EHA Library - The official digital education library of European Hematology Association (EHA)

THE COBALT-LYM STUDY OF CTX130: A PHASE 1 DOSE ESCALATION STUDY OF CD70-TARGETED ALLOGENEIC CRISPR-CAS9–ENGINEERED CAR T CELLS IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) T-CELL MALIGNANCIES
Author(s): ,
Swaminathan P. Iyer
Affiliations:
Department of Lymphoma and Myeloma,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Department of Lymphoma and Myeloma,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Department of Lymphoma and Myeloma,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Department of Lymphoma and Myeloma,The University of Texas MD Anderson Cancer C
,
R. Alejandro Sica
Affiliations:
Department of Oncology,Montefiore Medical Center, Albert Einstein Cancer Center,Bronx,États-unis;Department of Oncology,Montefiore Medical Center, Albert Einstein Cancer Center,Bronx,Vereinigte Staaten;Department of Oncology,Montefiore Medical Center, Albert Einstein Cancer Center,Bronx,Stati Uniti;Department of Oncology,Montefiore Medical Center, Albert Einstein Cancer Center,Bronx,United States;
,
P. Joy Ho
Affiliations:
Institute of Haematology,Royal Prince Alfred Hospital,Camperdown,Australie;Institute of Haematology,Royal Prince Alfred Hospital,Camperdown,Australien;Institute of Haematology,Royal Prince Alfred Hospital,Camperdown,Australia;Institute of Haematology,Royal Prince Alfred Hospital,Camperdown,Australia;Institute of Haematology,Royal Prince Alfred Hospital,Camperdown,Australia;Institute of Haematology
,
Boyu Hu
Affiliations:
Division of Hematology and Hematologic Malignancies,Huntsman Cancer Institute,Salt Lake City,États-unis;Division of Hematology and Hematologic Malignancies,Huntsman Cancer Institute,Salt Lake City,Vereinigte Staaten;Division of Hematology and Hematologic Malignancies,Huntsman Cancer Institute,Salt Lake City,Stati Uniti;Division of Hematology and Hematologic Malignancies,Huntsman Cancer Institute,S
,
Jasmine Zain
Affiliations:
Department of Hematology and Hematopoietic Cell Transplantation,City of Hope,Duarte,États-unis;Department of Hematology and Hematopoietic Cell Transplantation,City of Hope,Duarte,Vereinigte Staaten;Department of Hematology and Hematopoietic Cell Transplantation,City of Hope,Duarte,Stati Uniti;Department of Hematology and Hematopoietic Cell Transplantation,City of Hope,Duarte,United States;Departme
,
Anca Prica
Affiliations:
Princess Margaret Cancer Centre,Toronto,Canada;Princess Margaret Cancer Centre,Toronto,Kanada;Princess Margaret Cancer Centre,Toronto,Canada;Princess Margaret Cancer Centre,Toronto,Canada;Princess Margaret Cancer Centre,Toronto,Canadá;Princess Margaret Cancer Centre,Toronto,Canada;Princess Margaret Cancer Centre,Toronto,Canadá;Princess Margaret Cancer Centre,Toronto,Канада;Princess Margaret Cancer
,
Wen-Kai Weng
Affiliations:
Division of Blood and Marrow Transplantation and Cellular Therapy,Stanford University School of Medicine,Stanford,États-unis;Division of Blood and Marrow Transplantation and Cellular Therapy,Stanford University School of Medicine,Stanford,Vereinigte Staaten;Division of Blood and Marrow Transplantation and Cellular Therapy,Stanford University School of Medicine,Stanford,Stati Uniti;Division of Bloo
,
Youn H. Kim
Affiliations:
Department of Dermatology,Stanford University School of Medicine,Stanford,États-unis;Department of Dermatology,Stanford University School of Medicine,Stanford,Vereinigte Staaten;Department of Dermatology,Stanford University School of Medicine,Stanford,Stati Uniti;Department of Dermatology,Stanford University School of Medicine,Stanford,United States;Department of Dermatology,Stanford University Sc
,
Michael S. Khodadoust
Affiliations:
Division of Oncology, Department of Medicine,Stanford University School of Medicine,Stanford,États-unis;Division of Oncology, Department of Medicine,Stanford University School of Medicine,Stanford,Vereinigte Staaten;Division of Oncology, Department of Medicine,Stanford University School of Medicine,Stanford,Stati Uniti;Division of Oncology, Department of Medicine,Stanford University School of Medi
,
M. Lia Palomba
Affiliations:
Memorial Sloan Kettering Cancer Center,New York ,États-unis;Memorial Sloan Kettering Cancer Center,New York ,Vereinigte Staaten;Memorial Sloan Kettering Cancer Center,New York ,Stati Uniti;Memorial Sloan Kettering Cancer Center,New York ,United States;Memorial Sloan Kettering Cancer Center,New York ,Estados Unidos;Memorial Sloan Kettering Cancer Center,New York ,Verenigde Staten;Memorial Sloan Ket
,
Francine M. Foss
Affiliations:
Department of Dermatology,Yale School of Medicine,New Haven,États-unis;Department of Dermatology,Yale School of Medicine,New Haven,Vereinigte Staaten;Department of Dermatology,Yale School of Medicine,New Haven,Stati Uniti;Department of Dermatology,Yale School of Medicine,New Haven,United States;Department of Dermatology,Yale School of Medicine,New Haven,Estados Unidos;Department of Dermatology,Yal
,
Kimberly Tipton
Affiliations:
CRISPR Therapeutics,Cambridge,États-unis;CRISPR Therapeutics,Cambridge,Vereinigte Staaten;CRISPR Therapeutics,Cambridge,Stati Uniti;CRISPR Therapeutics,Cambridge,United States;CRISPR Therapeutics,Cambridge,Estados Unidos;CRISPR Therapeutics,Cambridge,Verenigde Staten;CRISPR Therapeutics,Cambridge,Estados Unidos;CRISPR Therapeutics,Cambridge,United States;CRISPR Therapeutics,Cambridge,USA
,
Erika L. Cullingford
Affiliations:
CRISPR Therapeutics,Cambridge,États-unis;CRISPR Therapeutics,Cambridge,Vereinigte Staaten;CRISPR Therapeutics,Cambridge,Stati Uniti;CRISPR Therapeutics,Cambridge,United States;CRISPR Therapeutics,Cambridge,Estados Unidos;CRISPR Therapeutics,Cambridge,Verenigde Staten;CRISPR Therapeutics,Cambridge,Estados Unidos;CRISPR Therapeutics,Cambridge,United States;CRISPR Therapeutics,Cambridge,USA
,
Qiuling He
Affiliations:
CRISPR Therapeutics,Cambridge,États-unis;CRISPR Therapeutics,Cambridge,Vereinigte Staaten;CRISPR Therapeutics,Cambridge,Stati Uniti;CRISPR Therapeutics,Cambridge,United States;CRISPR Therapeutics,Cambridge,Estados Unidos;CRISPR Therapeutics,Cambridge,Verenigde Staten;CRISPR Therapeutics,Cambridge,Estados Unidos;CRISPR Therapeutics,Cambridge,United States;CRISPR Therapeutics,Cambridge,USA
,
Anjali Sharma
Affiliations:
CRISPR Therapeutics,Cambridge,États-unis;CRISPR Therapeutics,Cambridge,Vereinigte Staaten;CRISPR Therapeutics,Cambridge,Stati Uniti;CRISPR Therapeutics,Cambridge,United States;CRISPR Therapeutics,Cambridge,Estados Unidos;CRISPR Therapeutics,Cambridge,Verenigde Staten;CRISPR Therapeutics,Cambridge,Estados Unidos;CRISPR Therapeutics,Cambridge,United States;CRISPR Therapeutics,Cambridge,USA
Steven M. Horwitz
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,États-unis;Memorial Sloan Kettering Cancer Center,New York,Vereinigte Staaten;Memorial Sloan Kettering Cancer Center,New York,Stati Uniti;Memorial Sloan Kettering Cancer Center,New York,United States;Memorial Sloan Kettering Cancer Center,New York,Estados Unidos;Memorial Sloan Kettering Cancer Center,New York,Verenigde Staten;Memorial Sloan Kettering
(Abstract release date: 05/12/22) EHA Library. P. Iyer S. 06/11/22; 357126; S262
Swaminathan P. Iyer
Swaminathan P. Iyer
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: S262

Type: Oral Presentation

Session title: Gene therapy and cellular immunotherapy - Clinical 2

Background
Overall survival (OS) in a subset of patients (pts) with T-cell lymphoma (TCL) has improved with front-line combination chemotherapy; however, R/R TCL pts continue to have very limited treatment options.  For pts with R/R peripheral (PTCL) and transformed cutaneous TCL (CTCL), median OS is 1-2.5 and <5 yrs, respectively. Adapting autologous chimeric antigen receptor (CAR) T cell therapy for TCL continues to be challenging due to poor function of donor T cells, fratricide effect, and risk of infusing transduced malignant CAR T cells into pts.  CTX130TM is a first-in-class, CD70-targeting allogeneic (allo) CAR T therapy that may allow for CAR T therapy in pts whose own T cells are not ideal to manufacture auto CAR T cells.  CD70 is a co-stimulatory protein with temporally limited expression on activated lymphocytes and is highly expressed in many TCLs.  CTX130 is modified with CRISPR/Cas9-editing to eliminate expression of: 1) T-cell receptor (TCR) by TCR alpha constant disruption, 2) major histocompatibility complex class I expression by β2-microglobulin disruption, and 3) CD70 to mitigate fratricide and enhance performance.

Aims
Investigate safety and efficacy of CTX130 in pts with R/R TCL.

Methods
COBALTTM-LYM (NCT04502446) is an open-label, multicenter, global study evaluating the safety and efficacy of CTX130 in pts ≥18 y with CD70+ (≥10% by immunohistochemistry) R/R TCL (PTCL or CTCL). Pts with PTCL and CTCL must have received ≥1 or ≥2 prior lines of systemic therapy, respectively. Pts received lymphodepleting chemotherapy (LDC) with fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 for 3 days, followed by CTX130. Pts were treated with CTX130 at doses from 3x107 (dose level [DL]1) to 9x108 (DL4) CAR+ T cells. Pts could receive a second course of CTX130 if response was not achieved but had experienced clinical benefit or disease progression. The primary endpoint is safety (incidence of dose limiting toxicities [DLTs]). Key secondary endpoints include overall response rate (ORR, by Lugano and ISCL criteria for PTCL and CTCL, respectively), disease control rate (DCR; ≥stable disease [SD]), duration of response and OS.

Results
As of 6 Dec, 2021, 17 pts with TCL were enrolled; 15 received CTX130, were evaluable for a Day 28 assessment and are included in the analysis. Among the pts who received CTX130, median age was 67 y, 7 pts had PTCL, and 8 pts had CTCL. Median CD70 expression was 90% (range, 20-100%). Median follow up was 3.1 months. At DL ≥3, ORR was 71%, CR rate was 29% and DCR was 100% (Table).  Responses were observed in PTCL (75% ORR at DL≥3) and CTCL (67% ORR at DL≥3) and across disease compartments. CTX130 had an acceptable safety profile across all DLs. There were no instances of graft versus host disease, tumor lysis syndrome, hemophagocytic lymphohistiocytosis, or infusion reactions with LDC or CTX130. There were no DLTs, no Grade (Gr) ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS); Gr 1-2 CRS and ICANS were 47% and 20%. There was no increase in frequency or severity of CRS in pts who received second infusions of CTX130. 1 pt (7%) experienced a Gr ≥3 infection. There was a sudden death in 1 pt with William’s syndrome in the context of a lung infection.

Conclusion
We have observed clinically meaningful responses, including CRs with CTX130, the first CAR T directed against the novel target, CD70. CTX130 has an acceptable safety profile in pts with heavily pretreated R/R TCL and will be investigated further in an expansion phase of the study.

Keyword(s): CAR-T, Mycosis fungoides, Peripheral T-cell lymphoma, T cell 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: S262

Type: Oral Presentation

Session title: Gene therapy and cellular immunotherapy - Clinical 2

Background
Overall survival (OS) in a subset of patients (pts) with T-cell lymphoma (TCL) has improved with front-line combination chemotherapy; however, R/R TCL pts continue to have very limited treatment options.  For pts with R/R peripheral (PTCL) and transformed cutaneous TCL (CTCL), median OS is 1-2.5 and <5 yrs, respectively. Adapting autologous chimeric antigen receptor (CAR) T cell therapy for TCL continues to be challenging due to poor function of donor T cells, fratricide effect, and risk of infusing transduced malignant CAR T cells into pts.  CTX130TM is a first-in-class, CD70-targeting allogeneic (allo) CAR T therapy that may allow for CAR T therapy in pts whose own T cells are not ideal to manufacture auto CAR T cells.  CD70 is a co-stimulatory protein with temporally limited expression on activated lymphocytes and is highly expressed in many TCLs.  CTX130 is modified with CRISPR/Cas9-editing to eliminate expression of: 1) T-cell receptor (TCR) by TCR alpha constant disruption, 2) major histocompatibility complex class I expression by β2-microglobulin disruption, and 3) CD70 to mitigate fratricide and enhance performance.

Aims
Investigate safety and efficacy of CTX130 in pts with R/R TCL.

Methods
COBALTTM-LYM (NCT04502446) is an open-label, multicenter, global study evaluating the safety and efficacy of CTX130 in pts ≥18 y with CD70+ (≥10% by immunohistochemistry) R/R TCL (PTCL or CTCL). Pts with PTCL and CTCL must have received ≥1 or ≥2 prior lines of systemic therapy, respectively. Pts received lymphodepleting chemotherapy (LDC) with fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 for 3 days, followed by CTX130. Pts were treated with CTX130 at doses from 3x107 (dose level [DL]1) to 9x108 (DL4) CAR+ T cells. Pts could receive a second course of CTX130 if response was not achieved but had experienced clinical benefit or disease progression. The primary endpoint is safety (incidence of dose limiting toxicities [DLTs]). Key secondary endpoints include overall response rate (ORR, by Lugano and ISCL criteria for PTCL and CTCL, respectively), disease control rate (DCR; ≥stable disease [SD]), duration of response and OS.

Results
As of 6 Dec, 2021, 17 pts with TCL were enrolled; 15 received CTX130, were evaluable for a Day 28 assessment and are included in the analysis. Among the pts who received CTX130, median age was 67 y, 7 pts had PTCL, and 8 pts had CTCL. Median CD70 expression was 90% (range, 20-100%). Median follow up was 3.1 months. At DL ≥3, ORR was 71%, CR rate was 29% and DCR was 100% (Table).  Responses were observed in PTCL (75% ORR at DL≥3) and CTCL (67% ORR at DL≥3) and across disease compartments. CTX130 had an acceptable safety profile across all DLs. There were no instances of graft versus host disease, tumor lysis syndrome, hemophagocytic lymphohistiocytosis, or infusion reactions with LDC or CTX130. There were no DLTs, no Grade (Gr) ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS); Gr 1-2 CRS and ICANS were 47% and 20%. There was no increase in frequency or severity of CRS in pts who received second infusions of CTX130. 1 pt (7%) experienced a Gr ≥3 infection. There was a sudden death in 1 pt with William’s syndrome in the context of a lung infection.

Conclusion
We have observed clinically meaningful responses, including CRs with CTX130, the first CAR T directed against the novel target, CD70. CTX130 has an acceptable safety profile in pts with heavily pretreated R/R TCL and will be investigated further in an expansion phase of the study.

Keyword(s): CAR-T, Mycosis fungoides, Peripheral T-cell lymphoma, T cell lymphoma

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies