CAR T-cell therapy makes it to the clinic in Hong Kong

Haematologists from the University of Hong Kong (HKU) have reported initial success with chimeric antigen receptor (CAR) T-cell therapy, treating the first patient in Hong Kong in May 2020 in a global lymphoma trial and another leukaemia patient in October 2020 in a real-world clinical practice setting.

“Queen Mary Hospital [QMH] is the first and currently the only centre in Hong Kong with the capability to provide CAR T-cell treatment, which requires a high level of expertise in terms of leukapheresis, cryopreservation, CAR T-cell reinfusion, and monitoring and management of possible adverse events,” said Professor Yuk-Lam Kwong of the Division of Haematology, Medical Oncology and Haematopoietic Stem Cell Transplantation, HKU. “We are likely to remain the only centre in Hong Kong with the capability to provide CAR T-cell therapy to patients in the next 4–5 years.”

“The Hospital Authority has been in discussion with us about making CAR T-cell therapy available to more patients in Hong Kong later this year. Depending on patients’ needs for treatment and our capacity at QMH, we anticipate that approximately 30 patients will be able to receive the therapy in 2021,” said Kwong.

First patients treated in clinical trial and real-world settings

The first patient treated with CAR T-cell therapy in Hong Kong had relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and received tisagenlecleucel at QMH in May 2020 as a participant of the phase III BELINDA trial – an ongoing, global, randomized, open-label, multicentre trial that evaluates tisagenlecleucel vs standard-of-care treatment (ie, platinum-based immunochemotherapy followed in responding patients with high-dose chemotherapy and autologous haematopoietic stem cell transplantation [HSCT]) in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma.

“Six patients have been recruited from QMH into the BELINDA trial. Two of the patients, including the first patient treated in May 2020, were randomized to receive tisagenlecleucel, while the remaining four were randomized to receive standard-of-care treatment,” said Professor Eric Tse of the Division of Haematology, Medical Oncology and Haematopoietic Stem Cell Transplantation, HKU.

The first patient treated with CAR T-cell therapy in a real-world clinical practice setting had B-cell acute lymphoblastic leukaemia (ALL) that relapsed about 1 year following HSCT and was refractory to salvage chemotherapy. “The patient received tisagenlecleucel at QMH in October 2020. Platelet transfusion and antibiotics were given in view of his very low platelet and white blood cell counts,” reported Dr Joycelyn Sim of the Division of Haematology, Medical Oncology and Haematopoietic Stem Cell Transplantation, HKU.

“The patient gradually recovered after treatment and did not experience serious complications. Recent bone marrow examinations showed no detectable leukaemia cells, indicating remission was achieved after CAR T-cell therapy,” said Sim.

CAR T-cell therapy: Current landscape

“CAR T-cell therapy provides an opportunity of cure for some patients with relapsed/refractory CD19-positive hematological malignancies,” said Dr Thomas Chan of the Division of Haematology, Medical Oncology and Haematopoietic Stem Cell Transplantation, HKU.

Tisagenlecleucel is the first and currently the only CAR T-cell therapy approved in Hong Kong. It is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for use in paediatric and young adult patients ≤25 years of age with B-cell ALL that is refractory, in relapse post-transplantation or in second or later relapse, as well as in adult patients with relapsed/refractory DLBCL after ≥2 lines of systemic therapy. [Kymriah Hong Kong prescribing information, September 2018]

Apart from tisagenlecleucel, the US FDA has approved two other CAR T-cell therapies – axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma, and brexucabtagene autoleucel for relapsed/refractory mantel cell lymphoma. Both therapies are CD19-directed.

Workflow and on-treatment monitoring

“With tisagenlecleucel, the leukocytes isolated from each patient are cryopreserved and shipped overseas for genetic modification and expansion. The manufactured CAR T-cells are then shipped back to Hong Kong for reinfusion into the patient following lymphodepleting chemotherapy,” explained Sim. “To ensure safety, each cell product is marked with an individual identity chain to facilitate tracking for each patient.”

“Potential adverse events of CAR T-cell therapy include neurotoxicity and cytokine release syndrome,” said Chan. [Science 2018;359:1361-1365] “However, the risk of these adverse events is generally relatively low and can be effectively mitigated with the use of immunosuppressants.”

“One of the most common and earliest symptoms of neurotoxicity is impaired handwriting. We therefore ask patients to show us handwriting of their address daily as part of on-treatment monitoring,” said Chan.

“We also monitor patients’ body temperature every 4 hours as fever is one of the earliest symptoms of cytokine release syndrome,” Sim added.

Future directions: Advanced therapy products made in HK

“We have plans to manufacture ‘home-made’ CAR T-cell products targeting various haematological malignancies and solid tumours for evaluation in preclinical and clinical studies. This will be carried out at the HKUMed Laboratory of Cellular Therapeutics located in the Sassoon Road campus. The facility is currently under construction in collaboration with the Hong Kong Science & Technology Parks Corporation, and is expected to be completed by the end of this year or the first quarter of 2022,” said Tse.

“Potential projects at the HKUMed Laboratory of Cellular Therapeutics include CD30-directed CAR T cells for CD30-positive lymphomas, such as T-cell lymphomas and Hodgkin lymphoma, and bispecific CAR T cells targeting CD19 and CD22 for ALL,” Tse continued. “Bispecific CAR T-cell therapies targeting both CD19 and CD22 may reduce the risk of relapse following treatment due to loss of CD19 expression on the cancer cells of some patients.”

The HKU researchers will also evaluate earlier use of CAR T-cell therapy – before HSCT – in some leukaemia or lymphoma patients.

“Other advanced therapy products, such as specific targeted therapy and gene therapy, are also our directions of leukaemia and lymphoma research in the foreseeable future,” said Kwong. “Hopefully we will be able to develop these advanced therapy products at the HKUMed Laboratory of Cellular Therapeutics in the next few years to help more patients.”

According to the Hospital Authority’s Hong Kong Cancer Information and Statistics Centre, more than 100 patients with haematological malignancies would be suitable for CAR T-cell therapy each year.

“The positioning of different treatment options in leukaemia and lymphoma management is a complicated decision requiring a team approach and a high level of expertise, to ensure the best treatment decision is made for each patient,” said Kwong.