Chulalongkorn University and the Faculty of Medicine, Chulalongkorn University, organized the 17^th Chula the Impact on "CAR T-Cell Cancer Therapy Innovation: New Hope for Thai Cancer Patients" on Tuesday, March 28, 2023, at Saranitet Conference Room, Chulalongkorn Auditorium. The talk presented the progress of CAR T-cell immunotherapy innovation for treating cancer in leukemia and B-cell lymphoma patients. This research project is a collaboration between the Cancer Immunotherapy Excellence Center, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thailand, and Tokai National Higher Education and Research System and School of Medicine, Nagoya University, Japan.

Assoc. Prof. Chanchai Sittipunt, M.D., Dean of the Faculty of Medicine, Chulalongkorn University, and Director of King Chulalongkorn Memorial Hospital, said that "the Cancer Immunotherapy Excellence Center is one of Chulalongkorn University's Faculty of Medicine's specialized projects. The CAR T-cell immunotherapy innovation, in particular, is a new treatment for leukemia and lymphoma, which can increase survival rates and decrease cancer recurrence. However, there are numerous limitations to the widespread application of this method, including high costs, complicated procedures, and further research needed for practicality in more cancer patients. This collaborative research with Nagoya University in Japan has helped advance the research tremendously. At the same time, the Faculty of Medicine has been continuously building the infrastructure to most quickly implement the research inpatient treatment. The cell production and quality control lab in the new integrated research building has been expanded and combined with the hospital ward that focuses on complete care for cancer patients to form "King Chulalongkorn Memorial Hospital's Integrated Cancer Research and Treatment Center" to sufficiently serve patients in the future."

Koramit Suppipat, M.D., Director of Cellular Immunotherapy Research Unit Faculty of Medicine Chulalongkorn University said that the CAR T-cell treatment is an immunotherapy that uses genetically modified T -cells to target and destroy cancer cells that do not respond to standard treatments. CAR T-cells are made from the patient's T cells by genetically modifying them to express CAR and then increasing their number outside the body in a clean room before injecting them back into the patient to destroy the remaining cancer cells. CAR T-cell therapy is highly effective in treating blood cancers, and it can control the disease in 50-80 percent of patients who have not responded to any other treatments, making this innovation a standard treatment for blood cancers in both the United States and Europe. However, commercial CAR T-cell therapy is very expensive, costing up to 15,000,000 baht ($470,000) per treatment, which is a major barrier for cancer patients in Thailand to access this highly effective treatment. 

The Cellular Immunotherapy Research Unit is committed to developing CAR T-cell treatment that is accessible to Thai cancer patients, starting with the establishment of a Cell and Gene Therapy Manufacturing Center using modern cell production technology for in-house manufacturing of cellular therapy. This center is the first and only cell production facility in the hospital that has been certified by the Food and Drug Administration of Thailand. The center has collaborated with Dr. Supannikar Tawinwung from the Faculty of Pharmaceutical Sciences, Chulalongkorn University, an expert in T-cell genetic modification, as well as experts from the National Blood Center and Thai FDA to develop a quality system for cell production to meet the international standards in point-of-care cellular therapy manufacturing.

The use of viral vectors for genetic modification is one of the main reasons for the high cost of commercial CAR T -cells, as the production and quality control processes for viral vectors used in humans are very complex and expensive. Our group has collaborated with researchers from Nagoya University, who are experienced in nonviral genetic modification technology for CAR T-cell production, which has a lower production cost compared to viral vector-based methods. We optimized a large-scale production process for nonviral CAR T-cells and successfully manufactured nonviral CAR T-cells for Thai volunteers, finding that the production cost was 10 times lower than that of commercial CAR T-cell products. This has led to the initiation of clinical research using nonviral CAR T-cells for the treatment of lymphoma patients in Thailand.

Prof. Yoshiyuki Takahashi, MD, Ph.D. Professor and Chairman, Department of Pediatrics Nagoya University Graduate School of Medicine said that the research group has developed a method for producing CAR T-cells by gene transfer using the PiggyBac transposon, a non-viral vector, and has started a clinical trial. This method is simpler than viral vectors and can be produced at a lower cost and is expected to have the same therapeutic effect as viral vectors. In 2018, the Faculty of Medicine, Nagoya University signed an MTA regarding support for CAR T-cell therapy using this technology with the Faculty of Medicine, Chulalongkorn University, Thailand.

In 2023, Nagoya University also plans to start an investigator-initiated clinical trial using CAR T-cells for relapsed/refractory malignant lymphoma, which will be used in clinical trials at Hokkaido University Hospital, National Cancer Center Hospital East, Nagoya University Hospital, Kyoto University Hospital, and Kyushu University Hospital.

"The PiggyBac transposon-mediated CAR T-cell innovation poses no limits regarding the age of the patients. Patients that can receive this therapy range from 1 year old to the elderly, given that they have the qualified physical characteristics. In the future, the team plans to expand the use PiggyBac transposon-mediated CAR T-cells to other types of cancer than leukemia and lymphoma, specifically cancerous tumors like brain tumors, neuroblastoma commonly found in children, and bone cancer," said Prof. Yoshiyuki Takahashi regarding the CAR T-cell research plans.

Asst. Prof. Udomsak Bunworasate, M.D., Chairman, Division of Hematology, Department of Internal Medicine, Faculty of Medicine Chulalongkorn University said that the knowledge of PiggyBac transposon-mediated CAR T-cell production has helped the Faculty of Medicine save substantial costs when compared to the viral CAR T-cell therapy. Treating patients with CAR T-cell therapy involves complex steps, including screening suitable patients, collecting their white blood cells, producing CAR T-cells from their white blood cells, administering immunosuppressive drugs before giving the cells, giving CAR T-cells to the patient, and monitoring the efficacy and side effects after cell administration. Chulalongkorn University has organized an interdisciplinary team consisting of experts in CAR T-cell production and quality control, blood bank specialists, hematologists, and specialists in infectious diseases, neurology, and critical care medicine to support the treatment and research of CAR T-cell therapy in Thai patients to ensure safety and maximum benefits from this technology.

We have begun a phase 1 clinical trial to study the safety and preliminary efficacy of CAR-T-cell therapy in patients aged 18-60 with B-cell lymphoma who do not respond to standard treatment. The project started in late 2020, marking the first time in Thailand that lymphoma patients could access CAR T-cell therapy. To date, five patients have been treated under the clinical trial, all of whom have no other treatment options. After receiving CAR T-cells, we detected an increase in the number of CAR T -cells in all patients. All patients showed a satisfactory initial response with manageable side effects, similar to commercial CAR T-cell products. One of our patients with a large 10-centimeter lymphoma in the abdomen that was unresponsive to any treatments had her disease controlled 1 month after CAR T-cell infusion and exceptionally remained disease-free for one year.

Currently, we continue enrolling the patient in a clinical trial with the hope of completing treatment in all 12 patients this year to evaluate the safety and efficacy of nonviral CAR T-cell therapy in Thai lymphoma patients. The team aims to offer not-for-profit CAR T-cell therapy services produced using in-house cell manufacturing to increase treatment accessibility for Thai lymphoma patients. This will be done under the collaboration between Chulalongkorn University and Nagoya University.

Koramit Suppipat, M.D. Director of Cellular Immunotherapy Research Unit Faculty of Medicine Chulalongkorn University concluded that the academic collaboration between Chulalongkorn University and Nagoya University in the development of nonviral CAR T-cell therapy has led to success in developing an in-house cell production facility, developing a team of experts in manufacturing, and conducting CAR T-cell treatment in Thailand. This has resulted in the successful treatment of Thai patients with lymphoma through clinical trials.

This is just the first step in the development of this technology, and the team is committed to developing this technology to accommodate the treatment of other common cancers in Thailand, continually reducing the cost of cell production, improving the quality control system to comply with international standards, and expanding cell production capacity so that Thai cancer patients can have sustainable access to CAR T-cell therapy.

We are grateful for the support from all sectors that have made the development of this project a leap forward. Support from government agencies (NSTDA, NRSA, TCELS, NSTA), private sector organizations (TISCO, MK, SCG), and public support through the Cancer Immunotherapy Fund at Chulalongkorn University is crucial for us to continue our stable progress in developing new cell and gene therapy technologies which enable Thai patients to access safe and highly effective treatment equitably and sustainably.

The press conference was attended by representatives from both universities, including Assoc. Prof. Chanchai Sittipunt, M.D., Dean of the Faculty of Medicine, Chulalongkorn University, and Director of King Chulalongkorn Memorial Hospital, Koramit Suppipat, M.D., Director of the Cellular Immunotherapy Research Unit, CU Cancer Immunotherapy Excellence Center, and Assist. Prof. Udomsak Bunworasate, M.D., Head of the Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University, from Thailand, and Prof. Seiichi Matsuo, M.D., Ph.D., President of Tokai National Higher Education and Research System, Nagoya University, Prof. Hiroshi Kimura, M.D., Ph.D., Dean of School of Medicine, Nagoya University, and Prof. Yoshiyuki Takahashi, M.D., Ph.D., from the Department of Pediatrics Graduate School of Medicine, Nagoya University, from Japan.