Cell based Immunotherapy (or Immuno-Cell Therapy) is a type of medicine utilizing the cell harvested from and transfused back into a patient. Some of the major innovations in immunotherapy, such as Autologous Immune Enhancement Therapy (AIET) and Immune Maximizing Therapy, WT-1 peptides, were developed by Japanese scientists, and immunotherapy in japan is leading the research at forefront.
The latest immunotherapy in Japan reached the level of clinical efficacy to outscore that of chemotherapy against the advanced stage cancers. Previously, the roles of Immunotherapy were limited to adjuvant therapy, but the recent results show that immunotherapy was undervalued due to its long-term effects which usually take 5 months to show any responses, too slow to be considered as the effective treatments supposed to shrink tumors within a few months. (See the figure below.)
Figure: Survival curves of advaned colorectal cancer patients (Sugiura, Okuno, 2007). FOLFOX4 (Adjuvant treatment against colorectal cancer), Bevacizumab (Targeted Therapy), UFT/LV + Peptide Vaccine (Immunotherapy).
There are eight types of treatments available in Japan, some of which are deemed the fifth generation therapy available only in japan.
- αβT Cell Immunotherapy
- Dendritic Cell based Immunotherapy
- Dendritic Cell with peptides for tumor antigen extracted from patients
- WT1(WT-1) vaccines (New)
- Peptide vaccines (RNF43 / TOMM34)
- CTL (Cytotoxic T Lymphocyte) Cell Immunotherapy
- NKT (Natural Killer) Cell Immunotherapy
- γδT Cell Immunotherapy (New)
- Dendritic Cell with WT1(WT-1) peptides (New)
Generally, lower side effects than other treatments are reported.
Dendritic Cell Immunotherapy or Autologous Immune Enhancement Therapy (AIET) in Japan
In Japanese hospitals and clinics, there has been a major progress in the cancer immunotherapy using the dendritic cell. Not only the immune cells but also the tumor cells are taken out from patient's body, which are reprocessed to destroy only specific type of tumor cells, and re-injected into the body.
Dendritic cells act as trainers to immune cells to learn the markers of the target tumor cells, and to destroy only the target while preserving the healthy cells.
Techniques to harvest the cells are extremely intricate and delicate processes. For the treatments to be rountinely available to the cancer patients apart from the clinical trials, advanced engineering cell reprocessing center must be available with good corroboration with the hospitals.
Since Japan made the Immuno-Cell Therapy to be a part of health care systems, the cell processing centers (CPCs) rapidly increased in the past decade. For the therapy of high complexity such as dendritic cell / autologous enhancement immunotherapy to be regularly practiced in the hospital, those CPCs were essential, and explain why much of innovations in cell based cancer immunotherapy took place in Japan.
WT1(WT-1) Peptides
WT1 is a special type of tumor antigens developed by Japanese researchers at Osaka University, Professor Haruo Sugiyama. WT1 peptides may be used with:
- Vaccinations
- Dendritic Cell Immunotherapy
WT1 peptides are more powerful than any other vaccines and could control even advanced stage cancers, results which had nullified the previous concept that immunotherapy cannot destroy big tumors.
But for the vaccines to work, WT1 peptides need to adapt to the HLA type of each patient, which makes vaccine development difficult. For 70% of Japanese population, HLA types are either A24, or A02, and this simplicity contributes to the wide use of WT1 peptides in Japan.
WT1 Vaccinations: Illustration
Figure (Above): Late stage breast cancer patients had been vaccinated twice, and as a result, the tumors surrounding colons shrinked.
Figure (Above): Stage IV lung cancer patients had been vaccinated. Tumor markers reduced by WT1 peptides.
Figure: 75 old women with hepatocellular carcinoma, bone metastasis, lymph node metastasis. Vaccinations effected the complete remission of some tumors, and shrinked the rest.
Research Center Conducting Clinical trials for WT1 Vaccinations
| Osaka University | Office for WT1 Clinical Trials | All Cancers |
| Iwate Medical University | Gastrointestinal, Kidney, Lung, Breast, Ovarian Cancer | |
| National Cancer Center Hospital | Narita, Yoshitaka | Brain Tumors |
| Chiba University Hospital | Ochiai, Takenori | Gastrointestinal Cancer |
| Kyoto University Hospital | Inoue, Masami | Leukemia |
| Osaka Medical Center and Research Institute for Maternal and Child Health | Pediatric Cancer | |
| Kochi University | Office for WT1 Clinical Trials | Solid tumors other than blood cancer |
Legend of Therapeutic Effects
|
CR (Complete Response) |
Removal of all target tumors |
|---|---|
|
PR (partial response) |
Greater than 30% decrease of the sum of lengths of target tumors |
| SD (Stable disease) | Not as good as CR, and not as bad as PD |
| PD (Progressive disease) | Greater than 20% increase of the sum of lengths of target tumors since the start of therapy |
Clinical Application (Dendritic Cell with WT1 Peptides)
Case 1: 63 years old male lung cancer patients
Patients received chemotherapy treatments with little effects, i.e., PD. After using TS-1 anti-cancer drug with dendritic cell with WT1 peptides, the tumor in lung shrinked, and other tumors all seemed to disappear from PET scan results.
Before Dendric Cell + WT1 Immunotherapy + TS-1 chemotherapy
After Dendric Cell + WT1 Immunotherapy + TS-1 chemotherapy
Case 2: 62 years old women with advanced breast cancer received chemo-radiotherapy, but the cancer progressed to metastasize to lung, liver, and bone. Switched to the stronger drugs but only to find the status to be PD. Patients could not withstand the chemo sessions, and further switched to the weaker drugs, furtulon (5'-deoxy-5-fluorouridine), in conjunction with dendritic cell + WT1 peptides. Later, metastasized lung tumors almost vanished, and liver and bone metastasis improved to PR or SD. Tumor markers diminished as in the table below.
Case 3: 65 years old male patients with stage IV pancreatic cancer could not have surgical treatments. Chemotherapy of Gemzar, (alpha-D-threo-pentofuranosyl)-isomer gemcitabine, and TS-1 were prescribed. However, the response of the drugs was disappointingly low to stay SD. With the start of Dendritic cell immunotherapy, complete remission, removal of tumors, were achieved, and tumor markers decreased to the normal level.
Immune Maximizing Therapy for Pancreatic Cancer (Dendritic Cell Therapy reported in ASCO)
In 2009, Professor Masato Okamoto, University of Musashino, reported the clinical outcomes of immune maximizing therapy combining the chemotherapy and dendritic cell immunotherapy (with WT1 tumor antigen and others). Results are shown in the table below.
| evaluation of clinical effectiveness | CR | PR | SD | PD | Total |
|---|---|---|---|---|---|
| Qty | 2 | 7 | 5 | 4 | 18 |
| Ratio (%) | 11.1 | 38.9 | 27.8 | 22.2 | 100.0 |
Cost
200,000 ~ 3,000,000 JPY