Results obtained in Japan on the efficacy of autologous activated lymphocyte therapy.
(Extracts from Immuno-cell therapy of cancer in Japan; Egawa K.; Anticancer Research, 24; 3321-3326, 2004)
Results obtained in Japan on the efficacy of autologous activated lymphocyte therapy.
The clinical efficacy of autologous activated lymphocyte therapy obtained in Japan are summarized in Table III. The table also contains representative reports on the original LAK therapy for comparison. There are several publications in Japanese and one publication on the result of allogeneic activated lymphocyte therapy (22). These were not included in the Table III-A.
The data shown in Table III are all of retrospective studies without control cases. Therefore, the data can not be considered statistical evidence of efficacy, but they suggest the usefulness and limitation of the therapy. Table includes reports from 13 groups. Except for one report (16), all of them dealt with the results of research carried out in university hospitals and cancer centers and the number of patients treated by one group is quite limited. The total number of patients described in the 13 reports is 260 while the average number of cases included in one report was 20.１ ± 4.2 (mean ± standard error). Patients were mostly in stage IV including those with inoperable and recurrent diseases. The efficacy of the therapy was evaluated according to the criteria of chemotherapy. Patients who completely responded (CR) or partially responded (PR) to the therapy were included in the responsive group while NC and PD were included in the non-responsive group. In two of the repots (16,17), patients who remained in NC for a period more than 6 months (prolonged NC, PNC) were included in the responsive group (number in the parentheses). PNC is considered quite beneficial to the patients when the therapy dose not produce considerable side-effects (16). In these reports, the efficacy rate including the PNC is apparently higher than that not including the PNC. With some exceptions in which the number of patients was less than 10, the response rates of systemically administered activated lymphocytes were generally between 10 and 25%. The overall response rate of the 260 patients not including the PNC was 23.8%. On the other hand, Table III-B shows the response rates of the original LAK therapy combined with IL-2 administration described in the representative five reports (1, 18-21). The overall response rate was 27.9% (78 responsive patients among 280 patients who underwent this therapy). However, high dose IL-2 administration alone shows (21). These results suggested that CD3-LAK therapy without IL-2 administration is not significantly different in efficacy from LAK therapy combined with toxic high-dose IL-2 administration.
In addition to the retrospective studies mentioned above, it is notable that there are other studies on prospective randomized controlled trials of autologous activated lymphocyte therapy. They are summarized in Table IV. When the therapy was performed on the patients after surgical resection of ovarian cancer (23), lung cancer (24) and liver cancer (25), it increased long-term survival rate or disease-free survival rate with statistical significance. This result shows that the therapy is effective at least when the number of the target cancer cells in the body of the patient is low. With regard to stomach cancer, it was demonstrated that the cytotoxic T lymphocyte (CTL) therapy, combined with chemotherapy, increased the survival rate of the patients in stage IV (26). These results seem to reveal that we could expect a better efficacy of immuno-cell therapy when used in combination with other therapies that bring about immediate reduction in tumor size. These therapies include standard cancer therapies such as surgical resection, radiation therapy and even chemotherapy.
Table III. Published results of autologous activated lymphocyte therapy carried out in Japan
| Reference | Year of publication | Author | Type of therapy | Organ with cancer |
Number of patients |
Efficacy rate (%) |
|---|---|---|---|---|---|---|
| (A)Published results of autologous activated lymphocyte therapy carried out in Japan | ||||||
| (5) | 1988 | Baba M et al. | LAK therapy high-dose IL-2 local administration |
Lung | 5 | 20 |
| (6) | 1990 | Komatsu T et al. | LAK therap y IL-2 |
Liver （primary and metastatic） | 26 | 23 |
| (7) | 1990 | Usui A et al. | CD3-LAK therapy low-dose IL-2 plasmapheresis |
Kidney | 9 | 11 |
| (8) | 1991 | Yamaguchi Y et al. | CD3-LAK therapy Low-dose IL-2 |
Liver, lung （advanced） |
24 | 20 |
| (9) | 1991 | Nakano E et al. | LAK therapy low-dose IL-2 plasmapheresis |
Kidney | 14 | 21 |
| (10) | 1991 | Aoki Yoichi et al. | TIL therapy | Ovary (advanced) （cyclophosphamide） （cisplatin） |
7 10 |
71 90 |
| (11) | 1993 | Nomura K et al. | LAK therapy IL-2 |
Kidney | 11 | 18 |
| (12) | 1993 | Ibayashi Y et al. | LAK therapy high-dose IL-2 |
Brain | 9 | 33 |
| (13) | 1996 | Haruta I et al. | LAK therapy or CTL therapy | Liver (CTL) (Stage IV) (LAK) |
18 8 |
28 0 |
| (14) | 1998 | Tomitra Y et al. | LAK therapy chemotherapy （cyclophosphamide） |
Kidney | 9 | 67 |
| (15) | 2000 | Toh U et al. | TIL therapy high-dose IL-2 |
Esophagus | 11 | 36 |
| (16) | 2002 | Goto S et al. | CD3-LAK therapy | Various organs with inoperable or recurrent cancer |
57 | 11(30)* |
| (17) | 2003 | Ebina T et al. | CD3-LAK therapy | Various organs with advanced cancer |
42 | 14(76)* |
| (B) Reports on the original LAK method | ||||||
| (1) | 1986 | Rosenberg SA et al. | LAK therapy high-dose IL-2 |
Various cancer (stage IV) |
41 | 34 |
| (18) | 1987 | Rosenberg SA et al. | LAK therapy high-dose IL-2 |
Various cancer (stage IV) |
108 | 22 |
| (19) | 1990 | Steis RG et al. | LAK therapy high-dose IL-2 intraperitoneal injection |
Various intraperitoneal cancer |
24 | 29 |
| (20) | 1992 | Thompson JA et al. | LAK therapy high-dose IL-2 |
Kidney (stage IV) | 22 | 41 |
| (21) | 1993 | Rosenberg SA et al. | LAK therapy With or without High-dose IL-2 |
Various cancer (stage IV) |
with IL-2: 85 without IL-2: 79 |
with IL-2: 28 without-IL-2: 20 |
LAK: lymphokine-activated killertherapy、CTL: cytotoxic T lymphocytestherapy
ＴＩＬ: tumor-infiltrating lymphocytestherapy
*( ) : including PNC (prolonged NC; patients remained in NC for a period of more than 6 months)
Table IV. Statistical evidence of efficacy of autologous activated lymphocyte therapy obtained in prospective randomized controlled studies.
| Reference | Author | Year of publication | Object and therapy | Number of patients (Treated：Control) |
Effect | Statistical Significance |
|---|---|---|---|---|---|---|
| (23) | Fujita K et al. | 1995 | Ovarian cancer after resection and chemotherapy (TIL therapy) |
13:11 | Increase in survival rate |
p<0.01 |
| disease-free survival rate |
p<0.05 | |||||
| (24) | Kimura H et al. | 1997 | Lung cancer (stage II ～ IV) after resection and chemotherapy or radiotherapy (LAK or TIL therapy) |
82 : 88 | Increase in survival rate |
p<0.001 |
| (25) | Takayama T et al. | 2000 | Liver cancer after curative resection （CD3-LAK therapy） |
74 : 76 | Increase in survival rate |
p<0.09 |
| Increase of disease-free survival rate |
p<0.01 | |||||
| (26) | Kono K et al. | 2002 | Stomach cancer (stage IV) chemotherapy (CTL therapy) Intraperitoneal injection |
22:22 | Increase in survival rate |
p<0.05 |
