Glossary

Natural Killer (NK) Cells

It is a cell with lytic activity such as virus-infected cells or cancer cells and is present in 15 to 20% of leukocyte components in the blood. It is thought that it works in infectious diseases, cancer, etc. and is involved in innate immune reactions.

Interleukin 2

It is a type of cytokine found in the 1970s as a substance that promotes the proliferation of T cells (substances produced by cells responsible for immunity, adjustment of immune response, activation of immuno-competent cells, proliferation action).

Chemobrain

Cerebral function disorder caused by chemotherapy. The result of neuro-psychological examination is poor and many cognitive dysfunctions are also observed. Typically, it says “the brain feels so heavy and tiring, everything feels as dull and cloudy”.

Activated Lymphocyte Therapy

By stimulating the lymphocytes of cancer patients themselves with anti-CD3 monoclonal antibody and growing them outside the patient’s body in the presence of interleukin 2, the activated lymphocytes are returned to the patient again killing the cancer cells and thereby destroy cancer tissue. Currently, it is being implemented as advanced advanced medical care at several university hospitals in Japan and private medical institutions as a free medical examination.

Cancer Vaccine Therapy

Whether the body’s immune system does or does not attack normal cells or whether only cancer cells can be eliminated was a matter of argu-ment. However, it has now been revealed that there are antigens specific to cancer cells and recognizable by killer T cells (CTL). To date, several hundreds of cancer antigens have been found and their genes have become clear. Recently, as a new immunotherapy using these antigens “cancer vaccine therapy” has come to be carried out. Is a therapeutic method of administering a cancer antigen protein or a peptide derived therefrom along with an auxiliary substance (called an adjuvant) that enhances an immune response, or a method of using a dendritic cell to express cancer-specific killer T cells. Although there are methods to induce cancer cells, the most attractive method is to use cancer cells and cancer tissue itself so as not to miss any cancer antigen in the cancer cells.

Anti-CD3 Monoclonal Antibody

CD3 is a molecule present on the surface of human T cells. Anti-CD3 monoclonal antibody specifically recognizes this CD3 molecule. When anti-CD3 monoclonal antibody binds to a CD3 molecule on a T lymphocyte, a T cell is activated.

Cytotoxic T lymphocytes (CTL)

T cells that kill cells that have specific antigens on the cell surface such as virus-infected cells or cancer cells. T cells with CD8 molecules are the main ones.

Dendritic Cells (DC)

In order for T cells to be activated against antigens and become killer T cells (CTL), they first need to be stimulated by cells called antigen presenting cells. Among antigen presenting cells, dendritic cells are particularly high in ability to present antigens.

What are Natural Killer (NK) Cells

It is a cell with lytic activity such as virus infected cells and cancer cells and is present in 15 to 20% of leukocyte components in the blood. It is thought that NK cells work in infectious diseases, cancer, etc. and are involved in innate immune reactions.

What are Hard criteria and Soft Criteria?

The usual cancer treatment effect is generally evaluated by the direct effect criterion (WHO standard) for solid cancer chemotherapy. This evaluates how much the cancer lesion has changed by the anticancer agent.

• Complete Response (CR): The lesion disappeared completely for more than 4 weeks
• Partial Response (PR): Tumor shrinkage of more than an estimated 50% persists for more than 4 weeks
• (SD, invariant NC): Does not change for more than 4 weeks, PR or less Progress of PD not reaching (PD): New lesion appears, Increase of lesion of 25% or more is described and the ratio of CR + PR cases in the total number of cases is Response Rate. The percentage is expressed as an evaluation standard of anticancer drugs recognized worldwide.

Recently, rather than WHO evaluation, evaluation by the more convenient RECIST method is now used. Guidelines are also issued in Japan. Recently, SD is being proposed as an effective range and the proportion of CR + PR + SD occupying in the total number of cases is often expressed as the disease control rate (%).

Frequent questions from patients are “What percentage of is effective for cancer” to which reference is made to the above response efficiency or disease control rate.

However, due to anticancer drugs, “Although cancer has become smaller, there is no continuous effect that goes far beyond 4 weeks, eventually the patient died, so the survival rate of the patient as a whole describes the survival benefit. This is a phenomenon that was often seen with conventional anti-cancer drugs (although outstanding successes like with leukemia and testicular cancer are also recorded, of course).

It is meaningless to say that a patient cannot actually live long. Therefore, each country has switched to a policy of not accepting it as a novel anticancer drug unless it is proven that even if it is evaluated in the overall survival rate (OS), a definite a survival benefit exists.

As described above, the response efficiency and the lifespan effect evaluated by the OS are classified as “hard criteria” because they are evaluation criteria with a solid scientific basis though they have different meanings.

On the other hand, when cancer immunotherapy is performed, there are not many striking cases of CR · PR. However, even though the size of cancer is invariable (SD), it occurs in as many cases as it cannot be ignored, that it lasts more than 4 weeks or more than half a year. The conference report that “patient was able to live long after all” continues. Therefore, it is advocated that long-term invariant cases should be effective cases.

Moreover, when cancer immunotherapy is carried out, patients who are staying at home asleep or getting up were very energetic, went to golf. The family watching by my side was surprised. There are many examples of drastic improvements when looking at QOL (Quality of Life) as an external improvement effect. However, there are drawbacks that QOL is difficult to accurately quantify and measure and it significantly changes depending on the subjectivity of the evaluator.

Also in the academic paper, as an evaluation method alternative to CR · PR, in addition to “long-term SD” (including no relapse for more than 1 year after autologous cancer vaccination) and “QOL”, “part of the cancer shrinks Evaluation criteria such as “I improved”, “clinical symptoms improved”, “lived longer than the physician forecast”, “tumor marker declined” and so on are occasionally used. A collection of these is the Soft Criteria which shows some improvement on cancer. The improvement rate is the percentage of cases in which improvement is recognized among the whole cases where evaluation has been completed. Currently, two types Improvement Rate 1 and Improvement Rate 2 are defined.

For these definitions
See the illustration on this page (Improvement Rate 1) and the footnote to the table (Improvement Rate 2) 

When developing a new cancer immunotherapy, CR, PR, OS etc can be easily measured in animal experiments which are always carried out during the development process but it is impossible to objectively measure quality of life. Also, even if CR and PR effects are given in animal experiments, there are quite a lot of treatments that resulted in “no effect at all, only toxicity appeared” when actually applied to humans.

Soft criteria is not a criterion that can withstand rigorous academic criticism but actually it is very useful for guessing “effects not known only in humans” like QOL. Especially in situations where clinical experience is limited, gathering some improvement effects on cancer allows to see the overall trend of whether a new cancer immunotherapy is viable.

For example, soft criteria is like predicting the weather of tomorrow by looking at the direction and speed of the clouds flowing. Although it is inferior to the weather forecast (“regular clinical trial = trial” is equivalent to this), which involves large-scale and expensive expenses for mobilizing satellites and supercomputers.

Since humans cannot be treated like mice in a lab, it is normal to apply new methods carefully to very few cases at first, carefully investigate whether there is any effect while checking safety. In such cases, it seems self-evident that if there no effect even with the software criteria, the trials will not be publicly discussed.

From this point of view, we decided to announce the clinical results of autologous cancer vaccine therapy that was strictly evaluated by hard criteria, as well as a treatment result table based on soft criteria.

Peptide Fragments
The antigen protein is broken down in the antigen presenting cell and becomes a peptide fragment with a short amino acid connected to the surface of the antigen presenting cell. T cells recognize peptide fragments presented by dendritic cells.