August 17, 2022

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CAR-T-mediated immunotherapy for glioblastoma multiforme

CAR-T-mediated immunotherapy for glioblastoma multiforme



CAR-T-mediated immunotherapy for glioblastoma multiforme.  The broad categories of immunotherapy include cancer vaccines, checkpoint inhibitors, oncolytic virus therapies, and chimeric antigen receptor (CAR) functionalized immune cell therapies. In this short chapter, we provide a brief view of the cell-based immunotherapy developed for GBM, with a focus on CAR-T cells.



Glioblastoma polymorphic immunosuppression

GBM is a highly immunosuppressive tumor. The functions of GBM cell secretion factors include inhibiting T cell activation and proliferation and inducing T cell apoptosis. GBM cells also do not have the costimulatory molecules needed to activate naive T cells. It is worth noting that regulatory T cells (Tregs) are attracted to the tumor site through these GBM cell secretion factors. Myeloid/microglia are M2 polarized and lack natural killer (NK) cells. All these factors combine It further exacerbates the immunosuppression in the tumor microenvironment (TME).


GBM cells reduce the expression of the major histocompatibility complex (MHC), thereby limiting their antigen presentation; the immunosuppressive microenvironment can also impair the antigen presentation ability of myeloid/microglia. As with other cancers, hypoxia plays an important role in the immunosuppressive GBM microenvironment.

In particular, a series of hypoxia-induced genes activate Tregs and up-regulate vascular endothelial growth factor (VEGF) to promote the vascularization of hypoxic tissues. VEGF itself has an immunosuppressive effect: it inhibits the recruitment, differentiation and function of immune cells, and at the same time promotes the cancer stemness of tumor cells themselves.

The hypoxic microenvironment also induces the conversion of CNS macrophages into M2 polarized tumor-associated macrophages, which is an immunosuppressive and tumor-supporting phenotype. Another challenge for immune cells to recognize tumor cells is the sub-average tumor mutation load (TML) that is commonly observed in gliomas, resulting in fewer neoantigen targets for the functionalization of immune targeted therapy, and The recognition rate of tumors is lower by the immune system.


Extracranial metastases rarely occur in GBM, which may be due to the rapid termination of the disease after the onset or the sensitivity of tumor cells outside the central nervous system. However, circulating tumor cells have been found in some GBM patients, and it has been proven that recipients of transplanted organs from GBM patient donors can develop this disease extracranially. Although the disease is mainly confined to the central nervous system, the patient exhibits systemic immunosuppression. It is worth noting that the current standard of care for GBM is also immunosuppressive, and patients receiving exploratory treatment and regulating the immune system are likely to have received one or more of these standard treatments.



Chimeric antigen receptor functional cell therapy in glioblastoma

The use of CAR-T cells to treat acute lymphoblastic leukemia (ALL) has achieved a significant remission rate, which indicates that this new treatment has the potential to change the paradigm. Therefore, although there are many obstacles to the treatment of solid tumors, how to deploy this new technology in solid tumor oncology is still worth exploring.


Chimeric antigen receptor

CAR is composed of antibody-derived antigen recognition domains. It is used to select tumor antigens, usually in the form of single-chain variable fragments, CD3-ζ domain for T cell activation and intracellular co-stimulation in the absence of a primary immune response. area. Importantly, CAR does not need to target MHC-presented antigens, and can theoretically be functionalized against any cell surface molecule including lipids and carbohydrates. Considering the down-regulation of MHC that is commonly observed in GBM cells, this Is an important difference. Although no standards have been established, CAR-T intervention in GBM can be treated intracranially after tumor resection, and systemic treatment can be performed because T cells can cross the blood-brain barrier; however, it is worth noting that this treatment is also used Cerebrospinal fluid.

GBM’s particularly immunosuppressive microenvironmental characteristics will naturally hinder the efficacy of CAR-based therapies; combined treatment with drugs that inhibit the main mechanism of GBM immunosuppression may be necessary to achieve the degree of efficacy of CAR-T in liquid cancers. Overall, to date, any strategy for GBM immunotherapy has limited clinical results, which indicates that immune-mediated treatment needs to increase complexity to match the complexity of metabolism and immune escape exhibited by GBM tumor cells. .


1. CAR-T cells for glioblastoma multiforme

As mentioned earlier, CAR-T therapy has recently achieved two major clinical victories, with Yescarta (axicabtagene ciloleucel, Kite Pharma Inc.) and Kymriah (tisagen lecleucel, Novartis) approved, both of which were approved in 2017 Obtained the FDA’s first market approval. They are the subtypes of large B-cell lymphoma and acute lymphoblastic leukemia. Here, T cells derived from the patient (ie, autologous) are extracted from the patient, genetically modified to express the CAR of interest to specifically target cancer cells, and then reintroduced into the patient’s body.


Although the average clinical efficacy is mixed, CAR-T cells have been shown to infiltrate tumors and have shown impressive efficacy in some case studies (Table 19.1). Due to the heterogeneity of GBM, as the polymorphism mentioned in its name, CAR-T targeting a single antigen may not be sufficient to ablate enough tumor cells to counteract the rapid proliferation of remaining cells.

According to this idea, the particularly rapid proliferation of GBM tumor cells provides ample opportunities for tumors to undergo microcellular evolution to select cells that do not express specific antigens or otherwise down-regulate attacking antigens (“antigen escape”). To counteract this phenomenon, bivalent and trivalent CAR-T are being developed to overcome the antigenic heterogeneity of GBM.

In fact, so far, CAR-T has shown the most impressive efficacy in the treatment of lymphoma and leukemia of highly clonal cancer. The clinical results of the three CAR targets of GBM have been published: interleukin receptor 13Rα2 (IL13Rα2), human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor variant III (EGFRvIII).


IL13Rα2 is present in more than 60% of GBM and has limited expression in healthy tissues. It is a prognostic factor for low patient survival, making it an attractive target for CAR-T therapy. This is the first CAR target used in GBM clinical practice. CAR-T targeting IL13Rα2 showed an encouraging initial response in a small sample study. IL13Rα2CAR-T showed tumor regression in a case study of a 50-year-old man with recurrent GBM who was resistant to standard treatment. The patient received 6 intracranial and 10 cycles of intravenous infusion. The resolution after treatment lasted for 7.5 months.

HER2 is another candidate target for CAR-T and is expressed in up to 80% of GBM. It is worth noting that CAR-T for HER2 raises safety issues when patients with refractory metastatic colon cancer die. The results of a recent phase I study of HER2 cytomegalovirus (CMV) bispecific CAR-T in 17 GBM patients showed preliminary safety and effectiveness. In short, the patient received 1 to 7 intravenous doses of treatment. The bispecific effect of CMV is to non-specifically increase the activity of CAR-T. After 24-29 months of follow-up after the end of the study, the three patients remained stable with no disease progression.

CAR-T-mediated immunotherapy for glioblastoma multiforme

Similarly, in the first human study, 10 patients received a single intravenous injection of EGFRvIII CAR-T cells. EGFRvIII is the most common variant of the tyrosine receptor kinase EGFR, which causes constitutive receptor activation and promotes cell proliferation, and is expressed in 30% of GBM tumors. Among them, 7 patients had their tumors removed after the infusion. The analysis of tumor tissue not only found that CAR-T metastasized to the active area of ​​the tumor, but also proved the highly immunosuppressive properties of GBM: especially the increased expression of inhibitory molecules and Treg. In addition, 5 of these 7 patients experienced a decrease in the expression of EGFRvIII in GBM tumor tissues relative to EGFR, which indicates a targeting effect. The detection of CAR-T cells in the peripheral blood assesses that these cells appear to have been implanted.


2. CAR-NK cell therapy

A major bottleneck in the wide clinical application of CAR-T therapy is that the T cells that need to be modified are autologous rather than allogeneic, although several ready-made so-called “universal” cell lines have been developed through inactivated genes. Disease risk, such a cell line can be used for multiple patients. However, natural killer (NK) cells can directly eliminate tumors without causing graft-versus-host disease, so they may provide an attractive allogeneic CAR treatment strategy for tumor indications including GBM.

A variety of CAR-NKs are in the preclinical development stage of GBM, mainly targeting the same antigens as the above CAR-T therapy, including EGFR/EGFRvIII and HER2, and have shown curative effects in GBM mouse models. Due to the heterogeneity of GBM mentioned above, NK cells have also explored multispecific antigen methods. At least one CAR-NK targeting HER2 is being explored in Phase I clinical trials for GBM (Table 19.1).



Sum up

GBM is a tumor indication that represents an urgent unmet medical need. So far, the lack of treatment success of traditional treatment methods strongly suggests that innovative treatment methods are needed to improve the remission outcomes of patients with this cancer, otherwise the overall prognosis is very poor.

Genetically engineered live drugs such as CAR-T cells and CAR-NK cells represent new treatment options and have shown preliminary signs of efficacy. However, in order to translate this hope into actual clinical benefits for patients who need them, there is still a need for a customized molecular CAR architecture that reflects the huge heterogeneity of GBM.

For example, multivalent CARs can simultaneously address various markers of GBM or have improved Tumor infiltration characteristics, and innovative combination therapies to combat the powerful immunosuppressive effects of GBM tumor microenvironment and other tumor proliferation and defense mechanisms.


(source:internet, reference only)

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