doi: 10.1056/NEJMoa1709866, 16. Thorough consideration must be given to optimizing CAR structure and controlling the character and potency of cell therapy products. “Knowing that this combination of drugs is well tolerated with expected side effects in brain tumor patients allowed us to move forward in planning our study using these immunotherapy drugs in this patient population,” says Dr. Gilbert. “There are quite a few visits in the first four months, but that is when we get the most activation of the immune system,” says Dr. Gilbert. MGMT plays an important role in increasing chemoresistance to alkylating agents (88). Results were reviewed 15-17 months after the start of the surgery. We should avoid any severe brain inflammation induced with ACT, in particular allogeneic ACT. doi: 10.1371/journal.pone.0077571, 111. This means NK cells regulate DC maturation which enhances the presentation of tumor antigen to modulate T-cell mediated anti-tumor adaptive immune responses (46). The levels of severity of the most common adverse events considered to be treatment-related were at grade 1 or 2. The proportion and proliferation of regulatory T cells (Tregs) increased and continued to be high with routine DI-TMZ cycles. “The primary goal of our new immune monitoring study is to determine whether the response in the blood is associated with a response in the brain tumor. doi: 10.1172/JCI89587, 5. Consequently, the entire tumor is nearly impossible to excise. Hickey MJ, Malone CC, Erickson KL, Jadus MR, Prins RM, Liau LM, et al. TME and GBM treatment regimens will impact the plasticity of γδ T cells. No use, distribution or reproduction is permitted which does not comply with these terms. doi: 10.1158/1078-0432.CCR-16-1421, 29. Mol Ther Methods Clin Dev (2018) 9:70–80. doi: 10.1080/09553006614550421, 12. In 2016, Dr. Brown et al. Nat Rev Cancer (2019) 19:568–86. The application of these inhibitors can rescue the immunosuppression of TME-constituting cells. Cellular responses were reported to have increased dramatically after the first cycle of DI-TMZ, and three doses of pp65-DCs. A Phase II Trial of Autologous Dendritic Cell Vaccination and Radiochemotherapy Following Fluorescence-Guided Surgery in Newly Diagnosed Glioblastoma Patients. Miller JS, Lanier LL. doi: 10.1093/neuonc/noac024, 46. doi: 10.1158/0008-5472.CAN-05-1682, 140. Better results were obtained in patients with several [213Bi]Bi-DOTA-SP doses of injections, which may be due to cumulatively a larger dose of treatment and/or finer clinical condition at the start of the treatment. The idea of theranostic treatment of glioblastoma with local and intravenous injection of radiopharmaceutical. Zusammenfassend lässt sich sagen, dass MGMT, das Alter und IDH1 in den letzten Jahren ganz handfeste Biomarker in der klinischen Routine waren, um Glioblastome prognostisch zu unterscheiden. In the previous studies, some of the targets were clinically evaluated for targeting radionuclide therapy of glioma (4–8). The progressive disappearance of large tumors could be detected several weeks after injection which led to the prolonged survival rate of tumor-bearing mice. doi: 10.1093/neuros/nyaa584, 35. This strategy has been shown to reduce systemic toxicity. Eine Phase-III-Studie, gefördert vom Bundesministerium für Bildung und Forschung, zeigte jetzt, dass die Kombination der Alkylanzien die Überlebenszeit tatsächlich deutlich verlängert. (2018) 45:1636–44. Calinescu AA, Kauss MC, Sultan Z, Al-Holou WN, O'shea SK. Strictly controlling the character and potency of cell therapy products not only can reduce the risk of severe immune inflammation and immune related adverse events, but also it can reduce the variables in the treatment that might contribute to the clinical outcome. Für Betroffene mit der Hirntumorart Glioblastom könnte das bei Erfolg zu einer lebensverlängernden Therapieoption führen. In recent years, a number of scientific investigations have focused on myeloid immune cells (Monocytes, DCs and Macrophages) for the treatment of GBM. Wan H, Dupasquier M. Dendritic Cells In Vivo and In Vitro. A combination of nanotechnology, chemotherapy and a monoclonal antibody could treat glioblastoma. CAR T cells therapy has been approved for the treatment of lymphoma and leukemia in multiple countries (17). Bioactivity and Safety of IL13Ralpha2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients With Recurrent Glioblastoma. Montag, 8. On the flip side, Type II NKT cells execute an immunosuppressive role in cancers. doi: 10.1093/neuonc/noab106, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. ©Universitätsklinikum Tübingen. This is due to GBM being among the immunologically “coldest” tumors, characterized by high intratumoral and intertumoral heterogeneity, low mutational burden, highly invasive and infiltrative GBM cell properties, systemic immunosuppression and the local severely immunosuppressive tumor microenvironment (TME) promoting GBM growth (7–9). Emerging Cellular Therapies for Cancer. It has the potential to generate off-the-shelf cellular therapy products. Um die Fragen zu klären, tritt die Deutsche Hirntumorhilfe für eine unabhängige klinische Prüfung der Methode ein. On the contrary, we can strictly select healthy donors and cells with beneficial anti GBM potential to produce allogeneic cell therapy products. Int J Oncol (2015) 46:147–52. Their specific role in GBM remains largely unclear and requires more investigation (99). Ex Vivo-Expanded Highly Purified Natural Killer Cells in Combination With Temozolomide Induce Antitumor Effects in Human Glioblastoma Cells In Vitro. doi: 10.1007/s11060-020-03448-1, 10. Fate Mapping of Human Glioblastoma Reveals an Invariant Stem Cell Hierarchy. It has passed the pre-clinical stage (86) and progressed into a Phase I study (87). Improved patient survival rates were observed when correlated with M1 polarization (109). Substance P (SP), the main ligand of neurokinin type 1 receptor (NK-1) which is consistently overexpressed in all gliomas irrespective of the degree of malignancy, was first applied by Kneifel et al. In preclinical models, the combination strategies have depicted the possibility of reversing the immunosuppressive impact of GBM. The trial will also evaluate a test that may help determine who is likely to get that response. Lan X, Jorg DJ, Cavalli FMG, Richards LM, Nguyen LV, Vanner RJ, et al. PloS One (2013) 8:e51805. Sengupta S. Gamma-Delta T Cells in Glioblastoma Immunotherapy. Regression of Glioblastoma After Chimeric Antigen Receptor T-Cell Therapy. Das Glioblastom ist bislang nicht heilbar. Parker CM, Groh V, Band H, Porcelli SA, Morita C, Fabbi M, et al. In 2005, it was demonstrated that intravenously injected hematopoietic stem/progenitor cells (HSPC) could home to experimental intracerebral gliomas, and this process was mediated by a CXC chemokine ligand (CXCL) 12-dependent pathway (147). The major component of the human cytomegalovirus (CMV) was pp65 (ppUL83). The expression of CD1d in GBM holds the promise of anti-GBM therapeutic potential using NKT cell-based cancer immunotherapy (100). Working Toward Better Radiation Responses Through Novel, Targeted Drugs, First-in-Human Trial for People with Recurrent Rare CNS Tumors, If you would like to reproduce some or all of this content, see Reuse of NCI Information for guidance about copyright and permissions. Improved Overall Survival, Relapse-Free-Survival, and Less Graft-Vs.-Host-Disease in Patients With High Immune Reconstitution of TCR Gamma Delta Cells 2 Months After Allogeneic Stem Cell Transplantation. J Transl Med (2010) 8:100. doi: 10.1186/1479-5876-8-100, 117. One of the innovative approaches is also targeting the tumor-specific DNA repair mechanism. Front Immunol (2020) 11:40. doi: 10.3389/fimmu.2020.00040, 73. 68. Meanwhile TMZ suppresses the anti GBM function of the lymphocyte effectors. Glioma (2019) 2:30–6. They have the capacity to self-renew and to differentiate into any somatic cell types. Cells (2020) 9:729. doi: 10.3390/cells9030729, 81. Safety is still at the forefront of concerns for GBM treatment. Meist kommt es trotz erfolgreicher Operation, Bestrahlung und Chemotherapie bereits innerhalb eines Jahres zu einem Rückfall. Allogeneic IL13Rα2-targeted CAR+ (IL13-zetakine+) T cells with a permanently disrupted glucocorticoid receptor (GR) (GRm13Z40-2) were generated from healthy donors. Merlo A, Hausmann O, Wasner M, Steiner P, Otte A, Jermann E, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. J Immunol (2009) 182:3530–9. Anticancer Res (2020) 40:5481–7. Ein Fachartikel zum CUSP9-Protokoll ist im Journal „Oncotarget" erschienen. Nguyen P, Okeke E, Clay M, Haydar D, Justice J, O'reilly C, et al. The toxicity of treatment was limited only to one patient with symptomatic radiogenic edema. Glioma Stem Cells Promote Radioresistance by Preferential Activation of the DNA Damage Response. Chitadze G, Lettau M, Luecke S, Wang T, Janssen O, Furst D, et al. The most common high-grade adverse event was a fever at the grade 3 level. Cell (2006) 126:663–76. Tisagenlecleucel in Children and Young Adults With B-Cell Lymphoblastic Leukemia. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Engineering the Bridge Between Innate and Adaptive Immunity for Cancer Immunotherapy: Focus on Gammadelta T and NK Cells. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Berlin 21.11.2022. Brettschneider EES, Terabe M. The Role of NKT Cells in Glioblastoma. Johnson J, Ascierto ML, Mittal S, Newsome D, Kang L, Briggs M, et al. Ronellenfitsch MW, Luger AL, Steinbach JP. Earlier this year, Stanford University published the clinical outcome of a GD2-CAR T cells phase I dose-escalation trial. Nuclear Targeting of the Tegument Protein Pp65 (UL83) of Human Cytomegalovirus: An Unusual Bipartite Nuclear Localization Signal Functions With Other Portions of the Protein to Mediate its Efficient Nuclear Transport. A Single Dose of Peripherally Infused EGFRvIII-Directed CAR T Cells Mediates Antigen Loss and Induces Adaptive Resistance in Patients With Recurrent Glioblastoma. Hambardzumyan D, Gutmann DH, Kettenmann H. The Role of Microglia and Macrophages in Glioma Maintenance and Progression. Nature (2017) 549:227–32. For approximately 7.5 months, after the initiation of treatment, both the intracranial and spinal tumors experienced regression. Although the injection was done to critically locate gliomas, no neurologic deficit was observed. Älteren Patienten mit Glioblastom wird in der Regel von einer Radiochemotherapie abgeraten. The patients had a local intratumoral injection of radiolabeled SP (5). It is important to note that GSCs appear highly susceptible to the killing ability of allogeneic NK cells (56). doi: 10.1158/1078-0432.CCR-05-2820, 6. Immunological Aspects of Allogeneic Mesenchymal Stem Cell Therapies. Die Prognose beim Glioblastom (GB) ist immer noch schlecht, es kommt fast immer zum Rezidiv. The breakthrough could benefit the 2,500 people a year in the UK who are diagnosed with glioblastoma, the commonest form of brain cancer and also one of the most aggressive.People with the disease . NK cells can also initiate the apoptosis of tumor cells through a caspase pathway. Adult stem cells can be found in most tissues in postnatal life. Stupp R, Mason W, van den Bent M, Weller M, Fisher B, Taphoorn M, et al. T Cells With Chimeric Antigen Receptors Have Potent Antitumor Effects and can Establish Memory in Patients With Advanced Leukemia. Cell therapy has demonstrated a few successes in GBM treatment so far. The patients received a single dose of up to 5 × 108 autologous EGFRvIII-specific CAR-T cells administered as an IV injection. Das Glioblastom ist der häufigste bösartige Hirntumor. Because of GBM’s intracranial location, drug pharmaceutical developers and physicians must carefully consider and balance the efficacy of cell therapy and the immune inflammation induced by the treatment. Receptor for Interleukin 13 is a Marker and Therapeutic Target for Human High-Grade Gliomas. Inoges S, Tejada S, De Cerio AL, Gallego Perez-Larraya J, Espinos J, Idoate MA, et al. Guo M, Wu T, Wan L. Cytotoxic Activity of Allogeneic Natural Killer Cells on U251 Glioma Cells In Vitro. Portnow J, Synold TW, Badie B, Tirughana R, Lacey SF, D'apuzzo M, et al. Kneifel S, Cordier D, Good S, Ionescu MC, Ghaffari A, Hofer S, et al. This MSC feature was originally demonstrated using fluorescently labeled human bone marrow-derived MSCs when transplanted into a mouse model (145). Promising, regional administration (ICT and/or ICV) of CAR T cells effectively restricts peripheral tissue toxicities. doi: 10.1007/s00259-018-4225-7, 17. Uzzaman M, Keller G, Germano IM. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. Local injection of the 90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades II and III: an extended pilot study. SCI-101 was developed for optimal crossing of the BBB and sustaining the NK cell–activating target antigens expression on tumor cells. Safety and efficacy of targeted alpha therapy with 213Bi-DOTA-substance P in recurrent glioblastoma. doi: 10.1161/CIRCRESAHA.117.305860, Keywords: glioblastoma, cell therapy, immunotherapy, clinical trials, CAR T cells, NK cells, myeloid immune cells, stem cells, Citation: Wang G and Wang W (2022) Advanced Cell Therapies for Glioblastoma. No dose limiting toxicities (DLTs) such as infusion reactions, cytokine release syndrome (CRS), or neurotoxicity were observed. In recent studies, most CARs include costimulatory signaling domains to increase the T-cell activation, survival and/or function. Nanomed (Lond) (2018) 13:157–78. Pullman Paris Roissy CDG Airport. Conversely, DCs have been found to enhance the direct anti-tumor activity of NK cells. Sci Rep (2020) 10:2815. doi: 10.1038/s41598-020-59736-3. Nature (2006) 444:756–60. 134. Miyashita M, Shimizu T, Ashihara E, Ukimura O. In seiner Videobotschaft 2021 rief Jens Spahn dazu auf, Teil unseres Netzwerkes zu werden. Many of the obstructing issues encountered with autologous cells including the variability from patient-to-patient and the actual production time can be deciphered (60, 61). 17 Articles, This article is part of the Research Topic, Clinical studies with targeted radioisotope therapy for glioma, https://doi.org/10.3389/fmed.2022.1085245, Creative Commons Attribution License (CC BY). The new immune monitoring study evaluates if there is an immune response in the participant’s blood, which could mean that some of the immune cells will cross the blood-brain-barrier to effectively reach and treat the tumor. We believe there is a subgroup of tumor types that may show response to these immunotherapy treatments. In contrast, type I NKT cells failed to hinder tumor growth of CD1d-negative U87 cells in the intracranial injection model. doi: 10.2217/nnm-2017-0266, 107. In this article, we summarize the experience with local treatment of primary and secondary GBs with locally used radioisotopes such as [213Bi]Bi-DOTA-SP or [225Ac]Ac-DOTA-SP. PLoS One. With the great advances in the iPSC field in recent years, it has the potential to allow the use of stem cell-derived products to treat GBM. Several types of adult stem cells, including neural stem cells (NSCs), mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) have been tested to treat GBM. At a minimum, three vaccines of pp65 lysosome-associated membrane glycoprotein mRNA-pulsed DCs admixed with GM-CSF were administered on day 23 ± 1 of each cycle. doi: 10.1038/s41587-020-0462-y, 113. The Epidemiology of Glioma in Adults: A "State of the Science" Review. Therapie. Nat Rev Immunol (2004) 4:231–7. 1 BlueRock Therapeutics, Department of Process Development, Cambridge, MA, United States. Generation of Tumor-Targeted Human T Lymphocytes From Induced Pluripotent Stem Cells for Cancer Therapy. Cell Therapy has revolutionized the treatment of multiple diseases, including several kinds of cancer. Front Immunol (2019) 10:2683. doi: 10.3389/fimmu.2019.02683, 47. If surgery is the option, brain surgery of course is a gauntlet of potential pitfalls in any attempt to fully resect the tumor. J Immunol (2013) 190:4868–76. If the patients had not progressed with the treatment, a dose of DI-TMZ and pp65-DCs were administered every month. Data were also collected in the trial’s overall intent-to-treat (ITT) patient population. Neuro Oncol (2010) 12:7–13. The aim is to remove as much of the tumor as safely as possible and prevent it from . Cross-Talk Between T Cells and Hematopoietic Stem Cells During Adoptive Cellular Therapy for Malignant Glioma. Then, doctors could predict which patients are likely to get an immune response. Adv Exp Med Biol (2012) 746:53–76. GBM also displays resistance to radiation and chemotherapy, resulting in GBM recurrence (4). When NSCs were injected directly into the tumor or implanted intracranially at a distance, they could migrate to and be distributed widely throughout the tumor.
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