Introduction: The era of chemotherapy cannot solve the "pain points" of relapsed and refractory diffuse large B-cell lymphoma, but the era of new cell drugs has solved them. And this new cellular drug, CAR-T cell therapy, which has become a hot topic in recent years, has opened up a new era of medical treatment, with a market size of trillions of dollars.

Immune cell therapy aims to enhance the immune system's ability to fight cancer. Manufacturing cell therapy requires collecting a specific set of cells from the blood, modifying them to produce more powerful attacks on the patient's cancer cells, and then re injecting them into the patient's body.

At present, many types of cancer cell therapies are being explored, including CAR-T cells, other genetically modified T cells, tumor infiltrating lymphocytes (TIL), NK cells, CIK cells, B cells, etc.

Extracting immune cells from patients' bodies and modifying them to make them more effective in fighting cancer has brought great potential for immune cell therapy. This new treatment has the potential to cure various types of cancer, including adult leukemia, lymphoma, and lung cancer, which have always been considered difficult to cure.

The specific method of CAR-T cell therapy is to collect white blood cells from peripheral blood, isolate T lymphocytes in vitro, use genetic technology to modify T cells, load single chain antibody genes that can recognize tumor cell specific antigens and genes that enhance T cell activation function, and finally transfuse the prepared T cells (CAR-T) back to the patient, which can be amplified in vivo to specifically recognize and kill tumor cells. Compared with traditional treatment, CAR-T cell therapy has fewer side effects and provides the possibility of cure for patients who are resistant to traditional chemotherapy.

1. Eight major immune cell therapies

1.1. TIL cell therapy

TIL therapy is a novel immunotherapy based on tumor infiltrating lymphocytes. TIL, also known as Tumor Infiltrating Lymphocytes, refers to immune cells that infiltrate tumor tissue, including T cells, NK cells, etc. These cells can recognize, resist, and attack cancer cells. However, the number of TILs in tumor tissue is extremely small and is inhibited by various factors, resulting in weak effects. Therefore, researchers extracted these cells, amplified them extensively in vitro, and then infused them back into the patient's body to kill cancer cells.

TIL therapy has helped many patients with advanced lung cancer, melanoma, breast cancer, bile duct cancer and other solid tumors to achieve long-term survival, opening a new era for solid tumor treatment. TIL therapy involves collecting tumor tissue samples and extracting T cells from them. These cells proliferate in the laboratory and are then injected into the patient's body. TIL therapy has been approved by the US FDA and can be used to treat some melanoma patients. Currently, trials have been conducted in various solid tumors such as cervical cancer and lung cancer.

1.2. TCR-T cell therapy

Engineering T-cell receptor (TCR) therapy involves genetically modifying T cells to produce a new receptor that can attach to specific target proteins on tumor cells. This enables TCR-T cells to specifically target cancer cells and avoid normal cells, thereby sparing patients from some of the side effects associated with CAR T cell therapy. In addition, unlike CAR T cells targeting tumor cell surface antigen proteins, TCR therapy targets antigens within tumor cells that are only activated during cellular carcinogenesis. This can also reduce side effects. The engineered TCR therapy is currently undergoing clinical trials for patients with melanoma, sarcoma, and head and neck cancer.

1.3. NK cell therapy

Natural Killer Cell Therapy is an immunotherapy that primarily focuses on the research and application of natural killer (NK) cells. NK cells are an important cell type in the immune system, responsible for identifying and eliminating infected or malignant cells. NK cells play a crucial role in immune responses such as anti-tumor, antiviral, and antibacterial effects.

The main purpose of NK cell therapy is to enhance a patient's ability to fight cancer or other diseases by activating or enhancing the function of NK cells. Specific methods may include:

(1) NK cell expansion: By culturing and expanding the patient's own NK cells in vitro, and then infusing them back into the patient's body, the number and activity of NK cells are increased.

(2) Cytokine stimulation: Using cytokines (such as IL-2, IL-12, IL-15, etc.) to stimulate NK cells and enhance their anti-tumor activity.

(3) Antibody therapy: Using antibody drugs to specifically bind to tumor cell surface antigens, activating NK cells to attack tumor cells.

(4) Gene editing: Using gene editing techniques such as CRISPR/Cas9 to modify NK cell genes and enhance their anti-tumor ability.

1.4. CAR-T cell therapy

CAR-T cell therapy is a novel precise targeted therapy for tumor cells, which involves modifying the patient's own T cells to recognize and attack cancer cells. The specific process includes: collecting T cells from the patient's body, modifying them through genetic engineering technology to express a specific chimeric antigen receptor (CAR), which can recognize and bind to specific antigens on the surface of tumor cells. The modified CART cells are amplified and re injected into the patient's body to exert anti-tumor effects. CART cell therapy has the advantages of precise identification, efficient killing, long-lasting relief, and personalized treatment. It is mainly used in clinical practice for refractory and recurrent malignant tumors, such as acute lymphoblastic leukemia and multiple myeloma.

1.5. CIK cell therapy

CIK cell therapy, also known as cytokine induced killer cell therapy, is a novel anti-tumor adoptive cell immunotherapy technique. This therapy extracts peripheral blood mononuclear cells from patients, and after co culturing with multiple cytokines in vitro for a period of time, obtains a group of heterogeneous cells, namely CIK cells. These cells express both CD3 and CD56 membrane protein molecules simultaneously, combining the strong anti-tumor activity of T lymphocytes with the non MHC restricted killing advantage of NK cells. The main advantages of CIK cell therapy include strong proliferation ability, high anti-tumor activity, wide anti-tumor spectrum, and minimal toxic side effects. This therapy can effectively remove residual cancer cells and small lesions after surgery, radiotherapy and chemotherapy, prevent tumor recurrence and metastasis, and can also be used for the treatment of patients who are ineffective in radiotherapy and chemotherapy or have developed resistance to chemotherapy drugs

1.6. B-cell therapy

B-cell therapy is an innovative medical approach that utilizes or modifies a patient's own B cells to treat diseases, particularly in tumors and autoimmune diseases, showing great potential.

In terms of tumor treatment, engineered B-cell therapies such as ISP-001 have been used in clinical trials for type 1 mucopolysaccharidosis and have achieved positive results. This therapy modifies B cells through genetic engineering technology to produce therapeutic proteins, thereby improving disease symptoms.

In the treatment of autoimmune diseases, B cells have also become important therapeutic targets. For example, B cell clearance therapy uses antibody drugs to target and bind to B cell specific antigens, mediating B cell lysis or apoptosis through different mechanisms to achieve the goal of clearing B cells, and has shown efficacy in various autoimmune diseases. The continuous development and improvement of B cell therapy have provided new treatment opportunities for more patients.

1.7. iNKT cell therapy

INKT cell therapy is an innovative immunotherapy method. INKT cells, also known as constant natural killer T cells, are a special subset of T cells that have the function of connecting innate and adaptive immunity. These cells have both T cell receptors and NK cell receptors on their surfaces, which can be specifically activated by antigen-presenting cells with CD1d molecules on their surfaces, rapidly releasing a large amount of cytokines. INKT cell therapy can activate and enhance the anti-tumor immune function of the body by using the functions of these cells, and has therapeutic effects on a variety of tumors, such as lung cancer, breast cancer, colorectal cancer, liver cancer, leukemia, etc. In addition, iNKT cell therapy has the potential to be applied in adoptive immunotherapy such as acute viral infections. This therapy enhances the body's cellular immune specificity, has a high practical effect on cancer prevention, and has almost no side effects.

1.8. CAR-M cell therapy

CAR-M cell therapy is an innovative tumor immunotherapy technology that demonstrates broad therapeutic prospects. CAR-M cell therapy utilizes genetic engineering techniques to introduce chimeric antigen receptors (CARs) into macrophages, enabling them to recognize and engulf specific tumor cells. This therapy has multiple advantages: firstly, CAR-M cells can improve the tumor microenvironment and mobilize various immune cells to participate in tumor killing activities; Secondly, macrophages have a strong ability to infiltrate tumors, and CAR-M cells can rapidly accumulate at the tumor site after infusion, producing significant tumor inhibitory effects; In addition, CAR-M cell therapy has high safety and therapeutic versatility, avoiding potential hazards that genetic engineering cells may bring, and allogeneic macrophages can be used to produce universal CAR-M cells.

2. Fighting against solid tumors, immune cell therapy is promising in the future

Cell therapy has shown great potential in the field of solid tumors, and the efficacy of CAR-T therapy drugs targeting multiple targets has been significantly improved. At present, China is facing great challenges in the field of cancer prevention and treatment. The high incidence rate and mortality of cancer in China has aroused widespread concern of the whole society.

Compared with developed countries, there is a significant gap in the long-term survival rate of cancer patients in China. At present, the 5-year survival rate of cancer patients in China is about 40.5%, while in the United States it is close to 69%, and in countries such as the United Kingdom, Canada, and Japan, the survival rate exceeds 70%. This reminds us that there is still a long way to go to achieve the 'Healthy China 2030' goal of increasing the 5-year survival rate of cancer patients by 15%.

The early symptoms of digestive tract tumors are insidious, often causing patients to progress to the middle and late stages by the time they are detected, missing the opportunity for early diagnosis and treatment, known as the "invisible killer". In recent years, the basic research, new drug development, and cell therapy of digestive system tumors in China have developed rapidly, providing more and more options for patients.

Immune cell therapy usually refers to a treatment method that uses the patient's own immune cells or genetically engineered immune cells to kill tumor cells, including CAR-T cell therapy, CAR-M cell therapy, TCR-T cell therapy, TIL cell therapy, CIK cell therapy, NK cell therapy, etc.

Currently, the field of cell therapy research and development continues to be hot. As of August 2024, there are 6448 registered clinical trials related to cell therapy worldwide, of which 2687 are in China, accounting for 41.7% of the global total; The United States has a total of 1859 items, accounting for 28.8% of the global total.

There are six cell therapy products on the market in China, all of which are CAR-T therapy products, mainly targeting specific types of lymphoma, leukemia, myeloma, etc. In the field of solid tumors, although there are currently no approved cell therapy products on the market in China, multiple centers have initiated clinical trials of cell therapy.

Since 2023, 30 solid tumor cell therapies have been approved for clinical trials in China, including 17 CAR-T cell therapies, 5 TCR-T cell therapies, 4 TIL cell therapies, as well as CAR-NK, CAR-INKT, universal cell therapies, etc., mainly targeting solid tumors such as digestive tract tumors, hepatocellular carcinoma, bone or soft tissue sarcoma, glioma, advanced ovarian cancer, nasopharyngeal carcinoma, cervical cancer, etc.

After CAR-T immune cell therapy, new immune cell therapies such as TCR-T, TIL and other cell therapies have successively entered clinical practice, and their indications have expanded from the field of hematological tumors to solid tumors, autoimmune diseases and other fields. Some domestic CAR-T therapies are at the forefront of progress in solid tumors.