It contains the history of immunotherapy from a frame perspective, the immune system understood from a perspective of balance, the mechanisms of immunotherapy, the achievements of immunotherapy and the issues raised in the process of application, an introduction and analysis of the latest research trends, and the 'minimum things you need to know to understand immunotherapy' surrounding all of this.

It is clear that efforts prior to 2010 laid the foundation for immunotherapy for cancer.
However, the process is largely remembered as a dark history.
Although outstanding scholars did their best to research, there was a problem with the frame.
First of all, there was a problem with the frame of immunity itself.
Until at least the 1990s, immunity was thought to be a system for responding to invasion by foreign substances such as viruses and pathogens.
That is, 'self vs. non-self'.
It is a frame of ‘non-self’.
Within this frame, cancer cells are the result of cells in the body becoming transformed.
The premise was that cancer cells were 'self' and had nothing to do with immunity.
Although cancer is a vicious lump that needs to be eliminated, I couldn't grasp the concept that 'it can be controlled by the immune system.'
The limitations of the concept led to limitations of the research.
The conservative frame also played a part.
In the early 2000s, clinical trials of immuno-oncology drug candidates, such as immune checkpoint inhibitors and cancer vaccines, were conducted primarily by small-scale bio-ventures and biotech companies.
This is because the interest of large pharmaceutical companies at the time, which were at the forefront of new drug development, was in targeted anticancer drugs.

Before the advent of targeted anticancer drugs, the mechanism of anticancer drugs was to kill cancer cells with toxic chemicals.
The drugs were developed primarily using toxic chemicals that responded to the rapid growth characteristics of cancer cells, but this method caused significant side effects as it also caused significant damage to normal cells.
However, targeted anticancer drugs target specific molecular characteristics of cancer cells.
Therefore, it is possible to selectively eliminate only cancer cells while minimizing side effects on normal cells.
Gleevec, which opened the era of targeted anticancer drugs with FDA approval in 2001, was successful as a treatment for chronic myeloid leukemia (CML).
However, although targeted anticancer drugs were also born from innovative science, their superior efficacy has again led to conservatism.
Everyone was only looking at research on targeted anticancer drugs, and immunotherapy was pushed out of the spotlight.
--- p.33~35

In the 1950s, there were quite a few patients whose blood cells died due to radiation exposure from nuclear power plant accidents or excessive exposure to toxic anticancer drugs or radiation during cancer treatment.
Dr. Edward Donnall Thomas (1920-2012) confirmed that bone marrow contains cells capable of producing blood cells and studied methods for treating patients using bone marrow transplants.
It was later discovered that hematopoietic stem cells produced in the bone marrow play a major role in the regeneration of blood cells such as white blood cells, red blood cells, and platelets.
Hematopoietic stem cells are also called hematopoietic stem cells because they have the ability to differentiate into various cells and to replicate themselves.
Thomas initially studied hematopoietic stem cell transplantation from a regenerative medicine perspective.
The idea was to transplant healthy hematopoietic stem cells to regenerate the bone marrow, which was damaged by radiation exposure and causing the blood cells to die.
Thomas saved the lives of many patients through hematopoietic stem cell transplantation, and was awarded the 1990 Nobel Prize in Physiology or Medicine in recognition of his contributions.
Hematopoietic stem cell transplantation is considered the origin of not only regenerative medicine but also immunotherapy.
It was thought that hematopoietic stem cells were transplanted, but in reality, various immune cells in the bone marrow were transplanted together.
Controlling the function of transplanted immune cells has become a key factor in successful hematopoietic stem cell therapy, and the technology and know-how developed in the process have since become key elements in the development of cancer treatment technologies using immune cells.
So the Fred Hutchinson Cancer Research Center in Seattle, where Thomas spent most of his research time, also played a key role in the development of immuno-oncology cell therapy technologies.
--- p.54~56

The important things in the immune system are direction and balance.
When we learn that immunity is what can fight against a powerful enemy like cancer, it is common to wonder, "How powerful is the power of immunity?"
It's important that our immune system is strong enough to overcome cancer, but more importantly, when it's out of balance and out of control, it can attack the wrong parts of our body with equal force.

When your immune system is suppressed, you become more susceptible to illness when exposed to infections and even cancer.
However, excessive activation of the immune system is also a problem.
This is because it can cause autoimmune diseases, allergies, and immune hypersensitivity such as asthma, in which the body's immune cells attack the body.
Immune checkpoints are what put the brakes on when the immune system becomes overly activated, losing direction and balance.

But clever(?) cancer uses the immune checkpoint for its own benefit.
It is to avoid an attack by putting the brakes on the immune system.
Immune checkpoint inhibitors are anticancer drugs that enhance the immune anticancer response by preventing the immune system from braking.
There are two places in the cancer-immune cycle where immune checkpoint inhibitors act.
The process of activating T cells in the lymph nodes (3) and the process of sending a signal to the cancer cells not to attack them, preventing the immune cells from killing the cancer cells (7).
--- p.111~113

All the biomarkers discussed so far were measured using tumor tissue.
Tumor tissue is rich in information, but difficult to obtain.
If the patient had surgery, they could have obtained a fairly large tumor tissue.
However, if tumor tissue is obtained for biomarker testing, only a minimal amount of tissue is extracted.
However, since tumors are not uniform across different parts, the question arises as to how much information the extracted tumor tissue can represent about the entire tumor.
For this reason, efforts to develop blood-based biomarkers are active.
Blood, unlike tumor tissue, can be obtained at any time.
This is a good way to look at changes over time.
First, we can imagine a way to utilize various immune cells in the blood.
You may also be able to see the number of cells of a particular type, the ratio of two types of cells, etc.
Meanwhile, by comparing the patient's blood before and after receiving immunotherapy, it may be possible to see changes in immune cells due to treatment.
Biomarker development is currently underway, utilizing the differences in blood immune cells between responders and non-responders to immunotherapy.
Next, there is a method of analyzing small amounts of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes in the blood using liquid biopsy.
The only problem is that the quantity is too small.
For example, there is about 1 CTC in the blood per million immune cells.
It is technically difficult to extract and analyze such a small amount of material.
Nevertheless, technological advancements have made it possible to test for TMB and MSI using liquid biopsies.
The efficacy in clinical trials is also in the verification stage.
--- p.170~171

Several phagocytes engulf dead tumor cells.
The subsequent immune response may also vary depending on which phagocytes are involved.
There are several types of macrophages and dendritic cells within tumor tissue.
Most of these enter the tumor tissue through the bloodstream.
They interact with various cells in tumor tissue and differentiate into cells with independent functions.
Among the various types of macrophages, some trigger an immune response against tumors, while others induce immunosuppression against tumors.
The origin, classification, and function of various intratumoral macrophages are currently being studied.
Here, we will briefly look at cDC1 (conventional Dendritic cell 1), which is receiving the most attention in the field of immuno-oncology drug development using dendritic cells.
cDC1 expresses the CD141 (CD103 in mice) receptor along with the transcription factor Batf3 (Basic leucine zipper ATF-Like transcription factor 3).
According to the research team led by Dr. Matthew Krummel of California State University, cDC1 carries tumor tissue information and moves to the lymph nodes to activate naive T cells (Cancer Cell, 2016) and also reactivates effector T cells in tumor tissue to promote cancer cell death (Cancer Cell, 2014). The fact that cDC1, which expresses textbook dendritic cell functions, is given such importance can be said to reveal an abnormal aspect of tumor tissue.
Although the number of cDC1 is usually low in solid tumors, it plays an important role in the prognosis of cancer patients and the response to immunotherapy.
So what factors regulate the number of cDC1s within tumors? --- p.186~187

Tumor tissues contain various immunosuppressive cells, including tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells.
Among these, TAM and CAF are cells that exist in normal tissues but have been transformed by tumors.
While macrophages engulf and destroy tumor cells, TAMs promote tumor development and suppress immunity.
Macrophages can be polarized into M1, which activates the immune response, and M2, which suppresses the immune response and promotes tissue regeneration.
When a tissue is infected, M1 must first be activated to eliminate the pathogen through a strong immune response.
During this process, tissues and normal cells are also damaged.
Therefore, in the later stages of the inflammatory response, M2 alleviates inflammation and regenerates tissue.
In this way, the activation and suppression of immunity must be appropriately regulated according to the situation.
In 1986, Dr. Harold Dvorak of Harvard Medical School published an article in the New England Journal of Medicine comparing tumors to a "wound that does not heal."
Wounds that do not heal cause chronic inflammation.
Chronic inflammation exhausts T cells.
Macrophages are polarized to M2 and suppress immunity.
Fibroblasts, which produce ECM to repair wounds in normal tissues, become CAFs in tumor tissues and continuously produce ECM to treat non-healing wounds, thereby inducing fibrosis.
Fibrosis prevents T cells from reaching tumor tissue.
In addition, CAFs secrete several immunosuppressive substances, thereby interfering with antitumor immunity.
Looking at the wounds that do not heal, many of the immunosuppressive properties of tumors can be explained as follows.

--- p.219~221