Anti-Cancer Immune Cell Therapy: DC, CIK, NK, TIL, γδT

Medicine is advancing, and in order to deal with the complex mechanism of tumors, scientists are constantly exploring new treatment paradigms. As two car-t immune cell drugs have been approved for commercial use in China, immune cell therapy as a new tumor treatment method has attracted widespread attention from all walks of life. For a time, a large number of biological companies focused on this track, promoting the rapid commercial transformation of basic research into drug manufacturing.

Cytokine-induced killer (CIK) cells, dendritic cells (DC)-CIK cells, T lymphocytes, natural killer cells (NK), tumor- infiltrating lymphocytes (TIL), and γδT cells have emerged in immune cell therapy. .

For clinical application, how to choose the appropriate immune cell therapy and timing, control the cell quality and uncertain factors involved in the treatment process, and provide a strong clinical basis for immune cell therapy of tumors is what medical personnel should strive to explore . The general public should also know the relevant information in advance.

Therefore, in this article, the editor lists the currently frequently mentioned immune cell therapies for readers, as well as a brief overview of their progress in tumor treatment.

CIK Cell Therapy

CIK cells were first discovered in the 1990s, which combine the phenotypes of T cells and NK cells and have tumor-killing activity.

The acquisition process of CIK cells: Human peripheral blood mononuclear cells are co-cultured with various cytokines in vitro [ 1] . CIK cells have the characteristics of fast proliferation, high activity, and broad tumor killing spectrum, and can secrete a variety of high-concentration cytokines. Cytokines have certain cytotoxic and inhibitory effects [2] .

The anti-tumor mechanism of CIK: ① directly kills cancer cells; ② induces effector T cells by releasing various cytokines, and indirectly kills tumor cells; ③ expresses apoptosis-inhibiting genes, induces tumor cell apoptosis, and continues to fight against tumors.

DC-CIK cell therapy

DC cells, also known as dendritic cells, are equivalent to the "communicators" of the immune force. They are professional antigen-presenting cells and have the ability to activate helper and cytotoxic T cells. The number of DCs is very small, accounting for about 1% of the total number of human peripheral blood mononuclear cells. According to the source, they are divided into two categories: myeloid and lymphoid. According to the function, it can be divided into immature DC (imperfect function) and mature (perfect function) DC. Immature DC needs to be stimulated by external antigens to mature. The "communication awareness" of mature DC cells can send battle reports to T lymphocytes in time to stimulate them to exert immune effects.

The DC-CIK immunotherapy we often hear is to co-cultivate DC and CIK in vitro, and then infuse them back into the body to kill tumors. The interaction between the two cells not only promotes DC maturation, but also enhances the killing effect of CIK cells.

This is also the immune cell therapy that was often recommended to tumor patients in the biological immunotherapy department of the hospital before the Wei Zexi incident in 2016. It is said that the price of a course of treatment at that time was about 30,000 meters. To this day, this therapy still plays an irreplaceable role in the research of tumor treatment. There is no right or wrong in science and technology, it lies in the heart of the user. As for the Wei Zexi incident, it is the inevitable outcome of transitional marketing and publicity.

It is safe and feasible to treat malignant tumors with CIK, which has been proved by a large number of basic and clinical studies. And now more research is to combine it with genetic engineering methods [3] , such as CAR-CIK, combined with nanomaterials and so on.

CIK/DC-CIK progress

As of today, according to (ClinicalTrials.gov) data, there are 108 clinical studies related to CIK/DC-CIK cell therapy, involving a variety of diseases, including esophageal cancer, bladder cancer, pancreatic cancer, gastric cancer, kidney cancer, triple negative Breast cancer, lung cancer, liver cancer, refractory non-Hodgkin's lymphoma, colorectal cancer, acute leukemia and other blood and solid tumors.

At present, many studies have confirmed that CIK/DC-CIK cell therapy can significantly improve the immune function of patients and prolong the survival period . Combining with chemoradiotherapy and targeted therapy, the quality of life of patients has been significantly improved.

NK cell therapy

NK cells are the "old friends" that our public account often mentions. Many people compare NK cells to the first line of defense against cancer immunity. NK cells have the ability to regulate immunity, and can produce a large number of cytokines to act on tumor tissues without the need for matching with other immune cells before treatment, and without prior sensitization or immunization . NK cells have broad-spectrum killing characteristics, which account for 5% to 20% of peripheral blood mononuclear cells [4] .

If you often pay attention to the self-media of the cell industry, you will find that there are slogans promoting immune cell storage through the benefits of NK cells everywhere.

NK cell mechanism of action

①Secrete perforin-granules to rapidly dissolve target cells ［5］ ;

②Induces apoptosis, but this mechanism is slow (several hours) and inefficient;

③ Activated NK cells secrete a variety of cytokines to regulate immunity. For example, anti-angiogenic factors are secreted to inhibit angiogenesis inside the tumor to inhibit cell proliferation and delay tumor growth; regulate T lymphocytes to control tumor [6] .

At present, NK cells are also a type of cell biological therapy that is often mentioned. Tumor patients achieve the purpose of killing tumor cells and treating cancer by reinfusing NK cells that have been "educated" in vitro [7] .

Current sources of NK cells include peripheral blood mononuclear cells (PBMCs), stem cells, and cord blood NK cell lines. Both autologous and allogeneic NK cells can be used for adoptive immunotherapy, but some studies have confirmed that allogeneic PBMC-expanded NK cells, in particular, have shown better efficacy [6] . Clinical research related to NK cells is being carried out extensively around the world, and the indications include hematopoietic malignancies and solid tumors.

Progress in NK cell therapy

As of the first half of 2022, data from ClinicalTrials.gov shows that there are more than 760 clinical studies related to NK cell therapy, covering a variety of cancers, including B-cell lymphoma, liver cancer, pancreatic cancer, cholangiocarcinoma, and acute myeloid leukemia , neuroblastoma, etc. Studies based in part on allogeneic NK cells have found effective control of hematological malignancies.

TIL cell therapy

In 1988, Rosenberg's group developed adoptive cell therapy for TILs. Adoptive cell therapy is to isolate endogenous TILs from tumors after surgical resection, expand them in vitro, and then reinfuse them into patients [10-11] . In the late 1980s, a single-center retrospective study evaluated the outcome of TIL cell therapy in patients with advanced melanoma and showed it to be safe and effective.

In the past 10 years, adoptive cell therapy of TILs has received much attention in anticancer treatment. Determine the specific gene mutation target in the patient, and then use the mutation information to extract and cultivate T cells that can recognize the specific target, which greatly improves the specific killing effect of TILs therapy on cancer cells [10] . Currently, mature TIL immune cell preparations are composed of CD8+ and CD4+ T cells and a small number of γδ T cells.