Advances in immunocell combination therapy
The American biologist George Daley once said that if the 20th century was the age of drug therapy, the 21st century will be the age of cell therapy. Immune cell therapy is a kind of cell therapy, as the fourth tumor treatment technology after surgery, radiotherapy and chemotherapy, after considerable development, has played a very good effect in the treatment of a variety of tumors. Chimeric Antigen Receptor T Cell (CAR-T) immunotherapy, as the fastest progressing immunocell therapy in the world, has shown great advantages in the treatment of hematological malignancies. However, in the field of solid tumors, CAR-T therapy has made slow progress, and the immunosuppression of tumor microenvironment (TME), T cell migration and invasion are important factors limiting the efficacy of CAR-T cell therapy in solid tumors. In order to deal with the trouble of CAR T cells in solid tumors, a combination therapy has emerged, that is, combining CAR T therapy with another tumor treatment method to achieve a greater than two effect. Currently known directions of CAR-T cell combination therapy are: checkpoint inhibitors, oncolytic viruses (OVs) or RNA vaccines.
Immune checkpoint is a small molecule protein produced by immune cells, which can be used to regulate autoimmune function and also play a certain role in cell monitoring. Tumor cells use this mechanism to suppress immune cells and survive by escaping from the body's immune system. Immune checkpoint inhibitors can effectively remove this inhibition and allow immune cells to reactivate their work. At present, the main immune checkpoint inhibitors on the market are CTLA-4 inhibitors and PD-1 inhibitors (PD-1/PD-L1 inhibitors). Data from a literature published in the Journal of Clinical Investigation showed that the effector function of CD28 CAR T cells could be restored by PD-1 antibody checkpoint blocking, which elaborated the potential mechanism of CAR-T cell depletion in solid tumor applications. It also suggests that PD-1 / PD-L1 blocking may be an effective strategy to improve the efficacy of CAR-T cell therapy [1].
OVs is a class of viruses that have the ability to selectively lyse tumor cells. The anti-tumor activity of OVs involves multiple mechanisms, including natural interactions between tumor cells, viruses, and the immune system. The mechanism of its anti-tumor activity can be mainly divided into two categories: one is that OVs selectively kills tumor cells. This effect is influenced by cell surface receptor expression and host cell antiviral response. Another mechanism is related to the induction of systemic anti-tumor immunity. Local delivery of immunomodulators by viral vectors is conducive to the creation of a pro-inflammatory tumor microenvironment, thus promoting systemic anti-tumor immunity. The potential of two cutting-edge technologies, collaborative immune cell Therapy and OVs, has been explored in many ways, according to a review published in June in the journal Molecular Therapy-Oncolytics, a subsidiary of CellPress. Preclinical studies on immunocell therapy and OVs combination therapy have reported relevant data in more than 20 literatures, and four phase I clinical trials have been initiated [2].
As an important method of tumor immunotherapy, tumor vaccine aims to stimulate the adaptive immune system of patients to attack specific tumor antigens to achieve the control and elimination of tumor growth. Over the past few decades, technological innovation and investment in research have enabled the development of multiple vaccine platforms. Tumor antigens can be made into tumor vaccines through a variety of candidate vaccine platforms, including DNA, RNA, peptides, dendritic cells, viral vectors, etc. With the successful development and wide application of mRNA vaccine in the fight against SARS-COV-2, mRNA vaccine technology has become a hot plate in tumor therapy. mRNA vaccines work by identifying one or more target proteins and then transfecting corresponding transcripts carrying tumor antigen information into cells of the host cell (usually APC). The encoded proteins are displayed on the APC surface by binding to MHC molecules, thereby activating the immune system, including B cell-mediated humoral responses and CD4+ T/CD8+ T cell-mediated responses. A literature study published in the journal SCIENCE designed a nanoparticle RNA vaccine targeting the chimeric receptor of CLDN6. This lipid complex RNA vaccine promotes CLDN6 expression on the surface of dendritic cells, thereby stimulating and enhancing the efficacy of CLDN6-CAR T cells to improve tumor therapy [3]. Meanwhile, a paper in the journal Cancer Research Communications combined a new type of CAR T cell with a nanoparticle RNA vaccine developed for in vivo expansion of CAR T cells. The in vivo expansion, survival and anti-tumor efficacy of CAR-T cells have been strictly controlled [4].
Although immunocell therapy has achieved good efficacy and progress in the field of hematoma, due to the heterogeneity of solid tumors and immunosuppressive tumor microenvironment, monotherapy of immunocell therapy often fails to overcome these difficulties, resulting in poor efficacy or secondary drug resistance. Therefore, the direction of immune cell therapy strategies requires some new breakthroughs, and the combined application between different therapeutic approaches is one of them. Currently, the FDA has approved a number of combination therapies to improve the clinical efficacy of immunotherapy. With the continuous deepening of research on reliable biomarkers and immunotumor mechanisms, more combinations including ACT, novel ICI, cancer vaccines, chemoradiotherapy and small molecule inhibitors of targeted therapy will continue to appear in the future. The future of tumor immunotherapy belongs to a truly patient-oriented, personalized treatment approach.
Reference：
[1] Cherkassky L, Morello A, Villena-Vargas J, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016; 126(8):3130-3144. doi:10.1172/JCI83092
[2] Mamola JA, Chen CY, Currier MA,et al. Opportunities and challenges of combining adoptive cellular therapy with oncolytic virotherapy. Mol Ther Oncolytics. 2023; 29:11 8-124 doi: 10.1016 / j.o mto 2023.04.008
[3] Reinhard K, Rengstl B, Oehm P, et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science. 2020; 367 (6476) : 446-453. The doi: 10.1126 / science aay5967
[4] Birtel M, Voss RH, Reinhard K, et al. A TCR-like CAR Promotes Sensitive Antigen Recognition and Controlled T-cell Expansion Upon mRNA Vaccination. Cancer Res Commun. 2022; 2(8):827-841. doi:10.1158/2767-9764.CRC-21-0154
Disclaimer: Shenzhen Cell Valley is committed to the research of cell and gene therapy, in order to promote emerging technologies, so that more people understand the new development of biomedicine. The content of this article is only used for information exchange, and the platform remains neutral on the content, statements and opinions of the article, and does not represent the position and views of Shenzhen Cell Valley. The relevant information in this article should not be used as a diagnosis or treatment, is not a substitute for professional medical advice, and the company's website will not assume any responsibility. The final interpretation of the content of the above statement belongs to the company's website, this statement will apply to the company's website all the time to share the article, thank you for your cooperation! Copyright description: The copyright of the article belongs to Shenzhen Cell Valley, individuals are welcome to forward to the circle of friends, media or institutions without authorization, reproduced in any form to other platforms, will be regarded as infringement. For reprinting, please contact email: contact@duanglink.com
Immune checkpoint is a small molecule protein produced by immune cells, which can be used to regulate autoimmune function and also play a certain role in cell monitoring. Tumor cells use this mechanism to suppress immune cells and survive by escaping from the body's immune system. Immune checkpoint inhibitors can effectively remove this inhibition and allow immune cells to reactivate their work. At present, the main immune checkpoint inhibitors on the market are CTLA-4 inhibitors and PD-1 inhibitors (PD-1/PD-L1 inhibitors). Data from a literature published in the Journal of Clinical Investigation showed that the effector function of CD28 CAR T cells could be restored by PD-1 antibody checkpoint blocking, which elaborated the potential mechanism of CAR-T cell depletion in solid tumor applications. It also suggests that PD-1 / PD-L1 blocking may be an effective strategy to improve the efficacy of CAR-T cell therapy [1].
OVs is a class of viruses that have the ability to selectively lyse tumor cells. The anti-tumor activity of OVs involves multiple mechanisms, including natural interactions between tumor cells, viruses, and the immune system. The mechanism of its anti-tumor activity can be mainly divided into two categories: one is that OVs selectively kills tumor cells. This effect is influenced by cell surface receptor expression and host cell antiviral response. Another mechanism is related to the induction of systemic anti-tumor immunity. Local delivery of immunomodulators by viral vectors is conducive to the creation of a pro-inflammatory tumor microenvironment, thus promoting systemic anti-tumor immunity. The potential of two cutting-edge technologies, collaborative immune cell Therapy and OVs, has been explored in many ways, according to a review published in June in the journal Molecular Therapy-Oncolytics, a subsidiary of CellPress. Preclinical studies on immunocell therapy and OVs combination therapy have reported relevant data in more than 20 literatures, and four phase I clinical trials have been initiated [2].
As an important method of tumor immunotherapy, tumor vaccine aims to stimulate the adaptive immune system of patients to attack specific tumor antigens to achieve the control and elimination of tumor growth. Over the past few decades, technological innovation and investment in research have enabled the development of multiple vaccine platforms. Tumor antigens can be made into tumor vaccines through a variety of candidate vaccine platforms, including DNA, RNA, peptides, dendritic cells, viral vectors, etc. With the successful development and wide application of mRNA vaccine in the fight against SARS-COV-2, mRNA vaccine technology has become a hot plate in tumor therapy. mRNA vaccines work by identifying one or more target proteins and then transfecting corresponding transcripts carrying tumor antigen information into cells of the host cell (usually APC). The encoded proteins are displayed on the APC surface by binding to MHC molecules, thereby activating the immune system, including B cell-mediated humoral responses and CD4+ T/CD8+ T cell-mediated responses. A literature study published in the journal SCIENCE designed a nanoparticle RNA vaccine targeting the chimeric receptor of CLDN6. This lipid complex RNA vaccine promotes CLDN6 expression on the surface of dendritic cells, thereby stimulating and enhancing the efficacy of CLDN6-CAR T cells to improve tumor therapy [3]. Meanwhile, a paper in the journal Cancer Research Communications combined a new type of CAR T cell with a nanoparticle RNA vaccine developed for in vivo expansion of CAR T cells. The in vivo expansion, survival and anti-tumor efficacy of CAR-T cells have been strictly controlled [4].
Although immunocell therapy has achieved good efficacy and progress in the field of hematoma, due to the heterogeneity of solid tumors and immunosuppressive tumor microenvironment, monotherapy of immunocell therapy often fails to overcome these difficulties, resulting in poor efficacy or secondary drug resistance. Therefore, the direction of immune cell therapy strategies requires some new breakthroughs, and the combined application between different therapeutic approaches is one of them. Currently, the FDA has approved a number of combination therapies to improve the clinical efficacy of immunotherapy. With the continuous deepening of research on reliable biomarkers and immunotumor mechanisms, more combinations including ACT, novel ICI, cancer vaccines, chemoradiotherapy and small molecule inhibitors of targeted therapy will continue to appear in the future. The future of tumor immunotherapy belongs to a truly patient-oriented, personalized treatment approach.
Reference：
[1] Cherkassky L, Morello A, Villena-Vargas J, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016; 126(8):3130-3144. doi:10.1172/JCI83092
[2] Mamola JA, Chen CY, Currier MA,et al. Opportunities and challenges of combining adoptive cellular therapy with oncolytic virotherapy. Mol Ther Oncolytics. 2023; 29:11 8-124 doi: 10.1016 / j.o mto 2023.04.008
[3] Reinhard K, Rengstl B, Oehm P, et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science. 2020; 367 (6476) : 446-453. The doi: 10.1126 / science aay5967
[4] Birtel M, Voss RH, Reinhard K, et al. A TCR-like CAR Promotes Sensitive Antigen Recognition and Controlled T-cell Expansion Upon mRNA Vaccination. Cancer Res Commun. 2022; 2(8):827-841. doi:10.1158/2767-9764.CRC-21-0154
Disclaimer: Shenzhen Cell Valley is committed to the research of cell and gene therapy, in order to promote emerging technologies, so that more people understand the new development of biomedicine. The content of this article is only used for information exchange, and the platform remains neutral on the content, statements and opinions of the article, and does not represent the position and views of Shenzhen Cell Valley. The relevant information in this article should not be used as a diagnosis or treatment, is not a substitute for professional medical advice, and the company's website will not assume any responsibility. The final interpretation of the content of the above statement belongs to the company's website, this statement will apply to the company's website all the time to share the article, thank you for your cooperation! Copyright description: The copyright of the article belongs to Shenzhen Cell Valley, individuals are welcome to forward to the circle of friends, media or institutions without authorization, reproduced in any form to other platforms, will be regarded as infringement. For reprinting, please contact email: contact@duanglink.com
