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PHASE I STUDY OF YTB323, A CHIMERIC ANTIGEN RECEPTOR (CAR)-T CELL THERAPY MANUFACTURED USING T-CHARGE™, IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA
Author(s): ,
Michael Dickinson
Affiliations:
Peter MacCallum Cancer Centre and Royal Melbourne Hospital and the University of Melbourne,Melbourne,Australie;Peter MacCallum Cancer Centre and Royal Melbourne Hospital and the University of Melbourne,Melbourne,Australien;Peter MacCallum Cancer Centre and Royal Melbourne Hospital and the University of Melbourne,Melbourne,Australia;Peter MacCallum Cancer Centre and Royal Melbourne Hospital and the
,
Mi Kwon
Affiliations:
Department of Hematology,Hospital General Universitario Gregorio Marañón, Institute of Health Research Gregorio Marañón,Madrid,Espagne;Department of Hematology,Hospital General Universitario Gregorio Marañón, Institute of Health Research Gregorio Marañón,Madrid,Spanien;Department of Hematology,Hospital General Universitario Gregorio Marañón, Institute of Health Research Gregorio Marañón,Madrid,Spa
,
Javier Briones
Affiliations:
Hematology Department,Hospital Santa Creu i Sant Pau,Barcelona,Espagne;Hematology Department,Hospital Santa Creu i Sant Pau,Barcelona,Spanien;Hematology Department,Hospital Santa Creu i Sant Pau,Barcelona,Spagna;Hematology Department,Hospital Santa Creu i Sant Pau,Barcelona,Spain;Hematology Department,Hospital Santa Creu i Sant Pau,Barcelona,España;Hematology Department,Hospital Santa Creu i Sant
,
Ulrich Jäger
Affiliations:
Clinical Division of Hematology and Hemostaseology, Department of Medicine I,Vienna General Hospital – Medical University of Vienna,Vienna,Autriche;Clinical Division of Hematology and Hemostaseology, Department of Medicine I,Vienna General Hospital – Medical University of Vienna,Vienna,Österreich;Clinical Division of Hematology and Hemostaseology, Department of Medicine I,Vienna General Hospital –
,
Koji Kato
Affiliations:
Department of Hematology, Oncology and Cardiovascular Medicine,Kyushu University Hospital,Fukuoka,Japon;Department of Hematology, Oncology and Cardiovascular Medicine,Kyushu University Hospital,Fukuoka,Japan;Department of Hematology, Oncology and Cardiovascular Medicine,Kyushu University Hospital,Fukuoka,Giappone;Department of Hematology, Oncology and Cardiovascular Medicine,Kyushu University Hosp
,
Emmanuel Bachy
Affiliations:
Hematology department,Hospices Civils de Lyon and Université Claude Bernard Lyon 1,Lyon,France;Hematology department,Hospices Civils de Lyon and Université Claude Bernard Lyon 1,Lyon,Frankreich;Hematology department,Hospices Civils de Lyon and Université Claude Bernard Lyon 1,Lyon,Francia;Hematology department,Hospices Civils de Lyon and Université Claude Bernard Lyon 1,Lyon,France;Hematology depa
,
Didier Blaise
Affiliations:
Département d'Hématologie, Programme de Transplantation et de Thérapie Cellulaire, Centre de Recherche en Cancérologie de Marseille,Aix-Marseille University, Institut Paoli Calmettes,Marseille,France;Département d'Hématologie, Programme de Transplantation et de Thérapie Cellulaire, Centre de Recherche en Cancérologie de Marseille,Aix-Marseille University, Institut Paoli Calmettes,Marseille,Frankre
,
Nicolas Boissel
Affiliations:
Hematology Adolescent and Young Adult Unit,Saint-Louis Hospital,Paris,France;Hematology Adolescent and Young Adult Unit,Saint-Louis Hospital,Paris,Frankreich;Hematology Adolescent and Young Adult Unit,Saint-Louis Hospital,Paris,Francia;Hematology Adolescent and Young Adult Unit,Saint-Louis Hospital,Paris,France;Hematology Adolescent and Young Adult Unit,Saint-Louis Hospital,Paris,Francia;Hematolog
,
Nirav Shah
Affiliations:
Medical College of Wisconsin,Milwaukee,États-unis;Medical College of Wisconsin,Milwaukee,Vereinigte Staaten;Medical College of Wisconsin,Milwaukee,Stati Uniti;Medical College of Wisconsin,Milwaukee,United States;Medical College of Wisconsin,Milwaukee,Estados Unidos;Medical College of Wisconsin,Milwaukee,Verenigde Staten;Medical College of Wisconsin,Milwaukee,Estados Unidos;Medical College of Wisco
,
Mathew Frigault
Affiliations:
Massachusetts General Hospital,Massachusetts,États-unis;Massachusetts General Hospital,Massachusetts,Vereinigte Staaten;Massachusetts General Hospital,Massachusetts,Stati Uniti;Massachusetts General Hospital,Massachusetts,United States;Massachusetts General Hospital,Massachusetts,Estados Unidos;Massachusetts General Hospital,Massachusetts,Verenigde Staten;Massachusetts General Hospital,Massachuset
,
Peter Riedell
Affiliations:
University of Chicago,Chicago,États-unis;University of Chicago,Chicago,Vereinigte Staaten;University of Chicago,Chicago,Stati Uniti;University of Chicago,Chicago,United States;University of Chicago,Chicago,Estados Unidos;University of Chicago,Chicago,Verenigde Staten;University of Chicago,Chicago,Estados Unidos;University of Chicago,Chicago,United States;University of Chicago,Chicago,USA
,
Leyla Shune
Affiliations:
Division of Hematologic Malignancies and Cellular Therapeutics,University of Kansas Medical Center,Kansas City,États-unis;Division of Hematologic Malignancies and Cellular Therapeutics,University of Kansas Medical Center,Kansas City,Vereinigte Staaten;Division of Hematologic Malignancies and Cellular Therapeutics,University of Kansas Medical Center,Kansas City,Stati Uniti;Division of Hematologic M
,
Takanori Teshima
Affiliations:
Department of Hematology,Hokkaido University Hospital,Sapporo,Japon;Department of Hematology,Hokkaido University Hospital,Sapporo,Japan;Department of Hematology,Hokkaido University Hospital,Sapporo,Giappone;Department of Hematology,Hokkaido University Hospital,Sapporo,Japan;Department of Hematology,Hokkaido University Hospital,Sapporo,Japón;Department of Hematology,Hokkaido University Hospital,Sap
,
Xu Zhu
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,États-unis;Novartis Institutes for BioMedical Research,Cambridge,Vereinigte Staaten;Novartis Institutes for BioMedical Research,Cambridge,Stati Uniti;Novartis Institutes for BioMedical Research,Cambridge,United States;Novartis Institutes for BioMedical Research,Cambridge,Estados Unidos;Novartis Institutes for BioMedical Research,Cambridge,Veren
,
Elena Orlando
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,États-unis;Novartis Institutes for BioMedical Research,Cambridge,Vereinigte Staaten;Novartis Institutes for BioMedical Research,Cambridge,Stati Uniti;Novartis Institutes for BioMedical Research,Cambridge,United States;Novartis Institutes for BioMedical Research,Cambridge,Estados Unidos;Novartis Institutes for BioMedical Research,Cambridge,Veren
,
Lan Yi
Affiliations:
Novartis Pharmaceuticals Corporation,Cambridge,États-unis;Novartis Pharmaceuticals Corporation,Cambridge,Vereinigte Staaten;Novartis Pharmaceuticals Corporation,Cambridge,Stati Uniti;Novartis Pharmaceuticals Corporation,Cambridge,United States;Novartis Pharmaceuticals Corporation,Cambridge,Estados Unidos;Novartis Pharmaceuticals Corporation,Cambridge,Verenigde Staten;Novartis Pharmaceuticals Corpo
,
Jaclyn Davis
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,États-unis;Novartis Pharmaceuticals Corporation,East Hanover,Vereinigte Staaten;Novartis Pharmaceuticals Corporation,East Hanover,Stati Uniti;Novartis Pharmaceuticals Corporation,East Hanover,United States;Novartis Pharmaceuticals Corporation,East Hanover,Estados Unidos;Novartis Pharmaceuticals Corporation,East Hanover,Verenigde Staten;Novartis Pha
,
Eric Bleickardt
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,États-unis;Novartis Pharmaceuticals Corporation,East Hanover,Vereinigte Staaten;Novartis Pharmaceuticals Corporation,East Hanover,Stati Uniti;Novartis Pharmaceuticals Corporation,East Hanover,United States;Novartis Pharmaceuticals Corporation,East Hanover,Estados Unidos;Novartis Pharmaceuticals Corporation,East Hanover,Verenigde Staten;Novartis Pha
,
Ian Flinn
Affiliations:
Sarah Cannon Research Institute and Tennessee Oncology,Nashville,États-unis;Sarah Cannon Research Institute and Tennessee Oncology,Nashville,Vereinigte Staaten;Sarah Cannon Research Institute and Tennessee Oncology,Nashville,Stati Uniti;Sarah Cannon Research Institute and Tennessee Oncology,Nashville,United States;Sarah Cannon Research Institute and Tennessee Oncology,Nashville,Estados Unidos;Sara
Pere Barba
Affiliations:
Hematology Department,Hospital Universitari Vall d'Hebrón, Universitat Autònoma de Barcelona,Barcelona,Espagne;Hematology Department,Hospital Universitari Vall d'Hebrón, Universitat Autònoma de Barcelona,Barcelona,Spanien;Hematology Department,Hospital Universitari Vall d'Hebrón, Universitat Autònoma de Barcelona,Barcelona,Spagna;Hematology Department,Hospital Universitari Vall d'Hebrón, Universit
(Abstract release date: 05/12/22) EHA Library. Dickinson M. 06/11/22; 357076; S212
Michael Dickinson
Michael Dickinson
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S212

Type: Oral Presentation

Session title: Aggressive Lymphoma - CART

Background
CD19-directed CAR-T cell therapies (tx) demonstrate efficacy in patients (pts) with B-cell malignancies. However, despite positive outcomes with currently approved CAR-T cell tx, many patients fail to respond or relapse after initial response. YTB323 is an autologous CD19-directed CAR-T cell tx generated by the innovative T-Charge™ platform, which demonstrates high potency, preserves T-cell stemness in the final product, and takes <2 d to manufacture. 

Aims
T-Charge™ is expected to prolong CAR-T cell persistence and yield higher response rates and durability. 

Methods
These data from the ongoing Phase I, multicenter, dose-escalation study (NCT03960840) focus on safety and efficacy of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Eligible pts had measurable disease at enrollment, ECOG 0-1, and r/r DLBCL after ≥2 lines of prior tx. Pts received single-dose YTB323 at targeted dose levels (DL) 1 (2.5×106 CAR+ cells), DL2 (12.5×106 CAR+ cells), DL3 (25×106 CAR+ cells), or DL4 (40×106 CAR+ cells). Results presented here focus on DL1 and DL2. The primary endpoints are to identify a recommended dose for subsequent trials and characterize the safety and dose-limiting toxicities. Secondary endpoints include overall response rate (ORR) by local investigator assessment and cellular kinetics.

Results
As of August 20, 2021, 20 pts with r/r DLBCL received YTB323: 4 at DL1 and 16 at DL2. Median age was 65 y, 65% received 2 prior lines of tx, and 35% had prior SCT. The median follow-up for pts in DL1 and DL2 was 20 and 7 months, respectively. Of 20 pts evaluable for safety, all experienced at least 1 adverse event (AE) of any Grade (Gr) and 80% at least 1 AE Gr ≥3. One pt (25%) experienced Gr 1 cytokine release syndrome (CRS) at DL1, and 5 (31%) pts experienced CRS at DL2, including 4 (25%) Gr 1 or 2 and 1 (6%) Gr 4 (Lee et al, 2014), which met protocol defined DLT criteria at DL2. Tocilizumab and corticosteroids were used for CRS management in 4 (80%) and 2 (40%) pts at DL2, respectively. Median time to CRS onset was 10 d (range, 1-17 d). Five pts (25%) had neurological events (NE), of which the majority were Gr 1. Median time to onset and resolution of NE was 7 and 12 d, respectively. Five pts died on trial (beyond 30 d); 3 pts died due to disease progression (1 at DL1, 2 at DL2), and 1 pt each due to sepsis (1 at DL1) and intestinal hemorrhage (1 at DL2). At DL1, ORR and complete response (CR) rate were both 75%. At DL2, ORR and CR rates were 81% and 75%, respectively. Of the 15 pts who received YTB323 at DL2 at least 3 mo prior to the data cutoff, CR rate at mo 3 was 73% (95% CI, 44.9%-92.2%) (Figure). Median time to peak YTB323 expansion was ~16 d and coincided with cytokine peak. YTB323 expansion (Cmax and AUC0-28d) with 12.5×106 CAR+ cells (DL2) was comparable to a median tisagenlecleucel dose of 312×106 CAR+ cells in pts with DLBCL, a 25-fold lower median dose (Awasthi R, et al. 2020). Limited data indicate that CAR expression was detectable by flow cytometry for at least 9 mo at DL2. T-Charge™ allowed preservation of CD4 and CD8 naive/stem memory T cells in the final product according to flow cytometry. Bulk RNAseq analysis demonstrated that YTB323 retained a naive stem-like gene signature.

Conclusion
YTB323 is a potent new CAR-T cell tx with distinct cellular kinetics, encouraging early efficacy results across DL1 and DL2, and a manageable safety profile. Updated results will be presented at the meeting along with a recommended dose for subsequent trials.

Keyword(s): Adult, Diffuse large B cell lymphoma, Relapsed lymphoma

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S212

Type: Oral Presentation

Session title: Aggressive Lymphoma - CART

Background
CD19-directed CAR-T cell therapies (tx) demonstrate efficacy in patients (pts) with B-cell malignancies. However, despite positive outcomes with currently approved CAR-T cell tx, many patients fail to respond or relapse after initial response. YTB323 is an autologous CD19-directed CAR-T cell tx generated by the innovative T-Charge™ platform, which demonstrates high potency, preserves T-cell stemness in the final product, and takes <2 d to manufacture. 

Aims
T-Charge™ is expected to prolong CAR-T cell persistence and yield higher response rates and durability. 

Methods
These data from the ongoing Phase I, multicenter, dose-escalation study (NCT03960840) focus on safety and efficacy of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Eligible pts had measurable disease at enrollment, ECOG 0-1, and r/r DLBCL after ≥2 lines of prior tx. Pts received single-dose YTB323 at targeted dose levels (DL) 1 (2.5×106 CAR+ cells), DL2 (12.5×106 CAR+ cells), DL3 (25×106 CAR+ cells), or DL4 (40×106 CAR+ cells). Results presented here focus on DL1 and DL2. The primary endpoints are to identify a recommended dose for subsequent trials and characterize the safety and dose-limiting toxicities. Secondary endpoints include overall response rate (ORR) by local investigator assessment and cellular kinetics.

Results
As of August 20, 2021, 20 pts with r/r DLBCL received YTB323: 4 at DL1 and 16 at DL2. Median age was 65 y, 65% received 2 prior lines of tx, and 35% had prior SCT. The median follow-up for pts in DL1 and DL2 was 20 and 7 months, respectively. Of 20 pts evaluable for safety, all experienced at least 1 adverse event (AE) of any Grade (Gr) and 80% at least 1 AE Gr ≥3. One pt (25%) experienced Gr 1 cytokine release syndrome (CRS) at DL1, and 5 (31%) pts experienced CRS at DL2, including 4 (25%) Gr 1 or 2 and 1 (6%) Gr 4 (Lee et al, 2014), which met protocol defined DLT criteria at DL2. Tocilizumab and corticosteroids were used for CRS management in 4 (80%) and 2 (40%) pts at DL2, respectively. Median time to CRS onset was 10 d (range, 1-17 d). Five pts (25%) had neurological events (NE), of which the majority were Gr 1. Median time to onset and resolution of NE was 7 and 12 d, respectively. Five pts died on trial (beyond 30 d); 3 pts died due to disease progression (1 at DL1, 2 at DL2), and 1 pt each due to sepsis (1 at DL1) and intestinal hemorrhage (1 at DL2). At DL1, ORR and complete response (CR) rate were both 75%. At DL2, ORR and CR rates were 81% and 75%, respectively. Of the 15 pts who received YTB323 at DL2 at least 3 mo prior to the data cutoff, CR rate at mo 3 was 73% (95% CI, 44.9%-92.2%) (Figure). Median time to peak YTB323 expansion was ~16 d and coincided with cytokine peak. YTB323 expansion (Cmax and AUC0-28d) with 12.5×106 CAR+ cells (DL2) was comparable to a median tisagenlecleucel dose of 312×106 CAR+ cells in pts with DLBCL, a 25-fold lower median dose (Awasthi R, et al. 2020). Limited data indicate that CAR expression was detectable by flow cytometry for at least 9 mo at DL2. T-Charge™ allowed preservation of CD4 and CD8 naive/stem memory T cells in the final product according to flow cytometry. Bulk RNAseq analysis demonstrated that YTB323 retained a naive stem-like gene signature.

Conclusion
YTB323 is a potent new CAR-T cell tx with distinct cellular kinetics, encouraging early efficacy results across DL1 and DL2, and a manageable safety profile. Updated results will be presented at the meeting along with a recommended dose for subsequent trials.

Keyword(s): Adult, Diffuse large B cell lymphoma, Relapsed lymphoma

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