (7) Combes AJ (8) Johri V (9) Davidson B (10) Wai K (11) Ha P (12) Hernandez G (13) Zaleta-Linares I (14) Krummel MF
A bispecific antibody-drug conjugate targeting EGFR and HER3 in metastatic esophageal squamous cell carcinoma: a phase 1b trial
(1) Liu C (2) Liu D (3) Ji Y (4) Sun M (5) Gao S (6) Ma X (7) Zhong D (8) Zhu J (9) Cao Y (10) Qi C (11) Zhang M (12) Zhang P (13) Xue R (14) Peng Z (15) Zhou J (16) Ge S (17) Lu M (18) Yuan J (19) Wang Y (20) Wang Z (21) Li J (22) Zhang X (23) Zhu Y (24) Zhu H (25) Xiao S (26) Gong J (27) Shen L (28) Lu Z
(1) Liu C (2) Liu D (3) Ji Y (4) Sun M (5) Gao S (6) Ma X (7) Zhong D (8) Zhu J (9) Cao Y (10) Qi C (11) Zhang M (12) Zhang P (13) Xue R (14) Peng Z (15) Zhou J (16) Ge S (17) Lu M (18) Yuan J (19) Wang Y (20) Wang Z (21) Li J (22) Zhang X (23) Zhu Y (24) Zhu H (25) Xiao S (26) Gong J (27) Shen L (28) Lu Z
Author Info: (1) Department of Early Drug Development Centre, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and
Author Info: (1) Department of Early Drug Development Centre, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. (2) Department of Early Drug Development Centre, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. (3) Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Henan, China. (4) Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Shandong, China. (5) Department of Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Henan, China. (6) Department of Biological Therapy, West China Hospital of Sichuan University, Sichuan, China. (7) Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China. (8) Department of Abdominal Radiotherapy, Zhejiang Cancer Hospital, Zhejiang, China. (9) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. (10) Department of Early Drug Development Centre, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China. (11) Department of Early Drug Development Centre, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. (12) Department of Early Drug Development Centre, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. (13) Department of Early Drug Development Centre, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. (14) Department of Gastrointestinal Oncology, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China. (15) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. (16) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. (17) Department of Gastrointestinal Oncology, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China. (18) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. (19) Department of Gastrointestinal Oncology, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China. (20) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. (21) Department of Gastrointestinal Oncology, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China. (22) Department of Gastrointestinal Oncology, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China. (23) Sichuan Biokin Pharmaceutical Co. Ltd., Chengdu, China. (24) Sichuan Biokin Pharmaceutical Co. Ltd., Chengdu, China. (25) Baili-Bio (Chengdu) Pharmaceutical Co. Ltd., Chengdu, China. (26) Department of Gastrointestinal Oncology, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China. goodjf@163.com. (27) Department of Gastrointestinal Oncology, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China. shenlin@bjmu.edu.cn. (28) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. zhihaolupku@bjmu.edu.cn.
Citation: Nat Med 2025 Jul 10 Epub07/10/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40640393
CTG-initiated cryptic peptide translation up and downstream of a canonical ATG start codon is enhanced by TLR stimulation and induces tumor regression in mice
(1) Song Z (2) Lim Y (3) van Krimpen A (4) Geleijnse MAA (5) Messchendorp M (6) Voerman JSA (7) Li L (8) Tondeur EGM (9) Mishra G (10) Hos BJ (11) Grashof DGB (12) Stadhouders R (13) van de Werken HJG (14) Katsikis PD (15) Schliehe C
(1) Song Z (2) Lim Y (3) van Krimpen A (4) Geleijnse MAA (5) Messchendorp M (6) Voerman JSA (7) Li L (8) Tondeur EGM (9) Mishra G (10) Hos BJ (11) Grashof DGB (12) Stadhouders R (13) van de Werken HJG (14) Katsikis PD (15) Schliehe C
Author Info: (1) Erasmus MC, Netherlands. (2) Erasmus MC, Rotterdam, ZH, Netherlands. (3) Erasmus MC Rotterdam, Rotterdam, Netherlands. (4) Erasmus MC, Netherlands. (5) Erasmus MC, Netherlands.
Author Info: (1) Erasmus MC, Netherlands. (2) Erasmus MC, Rotterdam, ZH, Netherlands. (3) Erasmus MC Rotterdam, Rotterdam, Netherlands. (4) Erasmus MC, Netherlands. (5) Erasmus MC, Netherlands. (6) Erasmus MC, Netherlands. (7) Erasmus MC, Rotterdam, Netherlands. (8) Erasmus MC, Netherlands. (9) Erasmus MC, Netherlands. (10) Erasmus MC, Netherlands. (11) Erasmus MC, Rotterdam, Netherlands. (12) Erasmus MC, Rotterdam, Netherlands. (13) Erasmus MC Cancer Institute, Rotterdam, Netherlands. (14) Erasmus MC, Rotterdam, Netherlands. (15) Erasmus MC, Rotterdam, Netherlands.
Citation: Cancer Immunol Res 2025 Jun 3 Epub06/03/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40459529
IGM-7354, an immunocytokine with IL-15 fused to an anti-PD-L1 IgM, induces NK and CD8+ T cell-mediated cytotoxicity of PD-L1 positive tumor cells
(1) Desbois M (2) Giffon T (3) Yakkundi P (4) Denson CR (5) Sekar K (6) Hart KC (7) Santos D (8) Calhoun SE (9) Logronio K (10) Pandey S (11) Ng D (12) Saini AK (13) Wang BT (14) Keyt BA (15) Sinclair AM (16) Kotturi MF
(1) Desbois M (2) Giffon T (3) Yakkundi P (4) Denson CR (5) Sekar K (6) Hart KC (7) Santos D (8) Calhoun SE (9) Logronio K (10) Pandey S (11) Ng D (12) Saini AK (13) Wang BT (14) Keyt BA (15) Sinclair AM (16) Kotturi MF
Author Info: (1) IGM Biosciences (United States), Mountain View, United States. (2) IGM Biosciences (United States), Mountain View, United States. (3) IGM Biosciences (United States), Mountain
Author Info: (1) IGM Biosciences (United States), Mountain View, United States. (2) IGM Biosciences (United States), Mountain View, United States. (3) IGM Biosciences (United States), Mountain View, United States. (4) IGM Biosciences (United States), Mountain View, United States. (5) IGM Biosciences (United States), Mountain View, United States. (6) IGM Biosciences (United States), Mountain View, United States. (7) IGM Biosciences (United States), Mountain View, United States. (8) IGM Biosciences Inc, Mountain View, CA, United States. (9) Compugen USA, South San Francisco, CA, United States. (10) IGM Biosciences (United States), Mountain View, United States. (11) IGM Biosciences (United States), Mountain View, United States. (12) IGM Biosciences (United States), Mountain View, CA, United States. (13) IGM Biosciences Inc, Mountain View, CA, United States. (14) IGM Biosciences (United States), Mountain View, CA, United States. (15) IGM Biosciences (United States), Mountain View, CA, United States. (16) IGM Biosciences (United States), Mountain View, CA, United States.
Citation: Cancer Immunol Res 2025 May 22 Epub05/22/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40402523
Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis
(1) Liu R (2) Liu Q (3) Wang Y (4) Liu T (5) Zhang Z (6) Zhao C (7) Tao H (8) Ogando-Rivas E (9) Castillo P (10) Zhang W
(1) Liu R (2) Liu Q (3) Wang Y (4) Liu T (5) Zhang Z (6) Zhao C (7) Tao H (8) Ogando-Rivas E (9) Castillo P (10) Zhang W
Author Info: (1) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China. (2) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China. (3) Shanghai Chest Hospital of Shanghai Jiao Tong Universi
Author Info: (1) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China. (2) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China. (3) Shanghai Chest Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China. (4) Neurology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. (5) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China. (6) Neurosurgery, University of Florida, Gainesville, Florida, USA. (7) Neurosurgery, University of Florida, Gainesville, Florida, USA. (8) Neurosurgery, University of Florida, Gainesville, Florida, USA. (9) Pediatrics, University of Florida, Gainesville, Florida, USA. (10) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China zwb10368@rjh.com.cn.
Citation: J Immunother Cancer 2025 Jul 1 13: Epub07/01/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40592739
Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants
(1) Revach OY (2) Cicerchia AM (3) Shorer O (4) Palin CA (5) Petrova B (6) Anderson S (7) Liu B (8) Park J (9) Chen L (10) Mehta A (11) Wright SJ (12) McNamee N (13) Tal-Mason A (14) Cattaneo G (15) Tiwari P (16) Xie H (17) Sweere JM (18) Cheng LC (19) Sigal N (20) Enrico E (21) Miljkovic M (22) Evans SA (23) Nguyen N (24) Whidden ME (25) Srinivasan R (26) Spitzer MH (27) Sun Y (28) Sharova T (29) Lawless AR (30) Michaud WA (31) Rasmussen MQ (32) Fang J (33) Brook JR (34) Chen F (35) Wang X (36) Ferrone CR (37) Lawrence DP (38) Sullivan RJ (39) Liu D (40) Sachdeva UM (41) Sen DR (42) Flaherty KT (43) Manguso RT (44) Bod L (45) Kellis M (46) Boland GM (47) Yizhak K (48) Yang J (49) Kanarek N (50) Sade-Feldman M (51) Hacohen N (52) Jenkins RW
(1) Revach OY (2) Cicerchia AM (3) Shorer O (4) Palin CA (5) Petrova B (6) Anderson S (7) Liu B (8) Park J (9) Chen L (10) Mehta A (11) Wright SJ (12) McNamee N (13) Tal-Mason A (14) Cattaneo G (15) Tiwari P (16) Xie H (17) Sweere JM (18) Cheng LC (19) Sigal N (20) Enrico E (21) Miljkovic M (22) Evans SA (23) Nguyen N (24) Whidden ME (25) Srinivasan R (26) Spitzer MH (27) Sun Y (28) Sharova T (29) Lawless AR (30) Michaud WA (31) Rasmussen MQ (32) Fang J (33) Brook JR (34) Chen F (35) Wang X (36) Ferrone CR (37) Lawrence DP (38) Sullivan RJ (39) Liu D (40) Sachdeva UM (41) Sen DR (42) Flaherty KT (43) Manguso RT (44) Bod L (45) Kellis M (46) Boland GM (47) Yizhak K (48) Yang J (49) Kanarek N (50) Sade-Feldman M (51) Hacohen N (52) Jenkins RW
Author Info: (1) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad In
Author Info: (1) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (2) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (3) Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3200003, Israel. (4) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (5) Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA; Medical University of Vienna, 1090 Vienna, Austria. (6) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (7) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (8) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (9) Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (10) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (11) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (12) Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (13) Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (14) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (15) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (16) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (17) Teiko Bio, Salt Lake City, UT 84108, USA. (18) Teiko Bio, Salt Lake City, UT 84108, USA. (19) Teiko Bio, Salt Lake City, UT 84108, USA. (20) Teiko Bio, Salt Lake City, UT 84108, USA. (21) Teiko Bio, Salt Lake City, UT 84108, USA. (22) Teiko Bio, Salt Lake City, UT 84108, USA. (23) Teiko Bio, Salt Lake City, UT 84108, USA. (24) Teiko Bio, Salt Lake City, UT 84108, USA. (25) Teiko Bio, Salt Lake City, UT 84108, USA. (26) Teiko Bio, Salt Lake City, UT 84108, USA; Department of Otolaryngology-Head and Neck Cancer, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (27) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (28) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (29) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (30) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (31) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (32) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (33) Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA. (34) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (35) Harvard Medical School, Boston, MA 02115, USA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (36) Harvard Medical School, Boston, MA 02115, USA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (37) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. (38) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. (39) Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (40) Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (41) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (42) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. (43) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (44) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (45) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (46) Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (47) Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3200003, Israel. (48) Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (49) Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA. (50) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (51) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (52) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: rjenkins@mgh.harvard.edu.
Citation: Cell Rep Med 2025 Jun 19 102210 Epub06/19/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40578364
CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming
(1) Venzin V (2) Beccaria CG (3) Perucchini C (4) Delfino P (5) Bono EB (6) Giustini L (7) Moalli F (8) Grillo M (9) Fumagalli V (10) Laura C (11) Di Lucia P (12) Reinhard K (13) Petschenka J (14) Omokoko TA (15) Celant A (16) Ottolini S (17) Kawashima K (18) Rav M (19) De Giovanni M (20) Inverso D (21) Kuka M (22) Kennedy PTF (23) Guilliams M (24) Casorati G (25) Pedica F (26) Ponzoni M (27) _ahin U (28) Le Bert N (29) Bertoletti A (30) Vascotto F (31) Guidotti LG (32) Iannacone M
(1) Venzin V (2) Beccaria CG (3) Perucchini C (4) Delfino P (5) Bono EB (6) Giustini L (7) Moalli F (8) Grillo M (9) Fumagalli V (10) Laura C (11) Di Lucia P (12) Reinhard K (13) Petschenka J (14) Omokoko TA (15) Celant A (16) Ottolini S (17) Kawashima K (18) Rav M (19) De Giovanni M (20) Inverso D (21) Kuka M (22) Kennedy PTF (23) Guilliams M (24) Casorati G (25) Pedica F (26) Ponzoni M (27) _ahin U (28) Le Bert N (29) Bertoletti A (30) Vascotto F (31) Guidotti LG (32) Iannacone M
Author Info: (1) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (2)
Author Info: (1) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (2) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (3) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (4) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (5) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (6) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (7) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. (8) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (9) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (10) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy. (11) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (12) Biopharmaceutical New Technologies (BioNTech), BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (13) Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany. (14) Biopharmaceutical New Technologies (BioNTech), BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (15) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (16) Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore. Department of Molecular Medicine, University of Pavia, Pavia, Italy. (17) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (18) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (19) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (20) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (21) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (22) Department of Hepatology, Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. (23) Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent, Belgium. Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium. (24) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (25) Vita-Salute San Raffaele University, Milan, Italy. Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. (26) Vita-Salute San Raffaele University, Milan, Italy. Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. (27) Biopharmaceutical New Technologies (BioNTech), BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. TRON, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany. (28) Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore. (29) Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore. (30) TRON, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany. (31) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (32) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. iannacone.matteo@hsr.it. Vita-Salute San Raffaele University, Milan, Italy. iannacone.matteo@hsr.it. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. iannacone.matteo@hsr.it.
Citation: Nat Immunol 2025 Jun 30 Epub06/30/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40588520
Different tumour-resident memory T-cell subsets regulate responses to anti-PD-1 and anti-CTLA-4 cancer immunotherapies Spotlight
(1) Damei I (2) Caidi A (3) Auclin E (4) Adam J (5) Mella S (6) Hasan M (7) Tartour E (8) Robert C (9) Corgnac S (10) Mami-Chouaib F
Using the MC38 tumor model, Damei et al. showed that CD103+CD8 TRM cells are involved in responses to anti-PD-1 treatment, but not CTLA-4 blockade. The benefits of anti-PD-1 treatment were compromised in animals challenged with anti-CD8 and anti-CD103 blocking antibodies. CTLA-4 blockade expanded CD49a+CD4+ TRM cells and increased tumor-specific CD4+ TIL-mediated cytotoxicity. CD49a+CD4+ TRM cells with cytotoxic potential were present in human melanoma and lung tumors. Furthermore, a high density of CD49a+CD4 TRM cells in pre-treatment melanoma was predictive of response to CTLA-4 plus PD-1 blockade therapy.
Contributed by Shishir Pant
(1) Damei I (2) Caidi A (3) Auclin E (4) Adam J (5) Mella S (6) Hasan M (7) Tartour E (8) Robert C (9) Corgnac S (10) Mami-Chouaib F
Using the MC38 tumor model, Damei et al. showed that CD103+CD8 TRM cells are involved in responses to anti-PD-1 treatment, but not CTLA-4 blockade. The benefits of anti-PD-1 treatment were compromised in animals challenged with anti-CD8 and anti-CD103 blocking antibodies. CTLA-4 blockade expanded CD49a+CD4+ TRM cells and increased tumor-specific CD4+ TIL-mediated cytotoxicity. CD49a+CD4+ TRM cells with cytotoxic potential were present in human melanoma and lung tumors. Furthermore, a high density of CD49a+CD4 TRM cells in pre-treatment melanoma was predictive of response to CTLA-4 plus PD-1 blockade therapy.
Contributed by Shishir Pant
ABSTRACT: The involvement of tumour-resident memory T (T(RM)) cells in responses to immune checkpoint inhibitors remains unclear. Here, we show that while CD103(+)CD8 T(RM) cells are involved in response to PD-1 blockade, CD49a(+)CD4 T(RM) cells are required for the response to anti-CTLA-4. Using preclinical mouse models, we demonstrate that the benefits of anti-PD-1 treatment are compromised in animals challenged with anti-CD8 and anti-CD103 blocking antibodies. By contrast, the benefits of anti-CTLA-4 are decreased by anti-CD4 and anti-CD49a neutralizing antibodies. Single-cell RNA sequencing on tumour-infiltrating T-lymphocytes (TIL) reveals a CD49a(+)CD4 T(RM) signature, enriched in Ctla-4 transcripts, exacerbated upon anti-CTLA-4. CTLA-4 blockade expands CD49a(+)CD4 T(RM) cells and increases tumour-specific CD4-TIL-mediated cytotoxicity. A CD49a(+)CD4 T(RM) signature enriched in CTLA-4 and cytotoxicity-linked transcripts is also identified in human TILs. Multiplex immunohistochemistry in a cohort of anti-CTLA-4-plus-anti-PD-1-treated melanomas reveals an increase in CD49a(+)CD4 T-cell density in pre-treatment tumours, which correlates with higher rates of patient progression-free survival. Thus, CD49a(+)CD4 T(RM) cells may correspond to a predictive biomarker of response to combined immunotherapy.
Author Info: (1) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. (2) INSE
Author Info: (1) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. (2) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. (3) Department of Medicine, Institut Bergonié, Bordeaux, France. (4) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. Department of Pathology, Paris Saint Joseph Hospital, Paris, France. (5) Single Cell Biomarkers UTechS, Institut Pasteur, Universit Paris Cité, Paris, France. (6) Single Cell Biomarkers UTechS, Institut Pasteur, Université Paris Cité, Paris, France. (7) INSERM U970, Paris Cardiovascular Research Centre, Université Paris-Descartes, Sorbonne Paris Cité, Equipe Labellisée Ligue Contre le Cancer, Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique, Paris, France. (8) Dermatology Unit, Department of Oncology, Institut Gustave Roussy, Villejuif, France. (9) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. (10) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. fathia.mami-chouaib@gustaveroussy.fr.
Citation: Nat Commun 2025 Jul 1 16:5588 Epub07/01/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40593647
Tumor site-directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors
Spotlight(1) Sek K (2) Chen AXY (3) Cole T (4) Armitage JD (5) Tong J (6) Yap KM (7) Munoz I (8) Dunbar PA (9) Wu S (10) van Elsas MJ (11) Hidajat O (12) Scheffler C (13) Giuffrida L (14) Henderson MA (15) Meyran D (16) Souza-Fonseca-Guimaraes F (17) Nguyen D (18) Huang YK (19) de Menezes MN (20) Derrick EB (21) Chan CW (22) Todd KL (23) Chan JD (24) Li J (25) Lai J (26) Petley EV (27) Mardiana S (28) Bosco A (29) Waithman J (30) Parish IA (31) M¿lck C (32) Stewart GD (33) Kats L (34) House IG (35) Darcy PK (36) Beavis PA
Sek and Chen et al. demonstrated that overexpression of the adenosine receptor A1R in CAR T cells reduced cAMP levels, and enhanced baseline and antigen-induced cytokine production and effector differentiation. However, these cells exhibited early terminal differentiation in vivo, leading to reduced persistence and loss of the stem-like memory fraction. A CRISPR KI approach was used to restrict A1R expression to the tumor site via the NR4A2 promoter, which enhanced the efficacy of the CAR T cells against solid tumors. Gene network analysis identified the transcription factor IRF8 to play a major role downstream of A1R signaling.
Contributed by Morgan Janes
(1) Sek K (2) Chen AXY (3) Cole T (4) Armitage JD (5) Tong J (6) Yap KM (7) Munoz I (8) Dunbar PA (9) Wu S (10) van Elsas MJ (11) Hidajat O (12) Scheffler C (13) Giuffrida L (14) Henderson MA (15) Meyran D (16) Souza-Fonseca-Guimaraes F (17) Nguyen D (18) Huang YK (19) de Menezes MN (20) Derrick EB (21) Chan CW (22) Todd KL (23) Chan JD (24) Li J (25) Lai J (26) Petley EV (27) Mardiana S (28) Bosco A (29) Waithman J (30) Parish IA (31) M¿lck C (32) Stewart GD (33) Kats L (34) House IG (35) Darcy PK (36) Beavis PA
Sek and Chen et al. demonstrated that overexpression of the adenosine receptor A1R in CAR T cells reduced cAMP levels, and enhanced baseline and antigen-induced cytokine production and effector differentiation. However, these cells exhibited early terminal differentiation in vivo, leading to reduced persistence and loss of the stem-like memory fraction. A CRISPR KI approach was used to restrict A1R expression to the tumor site via the NR4A2 promoter, which enhanced the efficacy of the CAR T cells against solid tumors. Gene network analysis identified the transcription factor IRF8 to play a major role downstream of A1R signaling.
Contributed by Morgan Janes
ABSTRACT: The efficacy of Chimeric Antigen Receptor T cells against solid tumors is limited by immunosuppressive factors in the tumor microenvironment including adenosine, which suppresses Chimeric Antigen Receptor T cells through activation of the A2A receptor. To overcome this, Chimeric Antigen Receptor T cells are engineered to express A1 receptor, a receptor that signals inversely to A2A receptor. Using murine and human Chimeric Antigen Receptor T cells, constitutive A1 receptor overexpression significantly enhances Chimeric Antigen Receptor T cell effector function albeit at the expense of Chimeric Antigen Receptor T cell persistence. Through a CRISPR/Cas9 homology directed repair "knock-in" approach we demonstrate that Chimeric Antigen Receptor T cells engineered to express A1 receptor in a tumor-localized manner, enhances anti-tumor therapeutic efficacy. This is dependent on the transcription factor IRF8 and is transcriptionally unique when compared to A2A receptor deletion. This data provides a novel approach for enhancing Chimeric Antigen Receptor T cell efficacy in solid tumors and provides proof of principle for site-directed expression of factors that promote effector T cell differentiation.
Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. kevin.sek@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbo
Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. kevin.sek@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. kevin.sek@petermac.org. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (3) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (4) University of Western Australia, Perth, WA, Australia. Telethon Kids Institute, Perth, WA, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (10) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (15) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (16) Frazer Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, QLD, Australia. (17) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (18) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (19) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (20) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (21) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (22) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (23) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (24) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (25) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (26) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (27) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (28) Asthma and Airway Disease Research Center, The University of Arizona, Tucson, AZ, USA. (29) University of Western Australia, Perth, WA, Australia. Telethon Kids Institute, Perth, WA, Australia. (30) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (31) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (32) Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. (33) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (34) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (35) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. phil.darcy@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. phil.darcy@petermac.org. (36) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. paul.beavis@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. paul.beavis@petermac.org.
Citation: Nat Commun 2025 Jul 3 16:6123 Epub07/03/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40610421
Tags:
Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny Spotlight
(1) Nowicki TS (2) Deen NNA (3) Peters CW (4) Comin-Anduix B (5) Medina E (6) Puig-Saus C (7) Carretero IB (8) Kaplan-Lefko P (9) Macabali MH (10) Garcilazo IP (11) Chen D (12) Pang J (13) Berent-Maoz B (14) Haile S (15) Rodriguez J (16) Kawakami M (17) Kidd CK (18) Champhekar A (19) Carlucci G (20) Vega-Crespo A (21) Chmielowski B (22) Singh A (23) Federman N (24) Schiller GM (25) Larson SJ (26) Allen-Auerbach M (27) Klomhaus AM (28) Zack J (29) Baltimore D (30) Yang L (31) Kohn DB (32) Witte ON (33) Ribas A
To overcome the poor persistence and progressive loss of functionality of TCR-engineered T cells, in vivo, Nowicki et al. evaluated tandem treatment with autologous blood-derived T cells and hematopoietic stem cells (HSCs), both engineered with an NY-ESO-TCR. The HSCs also contained the suicide/reporter gene sr39TK to allow for in vivo visualization. In a first-in-human clinical trial in patients with solid tumors, treatment was both safe and feasible (despite clinical difficulties), with early evidence of tumor regression. In circulation, T cell progeny derived from HSCs expressed the engineered TCRs and showed antigen-specific functionality. In vivo imaging aligned with peripheral blood samples.
Contributed by Lauren Hitchings
(1) Nowicki TS (2) Deen NNA (3) Peters CW (4) Comin-Anduix B (5) Medina E (6) Puig-Saus C (7) Carretero IB (8) Kaplan-Lefko P (9) Macabali MH (10) Garcilazo IP (11) Chen D (12) Pang J (13) Berent-Maoz B (14) Haile S (15) Rodriguez J (16) Kawakami M (17) Kidd CK (18) Champhekar A (19) Carlucci G (20) Vega-Crespo A (21) Chmielowski B (22) Singh A (23) Federman N (24) Schiller GM (25) Larson SJ (26) Allen-Auerbach M (27) Klomhaus AM (28) Zack J (29) Baltimore D (30) Yang L (31) Kohn DB (32) Witte ON (33) Ribas A
To overcome the poor persistence and progressive loss of functionality of TCR-engineered T cells, in vivo, Nowicki et al. evaluated tandem treatment with autologous blood-derived T cells and hematopoietic stem cells (HSCs), both engineered with an NY-ESO-TCR. The HSCs also contained the suicide/reporter gene sr39TK to allow for in vivo visualization. In a first-in-human clinical trial in patients with solid tumors, treatment was both safe and feasible (despite clinical difficulties), with early evidence of tumor regression. In circulation, T cell progeny derived from HSCs expressed the engineered TCRs and showed antigen-specific functionality. In vivo imaging aligned with peripheral blood samples.
Contributed by Lauren Hitchings
ABSTRACT: Adoptive transfer of genetically engineered T cells expressing a tumor-antigen-specific transgenic T cell receptor (TCR) can result in clinical responses in a variety of malignancies. However, these responses are frequently short-lived, and patients typically relapse within several months. This phenomenon is largely due to poor persistence of the transgenic T cells, as well as a progressive loss of their functionality and terminal differentiation in vivo. This underscores the need for cell therapy approaches able to sustain the initial antitumor efficacy and lead to long-term antitumor efficacy. Herein, we report the use of tandem cell therapies involving autologous T cells and hematopoietic stem cells engineered to express the NY-ESO-1 TCR for the treatment of solid tumors in a first-in-human phase I clinical trial (NCT03240861). This therapy is shown to be safe, feasible, and leads to initial tumor regression activity. T cell progeny from the HSC progenitors is shown to provide circulating transgenic NY-ESO-1 TCR-T cells, which display tumor-antigen-specific antitumor functionality, without any evidence of anergy or exhaustion. These results demonstrate the utility of transgenic HSCs to generate a self-renewing source of tumor-specific cellular immunotherapy in human participants. Clinicaltrials.gov: NCT NCT03240861.
Author Info: (1) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Department of Microbi
Author Info: (1) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. (2) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (3) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. (4) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. (5) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (6) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. (7) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (8) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (9) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (10) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (11) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (12) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (13) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (14) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (15) David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (16) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. (17) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. (18) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (19) Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. (20) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (21) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (22) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (23) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, CA, USA. (24) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (25) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (26) David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. (27) Department of Medicine Statistics Core, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (28) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (29) Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. (30) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. (31) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. (32) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. (33) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
Citation: Nat Commun 2025 Jul 1 16:5599 Epub07/01/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40593578