Experience of cytotoxic T lymphocytes therapy for malignancy

Abstract

Background Since the introduction of adoptive immunotherapy (AIT) using autologous lymphokine‐activated killer (LAK) cells for treating advanced cancer, many clinical trials were performed. However, their efficacy was much lower than expected. Thereafter, AIT with more specific targeting against tumour antigens, including tumour‐infiltrating lymphocytes and cytotoxic T lymphocytes (CTL), was developed, and a better clinical outcome is anticipated. Recently, we have started CTL therapy as ‘an advanced therapy’, which needs approval from the government and a special facility known as the Cell Processing Room (CPR).Materials and Methods Most ordinary treatments are subject to the medical insurance system in Japan where 70% of costs are covered by the official health insurance and the rest is at patients’ expense. However, some sophisticated therapies including CTLs are only available through either clinical research or an advanced therapy, which needs official approval, and whose expense can be charged to patients in addition to the ordinary expense. With regard to cellular therapy, the Japanese government recently set regulation, including two main points: one is that cells should be used inside the hospital, indicating the responsibility of medical doctors for cellular therapy according to the Medical Practitioner Law; the other is that hospitals performing cellular therapy must establish a CPR to ensure the safety of cells processed. Mononuclear cells (MNCs) are separated from 40 ml of peripheral blood by a density gradient. They are exposed to irradiated autologous tumour cells, at a ratio of tumour cells : MNC = 1 : 100, with recombinant interleukin‐2 (50 U/ml) for 4–5 days. Then, MNCs are stimulated by anti‐CD3 monoclonal antibody for a similar time and subjected to culture for growth for 10 days, in total 17–19 days. Before harvesting, CTL is screened for contamination and specificity against tumour cells. Usually, about 1 × 109 cells are obtained and administered to patients intravenously. CTL is administered every 2 weeks, totalling four doses (one course). Two days before administration, a patient receives cyclophosphamide (Endoxan, 200 mg/body) to suppress regulatory T cell activity. Subjects of CTL therapy are patients (i) aged below 70 years old, with cancer; (ii) with no serious complications regarding major organs and who are durable for this treatment; (iii) with tumours or tumour markers that can objectively be evaluated; (iv) whose tumour cells are available as tumour antigen; (v) whose tumour cells express class I human leucocyte antigens (HLA); and (vi) who give informed consent.Results We treated 22 patients with various cancers, including melanomas and sarcomas, most of which had been refractory to current chemotherapy. From these, eight patients showed no progress of disease for at least 2 months. Among them, two cases revealed a convincing efficacy of CTL therapy, one showed relapse‐free survival for 5 years and the other for 1 year.Conclusions Although in Japan circumstances to execute cellular therapy have become stricter, cellular therapy, including CTL, is considered feasible. Especially if it is taken into consideration that most of our cases are refractory to current chemotherapy and that two cases showed a remarkable response, it is a promising therapy for patients with advanced cancer.