J. Palomero , V. Galvao , I. Creus , J. Lostes , M. Aylagas , A. Marín-Bayo , M. Rotxés , M. Sanz , M. Lozano-Rabella , A. Garcia-Garijo , A. Yuste-Estevanez , D. Grases , J. Díaz-Gómez , J. González , J.F. Navarro , J.J. Gartner , I. Braña , X. Villalobos , N. Bayó-Puxan , J. Jiménez , E. Garralda
{"title":"新抗原反应性til治疗晚期上皮或icb耐药实体癌的I期临床试验的临床前数据和设计","authors":"J. Palomero , V. Galvao , I. Creus , J. Lostes , M. Aylagas , A. Marín-Bayo , M. Rotxés , M. Sanz , M. Lozano-Rabella , A. Garcia-Garijo , A. Yuste-Estevanez , D. Grases , J. Díaz-Gómez , J. González , J.F. Navarro , J.J. Gartner , I. Braña , X. Villalobos , N. Bayó-Puxan , J. Jiménez , E. Garralda","doi":"10.1016/j.iotech.2024.101030","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Adoptive cell therapy (ACT) of <em>ex vivo</em> expanded tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 28%-49% of metastatic melanoma patients. However, the efficacy of TIL therapy in most epithelial cancers remains limited. We present the design of a phase I clinical study that aims to assess the safety and efficacy of NEXTGEN-TIL, a TIL product selected based on <em>ex vivo</em> neoantigen recognition, in patients with advanced epithelial tumors and immune checkpoint blockade (ICB)-resistant solid tumors.</div></div><div><h3>Materials and methods</h3><div>Pre-rapid expansion protocol (REP) TIL cultures expanded in high-dose interleukin 2 (HD-IL-2) from patients with metastatic solid tumors were screened for recognition of autologous tumor cell lines (TCLs) and/or neoantigens. Six good manufacturing practice (GMP)-grade validations of pre-REP TIL expansion were carried out and TIL cultures from these six intermediate products were selected to carry out the clinical-scale GMP validation of the REP.</div></div><div><h3>Results</h3><div>TILs expanded in 82% of patient-derived tumor biopsies across different cancer types and these frequently contained tumor- and neoantigen-reactive T cells. During GMP validations, a variable number of TIL cultures expanded, constituting the intermediate products (pre-REP). Three finished products were manufactured using a REP which reached cell doses ranging from 4.3e9 to 1.1e11 and met the established specifications. The NEXTGEN-TIL clinical trial entails a first expansion of TILs from tumor fragments in HD-IL-2 followed by TIL screening for neoantigen recognition and REP of selected neoantigen-reactive TIL cultures. Treatment involves a classical non-myeloablative lymphodepleting chemotherapy followed by NEXTGEN-TIL product administration together with HD-IL-2.</div></div><div><h3>Conclusions</h3><div>NEXTGEN-TIL exploits ex vivo expanded neoantigen-reactive TIL to potentially improve efficacy in patients with epithelial and ICB-resistant tumors, with a safety profile like traditional TILs.</div></div>","PeriodicalId":73352,"journal":{"name":"Immuno-oncology technology","volume":"25 ","pages":"Article 101030"},"PeriodicalIF":0.0000,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Preclinical data and design of a phase I clinical trial of neoantigen-reactive TILs for advanced epithelial or ICB-resistant solid cancers\",\"authors\":\"J. Palomero , V. Galvao , I. Creus , J. Lostes , M. Aylagas , A. Marín-Bayo , M. Rotxés , M. Sanz , M. Lozano-Rabella , A. Garcia-Garijo , A. Yuste-Estevanez , D. Grases , J. Díaz-Gómez , J. González , J.F. Navarro , J.J. Gartner , I. Braña , X. Villalobos , N. Bayó-Puxan , J. Jiménez , E. Garralda\",\"doi\":\"10.1016/j.iotech.2024.101030\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Adoptive cell therapy (ACT) of <em>ex vivo</em> expanded tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 28%-49% of metastatic melanoma patients. However, the efficacy of TIL therapy in most epithelial cancers remains limited. We present the design of a phase I clinical study that aims to assess the safety and efficacy of NEXTGEN-TIL, a TIL product selected based on <em>ex vivo</em> neoantigen recognition, in patients with advanced epithelial tumors and immune checkpoint blockade (ICB)-resistant solid tumors.</div></div><div><h3>Materials and methods</h3><div>Pre-rapid expansion protocol (REP) TIL cultures expanded in high-dose interleukin 2 (HD-IL-2) from patients with metastatic solid tumors were screened for recognition of autologous tumor cell lines (TCLs) and/or neoantigens. Six good manufacturing practice (GMP)-grade validations of pre-REP TIL expansion were carried out and TIL cultures from these six intermediate products were selected to carry out the clinical-scale GMP validation of the REP.</div></div><div><h3>Results</h3><div>TILs expanded in 82% of patient-derived tumor biopsies across different cancer types and these frequently contained tumor- and neoantigen-reactive T cells. During GMP validations, a variable number of TIL cultures expanded, constituting the intermediate products (pre-REP). Three finished products were manufactured using a REP which reached cell doses ranging from 4.3e9 to 1.1e11 and met the established specifications. The NEXTGEN-TIL clinical trial entails a first expansion of TILs from tumor fragments in HD-IL-2 followed by TIL screening for neoantigen recognition and REP of selected neoantigen-reactive TIL cultures. Treatment involves a classical non-myeloablative lymphodepleting chemotherapy followed by NEXTGEN-TIL product administration together with HD-IL-2.</div></div><div><h3>Conclusions</h3><div>NEXTGEN-TIL exploits ex vivo expanded neoantigen-reactive TIL to potentially improve efficacy in patients with epithelial and ICB-resistant tumors, with a safety profile like traditional TILs.</div></div>\",\"PeriodicalId\":73352,\"journal\":{\"name\":\"Immuno-oncology technology\",\"volume\":\"25 \",\"pages\":\"Article 101030\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-12-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immuno-oncology technology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2590018824003277\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immuno-oncology technology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2590018824003277","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Preclinical data and design of a phase I clinical trial of neoantigen-reactive TILs for advanced epithelial or ICB-resistant solid cancers
Background
Adoptive cell therapy (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 28%-49% of metastatic melanoma patients. However, the efficacy of TIL therapy in most epithelial cancers remains limited. We present the design of a phase I clinical study that aims to assess the safety and efficacy of NEXTGEN-TIL, a TIL product selected based on ex vivo neoantigen recognition, in patients with advanced epithelial tumors and immune checkpoint blockade (ICB)-resistant solid tumors.
Materials and methods
Pre-rapid expansion protocol (REP) TIL cultures expanded in high-dose interleukin 2 (HD-IL-2) from patients with metastatic solid tumors were screened for recognition of autologous tumor cell lines (TCLs) and/or neoantigens. Six good manufacturing practice (GMP)-grade validations of pre-REP TIL expansion were carried out and TIL cultures from these six intermediate products were selected to carry out the clinical-scale GMP validation of the REP.
Results
TILs expanded in 82% of patient-derived tumor biopsies across different cancer types and these frequently contained tumor- and neoantigen-reactive T cells. During GMP validations, a variable number of TIL cultures expanded, constituting the intermediate products (pre-REP). Three finished products were manufactured using a REP which reached cell doses ranging from 4.3e9 to 1.1e11 and met the established specifications. The NEXTGEN-TIL clinical trial entails a first expansion of TILs from tumor fragments in HD-IL-2 followed by TIL screening for neoantigen recognition and REP of selected neoantigen-reactive TIL cultures. Treatment involves a classical non-myeloablative lymphodepleting chemotherapy followed by NEXTGEN-TIL product administration together with HD-IL-2.
Conclusions
NEXTGEN-TIL exploits ex vivo expanded neoantigen-reactive TIL to potentially improve efficacy in patients with epithelial and ICB-resistant tumors, with a safety profile like traditional TILs.
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