Objective: Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor (CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells, especially the lower incidence rate of severe adverse events. However, the median progression-free survival (mPFS) of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta (2.9 monthsvs. 5.9 months), suggesting that Kymriah was limited in the long-term efficacy. Thus, a safe and durable 4-1BB-based CD19 CAR-T needs to be developed. Methods: We designed a CD19-targeted CAR-T (named as IM19) which consisted of an FMC63 scFv, 4-1BB and CD3ζ intracellular domain and was manufactured into a memory T-enriched formulation. A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory (r/r) B cell non-Hodgkin lymphoma (B-NHL). Dose-escalation investigation (at a dose of 5×105/kg, 1×106/kg and 3×106/kg) was performed in 22 r/r B-NHL patients. All patients received a single infusion of IM19 after 3-day conditional regimen. Results: At month 3, the overall response rate (ORR) was 59.1%, the complete response rate (CRR) was 50.0%. The mPFS was 6 months and the 1-year overall survival rate was 77.8%. Cytokine release syndrome (CRS) occurred in 13 patients (59.1%), with 54.5% of grade 1-2 CRS. Only one patient (4.5%) experienced grade 3 CRS and grade 3 neurotoxicity. Conclusions: These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T, IM19, which is promising for further development and clinical investigation.
Objective: Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor (CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells, especially the lower incidence rate of severe adverse events. However, the median progression-free survival (mPFS) of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta (2.9 monthsvs. 5.9 months), suggesting that Kymriah was limited in the long-term efficacy. Thus, a safe and durable 4-1BB-based CD19 CAR-T needs to be developed. Methods: We designed a CD19-targeted CAR-T (named as IM19) which consisted of an FMC63 scFv, 4-1BB and CD3ζ intracellular domain and was manufactured into a memory T-enriched formulation. A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory (r/r) B cell non-Hodgkin lymphoma (B-NHL). Dose-escalation investigation (at a dose of 5×105/kg, 1×106/kg and 3×106/kg) was performed in 22 r/r B-NHL patients. All patients received a single infusion of IM19 after 3-day conditional regimen. Results: At month 3, the overall response rate (ORR) was 59.1%, the complete response rate (CRR) was 50.0%. The mPFS was 6 months and the 1-year overall survival rate was 77.8%. Cytokine release syndrome (CRS) occurred in 13 patients (59.1%), with 54.5% of grade 1-2 CRS. Only one patient (4.5%) experienced grade 3 CRS and grade 3 neurotoxicity. Conclusions: These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T, IM19, which is promising for further development and clinical investigation.
Authors: Nicolas Mounier; Carmen Canals; Christian Gisselbrecht; Jan Cornelissen; Roberto Foa; Eulogio Conde; John Maertens; Michel Attal; Alessandro Rambaldi; Charles Crawley; Jian-Jian Luan; Mats Brune; Sebastian Wittnebel; Gordon Cook; G W van Imhoff; Michael Pfreundschuh; Anna Sureda Journal: Biol Blood Marrow Transplant Date: 2011-10-17 Impact factor: 5.742
Authors: Frederick L Locke; Armin Ghobadi; Caron A Jacobson; David B Miklos; Lazaros J Lekakis; Olalekan O Oluwole; Yi Lin; Ira Braunschweig; Brian T Hill; John M Timmerman; Abhinav Deol; Patrick M Reagan; Patrick Stiff; Ian W Flinn; Umar Farooq; Andre Goy; Peter A McSweeney; Javier Munoz; Tanya Siddiqi; Julio C Chavez; Alex F Herrera; Nancy L Bartlett; Jeffrey S Wiezorek; Lynn Navale; Allen Xue; Yizhou Jiang; Adrian Bot; John M Rossi; Jenny J Kim; William Y Go; Sattva S Neelapu Journal: Lancet Oncol Date: 2018-12-02 Impact factor: 41.316
Authors: Bruce D Cheson; Richard I Fisher; Sally F Barrington; Franco Cavalli; Lawrence H Schwartz; Emanuele Zucca; T Andrew Lister Journal: J Clin Oncol Date: 2014-09-20 Impact factor: 44.544
Authors: Christian Gisselbrecht; Bertram Glass; Nicolas Mounier; Devinder Singh Gill; David C Linch; Marek Trneny; Andre Bosly; Nicolas Ketterer; Ofer Shpilberg; Hans Hagberg; David Ma; Josette Brière; Craig H Moskowitz; Norbert Schmitz Journal: J Clin Oncol Date: 2010-07-26 Impact factor: 44.544
Authors: Daniel W Lee; Bianca D Santomasso; Frederick L Locke; Armin Ghobadi; Cameron J Turtle; Jennifer N Brudno; Marcela V Maus; Jae H Park; Elena Mead; Steven Pavletic; William Y Go; Lamis Eldjerou; Rebecca A Gardner; Noelle Frey; Kevin J Curran; Karl Peggs; Marcelo Pasquini; John F DiPersio; Marcel R M van den Brink; Krishna V Komanduri; Stephan A Grupp; Sattva S Neelapu Journal: Biol Blood Marrow Transplant Date: 2018-12-25 Impact factor: 5.742
Authors: Jason R Westin; Marie José Kersten; Gilles Salles; Jeremy S Abramson; Stephen J Schuster; Frederick L Locke; Charalambos Andreadis Journal: Am J Hematol Date: 2021-08-13 Impact factor: 13.265