{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T06:08:22Z","timestamp":1777529302102,"version":"3.51.4"},"reference-count":96,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:00:00Z","timestamp":1689724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>In the past years cancer treatments have drastically changed, mainly due to the development of immune checkpoint inhibitors capable of immune modulation in vivo, thus providing major clinical benefit in a number of malignancies. Simultaneously, considerable technical refinements have opened new prospects for the development of immune cell-based medicinal products and unprecedented success with chimeric antigen receptor (CAR)-T cells targeting B-cell hematologic malignancies has been obtained. However, T cell therapies introduced and performed in the field of solid tumors have produced so far only limited responses in selected patient populations. This standstill is attributable to the difficulty in identifying target antigens which are homogeneously expressed by all tumor cells while absent from normal tissues, and the limited T cell persistence and proliferation in a hostile tumor microenvironment that favors immune escape. Replicating the results observed in hematology is a major scientific challenge in solid tumors, and ongoing translational and clinical research is focused on obtaining insight into the mechanisms of tumor recognition and evasion, and how to improve the efficacy of cellular therapies, also combining them with immune checkpoint inhibitors or other agents targeting either the cancer cell or the tumor environment. This paper provides an overview of current adaptive T cell therapy approaches in solid tumors, the research performed to increase their efficacy and safety, and results from ongoing clinical trials.<\/jats:p>","DOI":"10.3390\/cancers15143667","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T21:21:46Z","timestamp":1689801706000},"page":"3667","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Clinical Trials of Cellular Therapies in Solid Tumors"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8839-139X","authenticated-orcid":false,"given":"Simona","family":"Secondino","sequence":"first","affiliation":[{"name":"Oncology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Costanza","family":"Canino","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domiziana","family":"Alaimo","sequence":"additional","affiliation":[{"name":"Oncology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Department of Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Muzzana","sequence":"additional","affiliation":[{"name":"Oncology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Department of Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Galli","sequence":"additional","affiliation":[{"name":"Oncology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Borgetto","sequence":"additional","affiliation":[{"name":"Oncology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Department of Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Basso","sequence":"additional","affiliation":[{"name":"Cell Factory, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Pediatric Oncoematology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Bagnarino","sequence":"additional","affiliation":[{"name":"Cell Factory, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Pulvirenti","sequence":"additional","affiliation":[{"name":"Cell Factory, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Pediatric Oncoematology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrizia","family":"Comoli","sequence":"additional","affiliation":[{"name":"Cell Factory, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Pediatric Oncoematology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9419-7160","authenticated-orcid":false,"given":"Paolo","family":"Pedrazzoli","sequence":"additional","affiliation":[{"name":"Oncology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Department of Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1056\/NEJM198704093161501","article-title":"A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukine-2 or high-dose interleukin-2 alone","volume":"316","author":"Rosenberg","year":"1987","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1084\/jem.159.2.495","article-title":"Successful immunotherapy of natural killer-resistant established pulmonary melanoma metastases by intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin 2","volume":"159","author":"Mazumder","year":"1984","journal-title":"J. Exp. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1086862","DOI":"10.1080\/2162402X.2015.1086862","article-title":"Tumor-intrinsic oncogene pathways mediating immune avoidance","volume":"5","author":"Spranger","year":"2015","journal-title":"Oncoimmunology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1093\/annonc\/mdz285","article-title":"Development of adaptive immune effector therapies in solid tumors","volume":"30","author":"Comoli","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"vi339","DOI":"10.1093\/annonc\/mdq364","article-title":"Advances in systemic treatment of melanoma","volume":"21","author":"Eggermont","year":"2010","journal-title":"Ann. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1056\/NEJMoa1501824","article-title":"Pembrolizumab for the treatment of non-small-cell lung cancer","volume":"372","author":"Garon","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4828","DOI":"10.1200\/JCO.2011.38.0899","article-title":"Cancer immunotherapy comes of age","volume":"29","author":"Topalian","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1126\/science.aaa4967","article-title":"Adoptive cell transfer as personalized immunotherapy for human cancer","volume":"348","author":"Rosenberg","year":"2015","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1056\/NEJMoa1407222","article-title":"Chimeric antigen receptor T cells for sustained remissions in leukemia","volume":"317","author":"Maude","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10024","DOI":"10.1073\/pnas.86.24.10024","article-title":"Expression of immunoglobulin-T-cell-receptor chimeric molecules as functional receptors with antibody-type specificity","volume":"86","author":"Gross","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"980250","DOI":"10.1155\/2012\/980250","article-title":"scFv antibody: Principles and clinical application","volume":"2012","author":"Ahmad","year":"2012","journal-title":"Clin. Dev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1089\/hum.2009.142","article-title":"Fifteen years of gene therapy based on chimeric antigen receptors: \u201care we nearly there yet?\u201d","volume":"20","author":"Dotti","year":"2009","journal-title":"Hum. Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1056\/NEJMoa1709919","article-title":"Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia","volume":"378","author":"Park","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1093\/annonc\/mdv209","article-title":"Combining immunotherapy and anticancer agents: The right path to achieve cancer cure?","volume":"26","author":"Apetoh","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1056\/NEJM198812223192527","article-title":"Use of tumor infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report","volume":"319","author":"Rosenberg","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5233","DOI":"10.1200\/JCO.2008.16.5449","article-title":"Adoptive cell therapy for patients with metastatic melanoma: Evaluation of intensive myeloablative chemoradiation preparative regimens","volume":"26","author":"Dudley","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1200\/JCO.2016.66.7220","article-title":"Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma","volume":"34","author":"Goff","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/S0140-6736(00)02654-4","article-title":"Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomized trial","volume":"356","author":"Takayama","year":"2000","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"188441","DOI":"10.1016\/j.bbcan.2020.188441","article-title":"Immunotherapy for advanced hepatocellular carcinoma, where are we?","volume":"1874","author":"Zhang","year":"2020","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1200\/JCO.2014.58.9093","article-title":"Complete regression of metastatic cervical cancer after treatment with human papillomavirus targeted tumor-infiltratin T cells","volume":"33","author":"Draper","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1126\/science.1251102","article-title":"Cancer immunotherapy based in mutation-specific CD4+T cells in a patient with epithelial cancer","volume":"344","author":"Tran","year":"2014","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1038\/s41591-021-01462-y","article-title":"Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistent metatstatic lung cancer: A phase 1 trial","volume":"27","author":"Creelan","year":"2021","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1038\/s41467-018-03301-0","article-title":"Sensitive and frequent identification of high avidity neo-epitope specific CD8 (+) T cells in immunotherapy na\u00efve ovarian cancer","volume":"9","author":"Bobisse","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1056\/NEJMoa1609279","article-title":"Cell transfer therapy targeting mutant KRAS in cancer","volume":"375","author":"Tran","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/s41591-018-0040-8","article-title":"Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer","volume":"24","author":"Zacharakis","year":"2018","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1126\/science.aad1253","article-title":"Immunogenicity of somatic mutations in human gastrointestinal cancers","volume":"350","author":"Tran","year":"2015","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"690499","DOI":"10.3389\/fimmu.2021.690499","article-title":"Cell therapy with TILs: Training and taming T cells to fight cancer","volume":"12","author":"Kumar","year":"2021","journal-title":"Front. Imuunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6057","DOI":"10.4049\/jimmunol.172.10.6057","article-title":"T cells associated with tumor regression recognize frameshifted products of the CDKN2A tumor suppror gene locus and a mutated HLA Class I gene product","volume":"172","author":"Huang","year":"2004","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1097\/00002371-200501000-00007","article-title":"Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy","volume":"28","author":"Zhou","year":"2005","journal-title":"J. Immunother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.3389\/fonc.2020.01347","article-title":"The ways of isolating neoantigens-specific T cells","volume":"10","author":"Li","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/nm.3161","article-title":"Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells","volume":"19","author":"Robbins","year":"2013","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1200\/JCO.19.01381","article-title":"Phase III study of adjuvant Ipilimumab (3 or 10 mg\/kg) versus high-dose Interferon alfa-2B for resected high-risk melanoma: North American Itergroup E1609","volume":"38","author":"Tarhini","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","article-title":"Five-year survival with combined Nivolumab and Ipilimumab in advanced melanoma","volume":"381","author":"Garon","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1056\/NEJMoa1602252","article-title":"Nivolumab for recurrent squamous-cell carcinoma of head and neck","volume":"375","author":"Ferris","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1056\/NEJMoa1510665","article-title":"Nivolumab versus Everolimus in advanced renal-cell carcinoma","volume":"373","author":"Motzer","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardol","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.18632\/oncotarget.27604","article-title":"Adoptive cell therapy in combination with checkpoint inhibitors in ovarian cancer","volume":"11","author":"Kverneland","year":"2020","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/s41586-021-03752-4","article-title":"Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers","volume":"596","author":"Caushi","year":"2021","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1182\/blood-2008-12-195792","article-title":"Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired","volume":"114","author":"Ahmadzadeh","year":"2009","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zhou, X., Wu, J., Duan, C., and Liu, Y. (2020). Retrospective analysis of adoptive TIL therapy plus anti-PD1 therapy in patients with chemotherapy-resistant metastatic osteosarcoma. J. Immunol. Res., 7890985.","DOI":"10.1155\/2020\/7890985"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"100332","DOI":"10.1016\/j.jbo.2020.100332","article-title":"Adoptive transfer of TILs plus anti-PD1 therapy: An alternative combination therapy for treating metastatic osteosarcoma","volume":"25","author":"Wang","year":"2020","journal-title":"J. Bone Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1586\/14737140.6.7.1075","article-title":"Chemotherapy resistance in osteosarcoma: Current challenges and future directions","volume":"6","author":"Chou","year":"2006","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/S1470-2045(17)30624-1","article-title":"Pembrolizumab in advanced soft-tissue sarcoma and bone sarcomas (SARC028): A multicenter, two-cohort, single arm, open-label, phase 2 trial","volume":"18","author":"Tawbi","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13045-019-0743-4","article-title":"Immune checkpoint inhibitors in the treatment of virus-associated cancers","volume":"12","author":"Gao","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0140-6736(95)91150-2","article-title":"Use of gene-modified virus-specific T lymphocytes Epstein-Barr-virus-related lymphoproliferation","volume":"345","author":"Rooney","year":"1995","journal-title":"Lancet"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1182\/blood-2009-08-239186","article-title":"Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients","volume":"115","author":"Heslop","year":"2010","journal-title":"Blood"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1111\/j.1600-6143.2007.01823.x","article-title":"Preemptive therapy of EBV-related lymphoproliferative disease after pediatric haploidentical stem cell transplantation","volume":"7","author":"Comoli","year":"2007","journal-title":"Am. J. Transplant."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1182\/blood-2004-07-2975","article-title":"Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific T Lymphocytes","volume":"105","author":"Straathof","year":"2005","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"8942","DOI":"10.1200\/JCO.2005.02.6195","article-title":"Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes","volume":"23","author":"Comoli","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1182\/blood-2008-05-157222","article-title":"Enhancing the in-vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients","volume":"113","author":"Louis","year":"2009","journal-title":"Blood"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1093\/annonc\/mdr134","article-title":"T-cell theapy for EBV-associated nasopharyngeal carcinoma: Preparative lymphodepleting chemotherapy does not improve clinical results","volume":"23","author":"Secondino","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1158\/1078-0432.CCR-18-2722","article-title":"A phase II study of tumor-infiltrating lymphocyte therapy for human papillomavirus-associated epithelial cancers","volume":"25","author":"Helman","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3389\/fphar.2019.00065","article-title":"PD-1\/PD-L1 inhibitors in cervical cancer","volume":"10","author":"Liu","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1158\/1535-7163.MCT-17-0386","article-title":"Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers","volume":"16","author":"Goodman","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8345235","DOI":"10.1155\/2020\/8345235","article-title":"TILs and anti-PD1 therapy: An alternative combination therapy for PDL1 negative metastatic cervical cancer","volume":"2020","author":"Yin","year":"2020","journal-title":"J. Immunol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nature12213","article-title":"Mutational heterogeneity in cancer ant the search for new cancer-associated genes","volume":"499","author":"Lawrence","year":"2013","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1056\/NEJMoa1406498","article-title":"Genetic basis for clinical response to CTLA-4 blockade in melanoma","volume":"371","author":"Snyder","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.ccell.2020.07.013","article-title":"Identifying and targeting human tumor antigens for T cell-based immunotherapy of solid tumor","volume":"38","author":"Leko","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1146\/annurev-immunol-042617-053402","article-title":"Cancer neoantigens","volume":"37","author":"Schumaker","year":"2019","journal-title":"Ann. Rev. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1126\/science.aaa4971","article-title":"Neoantigens in cancer immunotherapy","volume":"348","author":"Schumaker","year":"2015","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature21349","article-title":"Elements of cancer immunity and the cancer immune set point","volume":"541","author":"Chen","year":"2017","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1016\/S1470-2045(20)30445-9","article-title":"Association of tumor mutational burden with outcomes in patients with advanced solid tumor treated with Pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study","volume":"21","author":"Marabelle","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"122","DOI":"10.3389\/fmolb.2020.00122","article-title":"Mismatch repair pathway, genome instability and cancer","volume":"7","author":"Kafka","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","article-title":"PD-1 blockade in tumors with mismatch-repair deficiency","volume":"372","author":"Le","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1056\/NEJMoa2017699","article-title":"Pembrolizumab in microsatellite instability-high advanced colorectal cancer","volume":"383","author":"Shiu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1007\/s00262-017-2034-7","article-title":"The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity","volume":"66","author":"Thistlethwaite","year":"2017","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.1182\/blood-2017-02-769208","article-title":"Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults","volume":"129","author":"Gardner","year":"2017","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1182\/blood-2006-05-018192","article-title":"Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12\/ECOG 2993 study","volume":"109","author":"Fielding","year":"2007","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"6106","DOI":"10.1158\/1078-0432.CCR-06-1183","article-title":"A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer","volume":"12","author":"Kershaw","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1200\/JCO.2006.05.9964","article-title":"Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: First clinical experience","volume":"24","author":"Lamers","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1038\/s41591-019-0564-6","article-title":"Clinical lessons learned from the first leg of the CAR T cell journey","volume":"25","author":"Majzner","year":"2019","journal-title":"Nat. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.3389\/fimmu.2018.02593","article-title":"Making CAR T cells a solid option for solid tumors","volume":"9","author":"Schmidts","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nri3405","article-title":"Molecular mechanism of T cell co-stimulation and co-inhibition","volume":"13","author":"Chen","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.1182\/blood-2002-04-1041","article-title":"Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors","volume":"100","author":"Haynes","year":"2002","journal-title":"Blood"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.ccell.2020.07.005","article-title":"Engineering CAR-T cells for next-generation cancer therapy","volume":"4","author":"Hong","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1038\/mt.2009.83","article-title":"Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo","volume":"17","author":"Milone","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/s41586-022-04489-4","article-title":"GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas","volume":"603","author":"Majzner","year":"2022","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1056\/NEJMoa2210859","article-title":"GD2-CART01 for relapsed or refractory high-risk neuroblastoma","volume":"388","author":"Caruana","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.it.2015.06.004","article-title":"Engineering CAR-T cells: Design concepts","volume":"36","author":"Srivastava","year":"2015","journal-title":"Trends Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1146\/annurev-med-062315-120245","article-title":"CART T cell therapy for solid tumors","volume":"68","author":"Newick","year":"2017","journal-title":"Annu. Rev. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1097\/CJI.0b013e3181ee6675","article-title":"Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b","volume":"33","author":"Craddock","year":"2010","journal-title":"J. Immunother."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4719","DOI":"10.1158\/1078-0432.CCR-11-0351","article-title":"Expression of a functional CCR2 receptor enhanced tumor localization and tumor eradication by targeted human T cells expressing a mesothelin-specific chimeric antibody receptor","volume":"17","author":"Moon","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/nm.3833","article-title":"Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes","volume":"21","author":"Caruana","year":"2015","journal-title":"Nat. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/imm.12036","article-title":"The immunosuppressive tumour network: Myeloid-derived suppressor cells, regulatory T cells and natural killer T cells","volume":"138","author":"Lindau","year":"2013","journal-title":"Immunology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: Integrating immunity\u2019s roles in cancer suppression and promotion","volume":"331","author":"Schreiber","year":"2011","journal-title":"Science"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/ncponc0666","article-title":"Increased intensity lymphodepletion and adoptive immunotherapy\u2014How far can we go?","volume":"3","author":"Muranski","year":"2006","journal-title":"Nat. Clin. Pract. Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4133","DOI":"10.1182\/blood-2011-12-400044","article-title":"Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning","volume":"119","author":"Pegram","year":"2012","journal-title":"Blood"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Boccalatte, F., Mina, R., Aroldi, A., Leone, S., Suryadevara, C.M., Placantonakis, D.G., and Bruno, B. (2022). Advances and hurdles in CAR T cell immune therapy for solid tumors. Cancers, 14.","DOI":"10.3390\/cancers14205108"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"39833","DOI":"10.1038\/srep39833","article-title":"An oxygen sensitive self-decision making engineered CAR T-cell","volume":"7","author":"Juillerat","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1158\/2326-6066.CIR-19-0293","article-title":"Glypican-3-specific CAR T cells co-expressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma","volume":"8","author":"Batra","year":"2020","journal-title":"Cancer Immunol. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.3389\/fimmu.2018.02493","article-title":"Engineering CAR-T cells for improved function against solid tumors","volume":"29","author":"Morgan","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/s41590-020-0676-7","article-title":"Adoptive cellular therapy with T. ells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity","volume":"21","author":"Lai","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/mt.2015.4","article-title":"Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression","volume":"23","author":"Curran","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1038\/s41587-019-0192-1","article-title":"CAR-T cells secreting Bites circumvent antigen escape without detectable toxicity","volume":"37","author":"Choi","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_95","first-page":"389","article-title":"Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program intiated early during tumorigenesis","volume":"45","author":"Schietinger","year":"2016","journal-title":"Immunology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"6081","DOI":"10.1016\/j.cell.2021.11.016","article-title":"An NK-like CAR T cell transition in CAR T cell dysfunction","volume":"184","author":"Good","year":"2021","journal-title":"Cell"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/14\/3667\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:14:31Z","timestamp":1760127271000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/14\/3667"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,19]]},"references-count":96,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["cancers15143667"],"URL":"https:\/\/doi.org\/10.3390\/cancers15143667","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,19]]}}}