Immune cell therapy pioneers in non-tumor fields
In recent years, CAR technology has developed rapidly, and breakthrough success has been achieved in the treatment of blood tumors, and a number of CAR-T drugs have been approved for market. CAR technology is far more than tumor treatment, and it also has new developments in the treatment of infectious diseases and autoimmune diseases. Treating non-cancer disease itself has many advantages over treating solid tumors. First, the tumor cell load is often very large, requiring a large infusion of CAR T cells, which increases the ratio of CRS risk to off-target tumor toxic events, whereas in other diseases, the number of target cells that need to be cleared is often smaller. Secondly, the treatment of cancer must remove 100% of the cancer cells, otherwise there is the possibility of recurrence, and the removal of some pathological cells in other diseases may also have a therapeutic effect. In addition, tumors continue to mutate under immune pressure until antigen escape (i.e. loss of the target antigen) is complete, while other diseases have few conditions for antigen escape to occur. Finally, and most critically, TME in solid tumors, the natural barrier it creates, and the immunosuppressant environment make it difficult for CAR-T to make a difference, and other diseases do not form such a microenvironment, making it easier for CAR-T to clear diseased cells. CAR-T therapy has advantages in other types of disease compared to cancer.
一、Autoimmune and inflammatory diseases
SLE (Systemic lupus erythematosus) is an immune disease that may endanger its own life. From 2021 to 2022, a research team has successively injected anti-CD19 (B-cell specific antigen) CAR-T into 6 patients, and CAR-T cells were amplified in all patients. B cells were rapidly eliminated, SLE symptoms were relieved, and markers of end-organ damage were significantly decreased. All patients stopped immunosuppressive drug therapy and were in drug-free remission. Short-term follow-up showed that several months after CAR T cell infusion, the naive B cells re-emerged and showed no signs of disease recurrence. CAR-T cells were well tolerated with only mild cases of CRS, which is consistent with the idea that lower target cell load may reduce the severity of CRS. [2]
Anti-CD19 CAR T cells are also used in patients with inflammatory myopathy caused by synthetase syndrome. After CAR T cell infusion, the patient experienced increased myalgia and serum creatinine kinase. After 180 days of infusion, the patient's physical function improved significantly, quadriceps and hamstring myositis gradually subsided, creatinine kinase and other clinical indicators gradually normalized. [3]
In fact, any autoimmune and inflammatory disease due to B cells or plasma cells may be a potential indication for CAR-T therapy, including neutrophil cytoplasmic antibody associated vasculitis, rheumatoid arthritis, myositis, multiple sclerosis, pemphigus extraformis, immune thrombocytopenia, myasthenia gravis, and retinomyelitis. In addition, as long as the target of B cell or plasma cell killing (BCMA,GPRC5D, CD20 and CD22) may become a potential CAR-T therapeutic target. [3-4]
Another way to eliminate inflammatory cells is to redirect regulatory T (Treg) cells to target tissue. These cells are not cytotoxic, but provide paracrine signals to suppress inflammation and autoimmune responses. Transfection of CAR into Treg cells improves specificity and reduces the risk of system-wide immunosuppression.
At present, CAR-T clinical trials and preclinical studies for various autoimmune diseases have proved that this disease may be one of the most promising areas of CAR-T therapy.
二、Organ fibrosis
Cardiac fibrosis is the result of acute injury, chronic disease, or aging, and it leads to increased near-term morbidity and long-term mortality. Currently, there are limited treatments for cardiac fibrosis. Recent preclinical studies have shown that CAR-T cells can target fibrosis and restore heart function after hypertensive damage. The researchers identified fibroblast-specific antigens in the hearts of patients with cardiomyopathy and found that fibroblast-activating protein (FAP) was the highest expressed target. Injection of anti-FAP CAR T cells can resolve fibrosis after heart injury and improve heart function. The implications of using CAR T cells to target pathological fibrosis extend beyond heart disease. Extracellular matrix deposition and fibrosis are pathological in a variety of diseases. Liver disease, chronic kidney disease, lung disease, skeletal muscle disease, and many other conditions can be tried with anti-fibrotic CAR T cells.
三、Aging
Multiple stressors can cause cells to undergo irreversible stagnation of proliferation, known as cellular senescence. Studies have shown that removing these cells is beneficial for a variety of chronic disease models. Small-molecule drugs that target intracellular pathways in senescent cells seem promising, but their potency, specificity, and side effects have limited its development. CAR-T is considered by researchers to be a very competitive new therapy due to its inherent specificity and potency. Senescent cells are physiologically cleared by the immune system early in life, and the use of CAR to enhance immune cells and prolong this process may lead to greater benefits for the body.
Recent research has shown that CAR-T cells can clear senescent cells in mice with cancer and liver disease. PLAUR encodes urokinase-type plasminogen activator receptor (uPAR), which is considered a potential serum antigen and is expressed at relatively low levels in important tissues. Anti-uPAR CAR-T successfully eliminated oncogene-induced liver senescent cells, tumor treatment-induced lung senescent cells, drug-induced liver fibrosis, and diet-induced nonalcoholic steatohepatitis senescent cells. Because of the heterogeneity of senescent cells, it is difficult and important to identify senescent antigens. Other targets that can be used to generate senescent CAR-T cells include NKG2D ligand, MICA, MICB, and ULBP1-5, which are expressed in a variety of senescent cells. Another potential target is glycoprotein non-metastatic melanoma Protein B (GPNMB), and immunotherapy targeting this target can clear senescent cells. Improve metabolic parameters, reduce atherosclerotic plaque and prolong the life span of male premature aging mice. Therefore, GPNMB may be a suitable aging target for CAR-T therapy. [5]
四、Infection
Targeting non-body antigens will greatly reduce the risk of offtumor toxicity. As mentioned earlier, the original intention of CAR-T is to treat HIV-infected patients. After the virus infects the host cell, it will display specific antigens on the cell surface, and CAR-T designed for these antigens will have the potential to clear the infection. With the optimization of CAR-T structure, CAR-T based on second-generation structure has also been applied to the treatment of HIV, and related clinical trials are being actively carried out. There is also CAR-T, developed using fungal pattern recognition receptors, which can recognize carbohydrate antigens in fungal cell walls. This method has significant antifungal properties in vitro and in mouse models. Similarly, recent studies testing the efficacy of CAR T cells against invasive pulmonary aspergillosis showed antifungal properties in vitro and in mouse models of invasive pulmonary aspergillosis.
Although CAR-T has a broad development space in chronic infections, for acute infections, emergency response is required, and the current in vitro CAR-T production process needs to be further optimized.
五、Graft-versus-host Disease (GVHD)
CAR-T cell therapy can reduce the inflammatory response by identifying and eliminating the immune cells that trigger GvHD. There have been attempts to engineer anti-OX40 CAR-T (OX40, a protein upregulated in pathogenic T cells in acute GVHD) to target GVHD-associated immune cells for clearance.
The above summary of clinical and preclinical studies of CAR-T in non-cancer diseases shows that the immune cell therapy approach can indeed alleviate or even cure a variety of diseases by eliminating specific diseased cells. Compared with small molecule drugs and monoclonal antibodies, it has a more thorough and long-lasting therapeutic effect. The fruitful results let more researchers believe that CAR T cell therapy will open up a new battlefield beyond cancer treatment.
Reference：
[1] Baker DJ, Arany Z, Baur JA, Epstein JA, June CH. CAR T therapy beyond cancer: the evolution
of a living drug. Nature. Jul 2023; 619(7971): 707-715. doi:10.1038/s41586-023-06243-w
[2] Mougiakakos D, KronkeG, Volkl S, et al. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. NEnglJ Med. 2021; 385(6): 567-5669. doi:10.1056/NEJMc2107725
[3] Muller F, Boeltz S, KnitzaJ, et al. CD19-targeted CAR T cells in refractory antisynthetase syndrome. Lancet. 2023; 401(10379):815-818. doi:10.1016/S0140-6736(23)00023-5
[4] Granit V, Benatar M, Kurtoglu M, et al. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study [published correction appears in Lancet Neurol. 2023 Sep; 22(9):e10] [published correction appears in Lancet Neurol. 2023 Sep;22(9):e10]. Lancet Neurol. 2023; 22(7):578-590. doi:10.1016/S1474-4422(23) 00194-1
[5] Suda, M., Shimizu, I., Katsuumi, G. et al. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat Aging 1, 1117– 1126 (2021).
https://doi.org/10.1038/s43587-021-00151-2
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
Differences between CAR-T therapy in cancer and other diseases [1]
一、Autoimmune and inflammatory diseases
SLE (Systemic lupus erythematosus) is an immune disease that may endanger its own life. From 2021 to 2022, a research team has successively injected anti-CD19 (B-cell specific antigen) CAR-T into 6 patients, and CAR-T cells were amplified in all patients. B cells were rapidly eliminated, SLE symptoms were relieved, and markers of end-organ damage were significantly decreased. All patients stopped immunosuppressive drug therapy and were in drug-free remission. Short-term follow-up showed that several months after CAR T cell infusion, the naive B cells re-emerged and showed no signs of disease recurrence. CAR-T cells were well tolerated with only mild cases of CRS, which is consistent with the idea that lower target cell load may reduce the severity of CRS. [2]
Anti-CD19 CAR T cells are also used in patients with inflammatory myopathy caused by synthetase syndrome. After CAR T cell infusion, the patient experienced increased myalgia and serum creatinine kinase. After 180 days of infusion, the patient's physical function improved significantly, quadriceps and hamstring myositis gradually subsided, creatinine kinase and other clinical indicators gradually normalized. [3]
In fact, any autoimmune and inflammatory disease due to B cells or plasma cells may be a potential indication for CAR-T therapy, including neutrophil cytoplasmic antibody associated vasculitis, rheumatoid arthritis, myositis, multiple sclerosis, pemphigus extraformis, immune thrombocytopenia, myasthenia gravis, and retinomyelitis. In addition, as long as the target of B cell or plasma cell killing (BCMA,GPRC5D, CD20 and CD22) may become a potential CAR-T therapeutic target. [3-4]
Another way to eliminate inflammatory cells is to redirect regulatory T (Treg) cells to target tissue. These cells are not cytotoxic, but provide paracrine signals to suppress inflammation and autoimmune responses. Transfection of CAR into Treg cells improves specificity and reduces the risk of system-wide immunosuppression.
At present, CAR-T clinical trials and preclinical studies for various autoimmune diseases have proved that this disease may be one of the most promising areas of CAR-T therapy.
二、Organ fibrosis
Cardiac fibrosis is the result of acute injury, chronic disease, or aging, and it leads to increased near-term morbidity and long-term mortality. Currently, there are limited treatments for cardiac fibrosis. Recent preclinical studies have shown that CAR-T cells can target fibrosis and restore heart function after hypertensive damage. The researchers identified fibroblast-specific antigens in the hearts of patients with cardiomyopathy and found that fibroblast-activating protein (FAP) was the highest expressed target. Injection of anti-FAP CAR T cells can resolve fibrosis after heart injury and improve heart function. The implications of using CAR T cells to target pathological fibrosis extend beyond heart disease. Extracellular matrix deposition and fibrosis are pathological in a variety of diseases. Liver disease, chronic kidney disease, lung disease, skeletal muscle disease, and many other conditions can be tried with anti-fibrotic CAR T cells.
三、Aging
Multiple stressors can cause cells to undergo irreversible stagnation of proliferation, known as cellular senescence. Studies have shown that removing these cells is beneficial for a variety of chronic disease models. Small-molecule drugs that target intracellular pathways in senescent cells seem promising, but their potency, specificity, and side effects have limited its development. CAR-T is considered by researchers to be a very competitive new therapy due to its inherent specificity and potency. Senescent cells are physiologically cleared by the immune system early in life, and the use of CAR to enhance immune cells and prolong this process may lead to greater benefits for the body.
Recent research has shown that CAR-T cells can clear senescent cells in mice with cancer and liver disease. PLAUR encodes urokinase-type plasminogen activator receptor (uPAR), which is considered a potential serum antigen and is expressed at relatively low levels in important tissues. Anti-uPAR CAR-T successfully eliminated oncogene-induced liver senescent cells, tumor treatment-induced lung senescent cells, drug-induced liver fibrosis, and diet-induced nonalcoholic steatohepatitis senescent cells. Because of the heterogeneity of senescent cells, it is difficult and important to identify senescent antigens. Other targets that can be used to generate senescent CAR-T cells include NKG2D ligand, MICA, MICB, and ULBP1-5, which are expressed in a variety of senescent cells. Another potential target is glycoprotein non-metastatic melanoma Protein B (GPNMB), and immunotherapy targeting this target can clear senescent cells. Improve metabolic parameters, reduce atherosclerotic plaque and prolong the life span of male premature aging mice. Therefore, GPNMB may be a suitable aging target for CAR-T therapy. [5]
四、Infection
Targeting non-body antigens will greatly reduce the risk of offtumor toxicity. As mentioned earlier, the original intention of CAR-T is to treat HIV-infected patients. After the virus infects the host cell, it will display specific antigens on the cell surface, and CAR-T designed for these antigens will have the potential to clear the infection. With the optimization of CAR-T structure, CAR-T based on second-generation structure has also been applied to the treatment of HIV, and related clinical trials are being actively carried out. There is also CAR-T, developed using fungal pattern recognition receptors, which can recognize carbohydrate antigens in fungal cell walls. This method has significant antifungal properties in vitro and in mouse models. Similarly, recent studies testing the efficacy of CAR T cells against invasive pulmonary aspergillosis showed antifungal properties in vitro and in mouse models of invasive pulmonary aspergillosis.
Although CAR-T has a broad development space in chronic infections, for acute infections, emergency response is required, and the current in vitro CAR-T production process needs to be further optimized.
五、Graft-versus-host Disease (GVHD)
CAR-T cell therapy can reduce the inflammatory response by identifying and eliminating the immune cells that trigger GvHD. There have been attempts to engineer anti-OX40 CAR-T (OX40, a protein upregulated in pathogenic T cells in acute GVHD) to target GVHD-associated immune cells for clearance.
The above summary of clinical and preclinical studies of CAR-T in non-cancer diseases shows that the immune cell therapy approach can indeed alleviate or even cure a variety of diseases by eliminating specific diseased cells. Compared with small molecule drugs and monoclonal antibodies, it has a more thorough and long-lasting therapeutic effect. The fruitful results let more researchers believe that CAR T cell therapy will open up a new battlefield beyond cancer treatment.
Reference：
[1] Baker DJ, Arany Z, Baur JA, Epstein JA, June CH. CAR T therapy beyond cancer: the evolution
of a living drug. Nature. Jul 2023; 619(7971): 707-715. doi:10.1038/s41586-023-06243-w
[2] Mougiakakos D, KronkeG, Volkl S, et al. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. NEnglJ Med. 2021; 385(6): 567-5669. doi:10.1056/NEJMc2107725
[3] Muller F, Boeltz S, KnitzaJ, et al. CD19-targeted CAR T cells in refractory antisynthetase syndrome. Lancet. 2023; 401(10379):815-818. doi:10.1016/S0140-6736(23)00023-5
[4] Granit V, Benatar M, Kurtoglu M, et al. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study [published correction appears in Lancet Neurol. 2023 Sep; 22(9):e10] [published correction appears in Lancet Neurol. 2023 Sep;22(9):e10]. Lancet Neurol. 2023; 22(7):578-590. doi:10.1016/S1474-4422(23) 00194-1
[5] Suda, M., Shimizu, I., Katsuumi, G. et al. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat Aging 1, 1117– 1126 (2021).
https://doi.org/10.1038/s43587-021-00151-2
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
