CN111228308A

CN111228308A - Application of TIL cell therapy in reducing interleukin 2 dosage

Info

Publication number: CN111228308A
Application number: CN202010045405.2A
Authority: CN
Inventors: 李军
Original assignee: Cati Shanghai Cell Biotechnology Co Ltd
Current assignee: Cati Shanghai Cell Biotechnology Co Ltd
Priority date: 2020-01-16
Filing date: 2020-01-16
Publication date: 2020-06-05

Abstract

The invention discloses an application of a TIL cell therapy in reducing the using dose of interleukin 2, wherein the application adopts the TIL cell therapy to be matched with low-dose interleukin 2, when the TIL cell therapy is used, the dose of the interleukin 2 is reduced, meanwhile, the intravenous injection is changed into subcutaneous injection, the side effect is reduced sharply, and the curative effect can be still maintained while the side effect is greatly reduced. We received this modified version of TIL cell technology in 12 patients with advanced malignant tumors of the invention and the results showed that: the tumor was significantly reduced in 3 patients, the disease was stable in 6 patients, and the disease progressed in 3 patients. And in the side effect aspect, the adverse reaction related to the low dose of interleukin 2 is very little, and most patients are 1-2 grade, which is in line with the expectation. In conclusion, the improved TIL cell therapy technology of the invention is safe and effective, and is worthy of developing further scale-up clinical tests in the future.

Description

Application of TIL cell therapy in reducing interleukin 2 dosage

Technical Field

The invention belongs to the technical field of immune cell therapy, and particularly relates to application of a TIL cell therapy in reducing the using dose of interleukin 2.

Background

Interleukin 2 is a kind of cytokine of chemokine family, it is a kind of cytokine with pleiotropic effects from the multicellular source, it is mainly produced by activated T cell, mainly promote lymphocyte growth, proliferate and differentiate, have important effects on immune response and antiviral infection of the organism, can stimulate the T cell already promoted by specific antigen or mitogenic factor to proliferate; interleukin 2 can activate T cells and promote the production of cytokines; stimulating NK cell proliferation, enhancing NK killing activity, generating cytokines, and inducing LAK cell generation; promoting B cell proliferation and secretion of antibodies; macrophages are activated.

Interleukins are a class of cytokines produced by and acting on a variety of cells, and are known for their initial production by and action among leukocytes. The first is the cytokine produced by leukocyte and having regulation function among leukocytes, and the second is the cytokine which has basically definite molecular structure and biological function, has important regulation function and is uniformly named, and belongs to the same category as the blood cell growth factor. The two are mutually coordinated and interacted to jointly complete the functions of hematopoiesis and immunoregulation. Interleukins play an important role in transmitting information, activating and regulating immune cells, mediating T, B cell activation and proliferation and differentiation, and in inflammatory responses. The interleukin, abbreviated as IL, is involved in the expression and regulation of a functional immune response by a number of factors derived from lymphocytes or macrophages.

The 1979 group proposed that of lymphokines and macrophage cytokines, the property known as interleukin was purified and clarified as a molecule. IL-1 and IL-2 were initially determined. IL-2 belongs to lymphokines and has been previously referred to by six names, i.e., thymocyte stimulating factor, T cell growth factor, and the like. During the course of the study of the immune response, a number of biologically active molecules were found in mitogen-stimulated cell culture supernatants, each named after its own measured activity, and over a decade several factors were reported. Later comparative studies with the aid of molecular biology techniques have shown that many of the factors named for biological activity in the past are in fact the same substances with pleiotropic properties.

Interleukins are a very important cytokine family, and interleukin 2 can be used for clinical research and tumor treatment, and as long as 12 months of 2013, at least 38 members are accepted, play important roles in a series of processes such as maturation, activation, proliferation and immunoregulation of immune cells, and are also involved in various physiological and pathological reactions of the body. IL-2 producing cells IL-2 is synthesized mainly by T cells stimulated by antigens or mitogens; IL-2 is also produced by B cells, NK cells and monocyte-macrophages. IL-2 has a certain species specificity, and human cells respond only to primate-derived IL-2, whereas almost all species of animal cells are sensitive to human IL-2.

Because IL-2 can induce and enhance cytotoxic activity, the research on treating certain diseases by applying IL-2 is widely carried out, especially on treating tumors, and certain curative effect is achieved by singly using IL-2 or jointly using IL-2 and LAK cells and the like to treat tumors; it is also expected to be used for the treatment of viral infection, immunodeficiency diseases and autoimmune diseases. However, the side effects of IL-2 are also attracting increasing attention: IL-2 can cause common symptoms such as fever, vomiting and the like, and can also cause water-salt metabolism disorder and dysfunction of kidney, liver, heart, lung and the like; the most common and serious is capillary leak syndrome, which forces the patient to discontinue treatment. The side effects of IL-2 are often related to the dose and time of administration of IL-2, and the symptoms are often reduced or eliminated rapidly after administration is stopped. The mechanism of side effects caused by IL-2 is multifaceted, but mainly indirect, i.e., certain factors or killer cells induced by IL-2 play an important role; LAK cells are known to cause a variety of side effects by lysing intravascular tissue. Administration of appropriate drugs such as meperidine, paracetamol, and the like, in combination, modification of the mode of administration, such as small multiple short-time infusions, and modification of the route of administration, will effectively alleviate adverse reactions.

Tumor immunotherapy is the most popular, even the hottest, cancer treatment for these years. In the case of tumor immunotherapy, it is likely that many patients with advanced cancer would benefit from the PD-1/PD-L1 antibody, K drug, O drug, and domestic PD-1 antibody. However, in addition to PD-1/PD-L1, tumor immunotherapy also includes immunocytotherapy, such as the well-known CAR-T technique, which achieves tumor control by reinfusing specific CAR-T cells into cancer patients. Most immunotherapy technologies require the formulation of large doses of interleukin 2. In practical application, after the immune cells are back-infused and injected, 6 courses of interleukin 2 are added, the dose of each course is 60 ten thousand units/kg, so that the side effect of the interleukin 2 with large dose is not small; other companies or teams used almost as much interleukin 2, and some teams used 72 ten thousand units/kg.

Disclosure of Invention

The invention provides an application of a TIL cell therapy in reducing the dosage of interleukin 2 in order to overcome the defects in the prior art.

The invention is realized by the following technical scheme: the application of TIL cell therapy in reducing the dosage of interleukin 2 adopts the combination of TIL cell therapy and low-dosage interleukin 2, and when the TIL cell therapy is used, the dosage of interleukin 2 is reduced, and simultaneously, the intravenous injection is changed into subcutaneous injection, so that the side effect is reduced sharply, and the curative effect can still be maintained.

The specific operation steps of the application of the TIL cell therapy in reducing the using dosage of interleukin 2 are as follows: tests were conducted on cancer patients, 12 patients with advanced malignant tumors received TIL cell therapy, and when TIL cell therapy was used, the patients underwent surgery in the hospital, and the excised tumor tissues were immediately transported to GMP laboratories for subsequent processing and culture; after 20 days, culturing and maturing the TIL cells, transporting the TIL cells back to a hospital, and returning the TIL cells to a patient, and after returning the TIL cells, receiving 3-4 courses of interleukin 2 subcutaneous injection, wherein the using dose of interleukin 2 is 30-40 ten thousand units/kg; the tumor was significantly reduced in 3 patients, the disease was stable in 6 patients, and the disease progressed in 3 patients.

Of 12 patients with advanced malignancy, 11 of them had received PD-1 antibody treatment but failed; 10 of these patients failed CTLA-4 antibody therapy.

As a preferred embodiment of the present invention, 3 courses of subcutaneous IL-2 were administered after the return infusion of TIL cells, and the IL-2 dose was 35 ten thousand units/kg.

T lymphocyte is an immune cell differentiated from hematopoietic stem cells, and TIL (tumor-infiltrating lymphocytes) is a T cell which is infiltrated in tumor tissues and can effectively recognize a tumor cell neoantigen. The T cell capable of recognizing the tumor cell neoantigen has the capacity of efficiently killing tumor cells, including killing tumor passage cells transferred to other parts from the focus.

The invention has the beneficial effects that: the invention adopts the TIL cell therapy to be matched with the low-dose interleukin 2, so that the side effect is reduced sharply, and the curative effect is good. It is also possible to use the TIL cell therapy of the present invention to reduce the IL-2 dose and to change intravenous injection to subcutaneous injection. The application of the TIL cell therapy disclosed by the invention in reducing the using dosage of interleukin 2 can greatly reduce side effects and simultaneously still maintain the curative effect. We have carried out similar attempts on cancer patients: 12 patients with advanced refractory malignant melanoma received this modified version of TIL cell technology. 11 of the patients had received PD-1 antibody treatment, but failed; 10 of these patients failed CTLA-4 antibody therapy. The results show that: the tumor was significantly reduced in 3 patients, the disease was stable in 6 patients, and the disease progressed in 3 patients. And in the side effect aspect, the adverse reaction related to the low dose of interleukin 2 is little, and most patients are 1-2 grade, which is expected. In conclusion, the improved TIL cell therapy technology is safe and effective, and is worthy of developing further scale-up clinical tests in the future.

Detailed Description

The present invention will be described in detail with reference to specific embodiments.

The invention discloses an application of a TIL cell therapy in reducing the using dose of interleukin 2, wherein the application adopts the TIL cell therapy to be matched with low-dose interleukin 2, when the TIL cell therapy is used, the dose of the interleukin 2 is reduced, and meanwhile, the intravenous injection is changed into subcutaneous injection, so that the side effect is reduced sharply, and the curative effect can still be maintained.

The specific operation steps of the application of the TIL cell therapy in reducing the using dosage of interleukin 2 are as follows: tests were conducted on cancer patients, 12 patients with advanced malignant tumors who received TIL cell therapy, of which 11 had received PD-1 antibody treatment but failed; 10 of these patients failed CTLA-4 antibody therapy. When using the TIL cell therapy, the patient is operated in a hospital, and the cut tumor tissue is immediately transported to a GMP laboratory for subsequent treatment and culture; after 20 days, culturing and maturing the TIL cells, transporting the TIL cells back to a hospital, and returning the TIL cells to a patient, and after returning the TIL cells, receiving 3-4 courses of interleukin 2 subcutaneous injection, wherein the using dose of interleukin 2 is 30-40 ten thousand units/kg; the tumor was significantly reduced in 3 patients, the disease was stable in 6 patients, and the disease progressed in 3 patients. As a preferred embodiment of the present invention, 3 courses of subcutaneous IL-2 were administered after the return infusion of TIL cells, and the IL-2 dose was 35 ten thousand units/kg.

Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. Use of TIL cell therapy for reducing the dose of interleukin 2, characterized in that: the application of the TIL cell therapy in reducing the using dosage of the interleukin 2 adopts the combination of the TIL cell therapy and the low-dosage interleukin 2, when the TIL cell therapy is used, the dosage of the interleukin 2 is reduced, and meanwhile, the intravenous injection is changed into subcutaneous injection, so that the side effect is reduced sharply, and the curative effect can still be kept.

2. Use of TIL cell therapy according to claim 1 for reducing the dosage of interleukin 2 used, characterized in that: the specific operation steps of the application of the TIL cell therapy in reducing the dosage of the interleukin 2 are as follows: tests were conducted on cancer patients, 12 patients with advanced malignant tumors received TIL cell therapy, and when TIL cell therapy was used, the patients underwent surgery in the hospital, and the excised tumor tissues were immediately transported to GMP laboratories for subsequent processing and culture; after 20 days, culturing and maturing the TIL cells, transporting the TIL cells back to a hospital, and returning the TIL cells to a patient, and after returning the TIL cells, receiving 3-4 courses of interleukin 2 subcutaneous injection, wherein the using dose of interleukin 2 is 30-40 ten thousand units/kg; the tumor was significantly reduced in 3 patients, the disease was stable in 6 patients, and the disease progressed in 3 patients.

3. Use of TIL cell therapy according to claim 2 for reducing the dose of interleukin 2 used, characterized in that: of the 12 patients with advanced malignancy, 11 of them had received PD-1 antibody treatment, but failed; 10 of these patients failed CTLA-4 antibody therapy.

4. Use of TIL cell therapy according to claim 2 or 3 for reducing the dose of interleukin 2 used, characterized in that: after the return infusion of TIL cells, 3 courses of interleukin 2 were injected subcutaneously, with an interleukin 2 dose of 35 ten thousand units/kg.