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The development of immunology has gone through a very long process, and people’s understanding of the immune system has been very shallow for a long time. Although people have long recognized the importance of IL-2 as a cytokine, its role is not known. Studies in the 1960s found that IL-2 promoted lymphocyte proliferation. In the 1970s, doctors began to study the effectiveness of using IL-2 to treat cancer. The development of recombinant DNA technology has also made it possible to mass produce this cytokine. Large doses of recombinant IL-2 (RIL-2) were found to be very effective in a small fraction of melanoma and renal cell carcinoma patients.

 

Steven Rosenberg and his colleagues found that peripheral blood lymphocytes cultured in vitro can effectively kill uncultured primary tumor cells by IL-2 activation and amplification. These cells are called LAK cells (Lymphokine-activated killer cell). , lymphokine activated killer cells). These cells are capable of killing tumor cells in a broad spectrum after being returned to the patient. LAK cells can kill tumor cells that do not express MHC, and LAK is distinct from natural killer cells (NK cells), which can kill tumor cells with no effect on NK cells. More importantly, NK cells are inactive against normal cells.

 

However, Rosenberg found that patients who used LAK cells alone to treat advanced cancer did not produce good results. RIL-2 alone dose-dependently reduced liver metastases in some advanced cancer patients. However, if RIL-2 and LAK cells are combined, it can increase the efficiency of IL-2 and significantly reduce liver metastasis.

 

At the same time, the researchers found that the therapy was too toxic and many patients developed severe fluid retention. Although there are problems with side effects, this therapy demonstrates the role of immune cells in combating tumors. Inspired by LAK cell therapy, Rosenberg decided to try other types of immune cells.

This time Rosenberg did not extract lymphocytes from the peripheral blood, but chose to extract it from the surgically removed tumor tissue. In many tumor patients, there is lymphocyte infiltration in the tumor, and patients with intratumoral lymphocytic infiltration tend to have better prognosis, so it may be a good choice to extract lymphocytes directly from the tumor.

 

Rosenberg found that these extracted tumor-infiltrating lymphocytes (TIL) were 50 to 100 times more potent than LAK in killing tumor cells in animal models. He referred to this therapy as TIL therapy: TIL cells were isolated from tissues near the tumor, and IL-2 was added for in vitro expansion and then returned to the patient, thereby expanding the immune response to treat primary or secondary tumors.

 

Rosenberg then treated the melanoma patient with the therapy and published the results in the New England Journal of Medicine in 1988. In 15 patients with metastatic melanoma, after treatment with TIL cells in combination with IL-2 and cyclophosphamide, 9 patients had an objective response with a response time of 2-13 months. IL-2 related side effects were found in the trial but were alleviated after discontinuation. This clinical trial confirmed for the first time the efficacy of TIL in the treatment of metastatic melanoma.

 

II

 

In addition to the above two therapies, immune cells used in tumor therapy include dendritic cells (DC cells), CIK cells, natural killer (NK) cells, and other cells derived from this, such as DC cell association. CIK cells (DC-CIK), CIK-NK cells alternate, and the like. The operation of these techniques is not very different. The lymphocytes are separated after the peripheral blood of the patient is taken, cultured, expanded, and then returned to the tumor patient.

 

Although the safety of these technologies is relatively good (the side effects of TIL therapy are mainly produced by IL-2), most of these lymphocytes isolated and cultured in vitro do not have the effect of killing tumor cells, so the efficacy is difficult to guarantee.  However, due to its high safety, this type of therapy has been popular in China.

Summary of tumor-related immune cell therapy

Name                        Introduction
LAK therapy LAK therapy is a treatment method in which peripheral blood lymphocytes are cultured in vitro, activated by IL-2, and then regenerated into a patient to broadly kill tumor cells. LAK cells are cytokine-activated killer cells that form cytokine-inducible tumor cells that are insensitive to NK cells when cultured in vitro. Its preparation is relatively easy, but its specificity is poor.
DC therapy DC therapy extracts the patient’s own monocytes, proliferates, cultures, and induces DC cells in vitro, and allows DC cells to load the corresponding tumor antigens and then return them to the patient to induce a specific or non-specific immune response. Activates the natural anti-tumor system in the human body to achieve the effect of killing tumor cells.
NK cell therapy NK therapy extracts NK cells from patients and uses cell culture techniques to multiply them in vitro and then return them to patients to play a role in regulating immune responses and directly killing tumor cells. NK cells are the first barrier of the human defense system. The killing activity is not restricted by MHC and is independent of antibodies, so it is called natural killing activity. The mechanism of action of NK cells is to kill tumor cells by releasing perforin, cytokines, etc., and activated NK cells can play a regulatory immune role.
CIK therapy CIK cell therapy is to culture human peripheral blood mononuclear cells in vitro with a variety of cytokines for a period of time, obtain a large number of T cells and then return to the patient, so as to accurately kill tumor cells without damaging normal tissues. CIK is a T lymphocyte in human peripheral blood. The membrane surface markers are CD3+ and CD56+, which directly kill tumor cells by releasing perforin granzyme, or indirectly kill tumor cells by secreting various cytokines. In addition, apoptosis of tumor cells can be induced by activating an apoptotic gene.

 

DC-CIK therapy DC-CIK Cell Tumor Biotherapy is the treatment of tumors using a combination of dendritic cells (DC) and cytokine-induced killer cells (CIK).

 

TIL therapy TIL cell therapy is a method in which TIL cells are isolated from tissues near the tumor, and IL-2 is added for large-scale expansion in vitro and then returned to the patient, thereby expanding the immune response to treat primary or secondary tumors.

 

CTL therapy CTL cell therapy is the use of lymphocytes of its own venous blood, in vitro through the induction of target cell antigens and lymphokines, differentiation and expansion into a CTS cell with strong lethality, and then intravenously returned to the body, thereby effectively exerting immunity Effect, the role of clearing the virus and killing tumor cells.

 

TCR-T therapy TCR-T therapy separates common T cells from patients and uses genetic engineering techniques to introduce new genes to enable transgenic T cells to express TCRs that recognize cancer cells. A method of treatment that is returned to the patient to kill the tumor cells. TCR is a specific receptor on the surface of T cells that binds to CD3 to form a TCR-CD3 complex that activates T cells by recognizing and binding to antigens presented by MHC.

 

CAR-T therapy The principle of CAR-T therapy is similar to that of TCR therapy, in which patient T cells are able to express the chimeric antigen receptor CAR by gene transduction. After the transformed T cells are returned to the patient, a large number of CAR-T cells specifically recognizing the tumor are generated, thereby killing the tumor cells. CAR is a T cell surface chimeric antigen receptor that recognizes tumor cells in a non-MHC-restricted manner.

However, Rosenberg discovered long ago that T cells differ greatly from other types of lymphocytes in their ability to kill tumor cells, such as the TIL containing a large number of T cells mentioned above. In 2002, the field ushered in an important breakthrough.

Although TIL therapy has a certain effect in the treatment of melanoma patients, usually the patient’s response time is relatively short, and the cells returned to the patient’s body disappeared after a few days, and they could not be found in the patient’s circulatory system. trace.

 

Rosenberg found that if the mice were pretreated before reintroducing the immune cells, clearing the lymphocytes in the mice significantly improved the efficacy of the therapy. The principle may be to clear Treg, destroy T cell regulation of homeostasis, or eliminate the functional inhibition state of T cells in vivo. This strategy has also been demonstrated in clinical trials: Pretreatment with cyclophosphamide and fludarabine can significantly prolong reinfusion of T cells in patients with metastatic melanoma before returning T cells with tumor-killing effects. Survival time and proliferative capacity improve patient remission rate.

 

TIL therapy is only effective in patients with melanoma, but the next two very important therapies (TCR-T and CAR-T) extend the treatment of immune cell therapy to other cancer types. After that, if there is an opportunity, CAR-T and TCR-T will be introduced in detail. Here is only a brief description of the main differences between the two therapies. CAR-T and TCR-T therapy first need to extract T cells from patients, and then genomically modify T cells in the laboratory to enable T cell surface to express specific protein receptors. The receptor on the surface of TCR-T cells belongs to the T cell receptor and is capable of recognizing antigen by binding to a protein fragment on MHC. The protein fragment is derived from the antigenic digestion process in the cell, so the TCR-T cell can recognize the antigen present in the cell, such as NY-ESO-1. The chimeric antigen receptor recognition on the surface of CAR-T cells is independent of MHC, and its mechanism of action is similar to the recognition of antibodies and antigens, and can recognize cell surface antibodies such as CD-19.

 

III

 

Eighty-five percent of ALL children can be cured after 2 years of standard chemotherapy, but 15% of patients will not be able to relieve the disease even with the highest-intensity chemotherapy. At first, Emily’s doctor thought she was suffering from normal leukemia, but after the disease relapsed, the doctor realized that her ALL was not so easy to treat.

 

Emily’s parents were extremely worried about the development of her next treatment plan and they decided to consult other doctors. However, Dr. Rheingold from the Children’s Hospital of Philadelphia gave treatment recommendations consistent with Emily’s then-attendant: I hope that Emily will be able to carry out the next round of higher-intensity chemotherapy. But Dr. Rheingold also said that if they want to choose other treatment options, she can help them.

 

Emily’s parents accepted their advice for chemotherapy. But just four months later, Emily had a second relapse and her condition deteriorated rapidly. At this point, Emily’s parents realized that they had to change the attending doctor and look for more cutting-edge treatments that are different from ordinary chemotherapy. The recommendation given by Philadelphia Children’s Hospital after determining that bone marrow transplantation is not possible is to participate in a clinical trial of CAR-T therapy. The therapy requires genetic modification of T cells to enable recognition of CD19, which allows T cells to recognize CD19 on the surface of B cells after in vitro culture of completed T cells, thereby triggering an immune response to kill cancerous B cells.

 

Three adult patients have been recruited into the clinical trial before, and these patients responded very well to the therapy. But no one knows how children’s patients work with CAR-T. After talking to Dr. Rheingold and Stephan Grupp at the Children’s Hospital of Philadelphia, Emily’s parents decided to take the risk to get her involved in the clinical trial. If this time is not successful, Emily will probably have only a few months of life.

After 4 weeks, T cells were prepared. On April 17, 2012, Emily became the first pediatric patient to receive T cell therapy. Dr. Grupp plans to enter CAR-T cells into her body three times. On the second day after the initial entry of 10% T cells, Emily received a second treatment, this time the doctor entered 30% of CAR-T cells into her body.

Dr. Grupp said Emily may have flu-like symptoms a few days after returning T cells, and the previous three patients also responded the same way. Surprisingly, Emily’s symptoms are much more serious than doctors expected.

 

On April 18, 2012, Emily returned home after a second treatment with her parents. Emily was in a very good mood at night, and she was still pestering her father Tom, who wanted to ride on his back. But in the middle of the night, Emily suddenly began to have a fever. Her parents quickly sent her to the emergency department at the Children’s Hospital in Philadelphia. After the hospital quickly convened a number of doctors to consult the body, while Tom stood aside, watching his daughter’s wrist, thigh artery and carotid artery were cut open, and inserted 17 IV tubes to maintain her life.

The doctor told Emily’s parents that they had never seen such a seriously ill patient, and Emily probably couldn’t have been this night. Although they knew that Emily’s condition was caused by the input T cells, it was not clear what happened to her body. Emily’s mother sat by her bed and quietly looked at the ventilator at the bedside. She firmly believed that it was impossible to end this way.

 

At this time, Carl June’s medical team did not give up and stepped up another blood test to confirm the immune response in Emily’s body. The results of the examination made the doctors very surprised. The IL-6 in Emily was nearly a thousand times higher than normal. Doctors speculate that IL-6 is the cause of Emily’s condition. Fortunately, Carl knows how to deal with it. His daughter is using an IL-6 inhibitor, tocilizumab, for rheumatoid arthritis. Although tocilizumab has never been used in the treatment of cancer patients, the efficacy and safety are difficult to guarantee, but with the use of tocilizumab, Emily’s condition can not be worse.

 

There is indeed great luck and chance in the treatment of Emily. After Grupp used tocilizumab for Emily, Emily’s reaction was incredible. ICU health care workers say they have never seen such a serious person recover quickly in such a short period of time, and Emily’s condition quickly eases within a few hours.

 

A week later, Emily woke up on her 7th birthday. The medical staff in the intensive care unit sang a happy birthday song for her. Although they have passed the ghost gate, doctors still don’t know if the returned T cells can affect her cancer.

 

Three weeks later, the doctors underwent a bone marrow examination of Emily and the result was negative. Emily’s leukemia disappeared. Dr. Grupp said that CAR-T therapy saved Emily, but Emily also saved CAR-T therapy. If Emily died, probably CAR-T therapy would not exist.

 

Until now, Emily’s ALL still has no recurrence. On January 27, 2015, Emily’s parents and Emily formed the EmilyWhitehead Foundation to support research in pediatric cancer. On August 30, 2017, the FDA approved Novartis’s CAR-T therapy, Kymriah, to be marketed.

 

IV

In the year after the CAR-T product was approved for marketing, the CAR-T treatment field quickly became a hot spot and attracted numerous attentions, both in the emergence of new technologies, in the progress of clinical research, and in the regulation of Chinese and American drug regulatory authorities. Updates are growing at an alarming rate. In just a few months, billions of dollars in CAR-T asset transactions were completed, and millions of dollars of investment were injected into CAR-T startups.

After the approval of the FDA by Kymriah and Yescarta in 2017, the first International Summit on Cellular Therapy Shanghai (ACTSS2017) was successfully held in Shanghai. More than 50 top CAR-T experts in the world, including European and American drug regulatory agencies review experts, clinical KOL, well-known companies, investors, patent attorneys, etc., from supervision, clinical, production, technology, intellectual property, corporate financing, etc. The angle brings you a wonderful theme to share. More than 400 people from around 208 companies including cell therapy research and development companies, upstream and downstream suppliers, investment institutions, and research institutions attended the conference.

Let us meet again for a wonderful journey!

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