New cell therapy offers effective treatment for patients with T-cell acute lymphoblastic leukemia

A new cell therapy, targeting CD7 on leukemia cells, gives a potentially effective treatment for patients with T-cell acute lymphoblastic leukemia (T-ALL) who have exhausted all standard treatment options. Published in the prestigious medical journal Nature Medicine on 3 September 2024, the study highlights the effectiveness of a new chimeric antigen receptor (CAR) T-cell therapy.

Developed in-house by researchers and clinicians from the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine) and the National University Health System (NUHS), the therapy was given to 17 patients between April 2019 and October 2023 at the National University Hospital (NUH) in Singapore and Ospedale Pediatrico Bambino Gesù in Rome, Italy.

All the 17 patients, ranging from two to 72 years of age, had T-ALL that could not be eliminated with chemotherapy or had relapsed after treatment. Using a technology developed in Professor Dario Campana's laboratory under the Department of Paediatrics at NUS Medicine, the patient's own T cells were reprogrammed to express an anti-CD7 CAR, and then re-infused into the patients. The anti-CD7 CAR protein redirects the CAR T-cells to kill T-leukemia cells that have CD7 protein on their surface.

Notably, 16 of the 17 patients achieved complete remission within one month, and leukaemic cells became undetectable even with ultra-sensitive flow cytometry tests that can detect one leukemia cell in the background of 10,000 normal cells, developed by Ms Elaine Coustan-Smith's laboratory at NUS Medicine. The same techniques were key to analyze CD7 expression in leukaemic cells and determining patient eligibility as well as to monitor expansion and persistence of CAR-T cells after infusion. The first patient treated with this therapy has been in remission for five years, without needing additional chemotherapy or a bone marrow transplant.

The treatment was well-tolerated, and side effects were mild, given the fact that all patients enrolled had a high tumor burden and had received prolonged and intensive treatment prior to CAR-T therapy.

T-ALL accounts for approximately 10 per cent of ALL cases in children and 25 to 30 per cent in adolescents and young adults2,3 . Although 70 to 80 per cent of children are cured with intensive and prolonged chemotherapy, the cure rate in adults remains approximately 60 per cent or lower.

Patients with relapsed or refractory T-ALL have less than 10 per cent survival, while in this series, 50 per cent survived. This fratricide-resistant CD7 CAR-T therapy is being trialled in NUH.

Dr Bernice Oh, the first author of the study and a Consultant in the Division of Paediatric Haematology and Oncology at the Khoo Teck Puat – National University Children's Medical Institute (KTP-NUCMI), NUH, said: "This CAR-T therapy is a new and promising tool to treat T-ALL patients who have failed conventional treatment. These patients had exhausted all potentially curative options, and we are heartened that we could give them another clear chance at cure without severe side-effects. We are committed to seek better cures for patients with complex and treatment-resistant cancers."

Professor Allen Yeoh, who led the clinical application of this new technology and is Head and Senior Consultant in the Division of Paediatric Haematology and Oncology at NUH's KTP-NUCMI and the National University Cancer Institute, Singapore, said: "While we celebrate this wonderful milestone, we are only at the beginning of this exciting journey. There is a lot of scientific and medical enquiry to understand how to better use CD7 CAR T-cells. Each patient, in this series, taught us a lot. Ultimately, for every member of our team, seeing each patient smile and given another chance, after achieving remission, is priceless." Professor Yeoh is also the VIVA-Goh Foundation Professor in Paediatric Oncology at NUS Medicine.

This research is supported by the Singapore Ministry of Health through the National Medical Research Council (NMRC) Office, MOH Holdings Pte Ltd under the NMRC Singapore Translational Research Investigator Award (MOH-000708), NMRC Research Training Fellowship (MOH-000616), NMRC Clinician Scientist Award (NMRC/CSA/003/2008 and NMRC/CSA/0053/2013) and NMRC Centre Grant (NMRC/CG/NCIS/2010), as well as the Cancer Science Institute of Singapore, National University of Singapore, the Goh Foundation, Children's Cancer Foundation, Singapore Totalisator Board, Bone Marrow Donor Programme (Singapore) and VIVA Foundation for Children with Cancer.

A new cell therapy, targeting CD7 on leukemia cells, gives a potentially effective treatment for patients with T-cell acute lymphoblastic leukemia (T-ALL) who have exhausted all standard treatment options. Published in the prestigious medical journal Nature Medicine on 3 September 2024, the study highlights the effectiveness of a new chimeric antigen receptor (CAR) T-cell therapy.

Developed in-house by researchers and clinicians from the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine) and the National University Health System (NUHS), the therapy was given to 17 patients between April 2019 and October 2023 at the National University Hospital (NUH) in Singapore and Ospedale Pediatrico Bambino Gesù in Rome, Italy.

All the 17 patients, ranging from two to 72 years of age, had T-ALL that could not be eliminated with chemotherapy or had relapsed after treatment. Using a technology developed in Professor Dario Campana's laboratory under the Department of Paediatrics at NUS Medicine, the patient's own T cells were reprogrammed to express an anti-CD7 CAR, and then re-infused into the patients. The anti-CD7 CAR protein redirects the CAR T-cells to kill T-leukemia cells that have CD7 protein on their surface.

Notably, 16 of the 17 patients achieved complete remission within one month, and leukaemic cells became undetectable even with ultra-sensitive flow cytometry tests that can detect one leukemia cell in the background of 10,000 normal cells, developed by Ms Elaine Coustan-Smith's laboratory at NUS Medicine. The same techniques were key to analyze CD7 expression in leukaemic cells and determining patient eligibility as well as to monitor expansion and persistence of CAR-T cells after infusion. The first patient treated with this therapy has been in remission for five years, without needing additional chemotherapy or a bone marrow transplant.

The treatment was well-tolerated, and side effects were mild, given the fact that all patients enrolled had a high tumor burden and had received prolonged and intensive treatment prior to CAR-T therapy.

T-ALL accounts for approximately 10 per cent of ALL cases in children and 25 to 30 per cent in adolescents and young adults2,3 . Although 70 to 80 per cent of children are cured with intensive and prolonged chemotherapy, the cure rate in adults remains approximately 60 per cent or lower.

Patients with relapsed or refractory T-ALL have less than 10 per cent survival, while in this series, 50 per cent survived. This fratricide-resistant CD7 CAR-T therapy is being trialled in NUH.

This CAR-T therapy is a new and promising tool to treat T-ALL patients who have failed conventional treatment. These patients had exhausted all potentially curative options, and we are heartened that we could give them another clear chance at cure without severe side-effects. We are committed to seek better cures for patients with complex and treatment-resistant cancers."

Dr. Bernice Oh, first author of the study and Consultant in the Division of Paediatric Hematology and Oncology at the Khoo Teck Puat – National University Children's Medical Institute (KTP-NUCMI), NUH

Professor Allen Yeoh, who led the clinical application of this new technology and is Head and Senior Consultant in the Division of Paediatric Haematology and Oncology at NUH's KTP-NUCMI and the National University Cancer Institute, Singapore, said: "While we celebrate this wonderful milestone, we are only at the beginning of this exciting journey. There is a lot of scientific and medical enquiry to understand how to better use CD7 CAR T-cells. Each patient, in this series, taught us a lot. Ultimately, for every member of our team, seeing each patient smile and given another chance, after achieving remission, is priceless." Professor Yeoh is also the VIVA-Goh Foundation Professor in Paediatric Oncology at NUS Medicine.

This research is supported by the Singapore Ministry of Health through the National Medical Research Council (NMRC) Office, MOH Holdings Pte Ltd under the NMRC Singapore Translational Research Investigator Award (MOH-000708), NMRC Research Training Fellowship (MOH-000616), NMRC Clinician Scientist Award (NMRC/CSA/003/2008 and NMRC/CSA/0053/2013) and NMRC Centre Grant (NMRC/CG/NCIS/2010), as well as the Cancer Science Institute of Singapore, National University of Singapore, the Goh Foundation, Children's Cancer Foundation, Singapore Totalisator Board, Bone Marrow Donor Programme (Singapore) and VIVA Foundation for Children with Cancer.