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/lp/wolters-kluwer-health/bottlenecks-and-opportunities-in-immunotherapy-for-glioma-a-narrative-ln6AAtGRV6
- Publisher
- Wolters Kluwer Health
- Copyright
- Copyright © 2022 The Chinese Medical Association, Published by Wolters Kluwer Health, Inc.
- ISSN
- 2577-3585
- eISSN
- 2096-5672
- DOI
- 10.1097/jbr.0000000000000135
- Publisher site
- See Article on Publisher Site
Abstract
Glioma is the most aggressive brain tumor having invasive ability and a highly heterogeneous phenotype. Many patients with glioma respond poorly to traditional surgery or temozolomide-based chemotherapy. Over the past few decades, developments in immunotherapeutic strategies have provided newer insights into the treatment of gliomas. Immunotherapy is based on the principle of normalization or recovery of T cell-mediated anti-tumor immunoreaction. Different innovative strategies have been used; these include enhancement of immunogenicity by administration of tumor antigens or dendritic cell vaccines, replenishment of cytotoxic T cells by adoptive T cell transfer, repair of exhausted T cells by immune checkpoint inhibitors, and the use of other immune activators such as oncolytic viruses. However, many immunotherapy-based clinical trials did not meet the expected therapeutic endpoints in patients with glioma. Gliomas use unique strategies to generate an immune-suppressive microenvironment; these include limiting immunogenicity and repressing T cell infiltration or activation. This may be addressed by the incorporation of immunotherapy with standard therapy or by use of certain innovative approaches such as tumor-treating fields. In this review, we summarize the updated immunotherapies in glioma and discuss current limitations and future prospects. Keywords: chimeric antigen receptor T cells, glioma, immune checkpoint inhibitor, immunotherapy, neoantigen [2] 1p/19q co-deletion. Surgical removal of tumor tissue followed Introduction by radiotherapy and/or chemotherapy (including temozolomide Gliomas are the most common primary malignant tumors of [TMZ], lomustine, intravenous carmustine, carmustine wafer the central nervous system (CNS) that originate from glial cells. implants, and bevacizumab) has remained the standard therapy They rank among the top four most lethal malignant tumors, [3] for gliomas. However, the median survival time of patients [1] with an incidence of 4.67 to 5.73 per 100,000 persons. The who undergo standard therapy is only 14.6 months; this may fifth edition of the World Health Organization classification of be is attributed to tumoral heterogeneity and limited access to central nervous system tumors (WHO CNS 5) classifies gliomas [4] current medicines. into diffuse gliomas, astrocytomas, oligodendrogliomas, and Since the last century, innovations in immunotherapy have glioblastomas based on their histological features. More accu- attempted to address the dilemmas in the treatment of gliomas. rate molecular phenotypes are also mentioned, including those The brain is an immune privileged organ, with lower lympho- with mutations of isocitrate dehydrogenases (IDH)-1/2 and cyte quantity and activity. The immunosuppressive intracra- nial microenvironment is regulated by abundant cell types and Supplemental Digital Content is available for this article. their products, such as vascular cells, microglia, neural precur- YS, MW, and YL contributed equally to the writing of the article. [5] sor cells, and peripheral immune cells. Three main obstacles Department of Oncology, Sichuan Academy of Medical Sciences, Sichuan impede adequate mobilization of effective immune cells (Fig. 1). Provincial People’s Hospital, University of Electronic Science and Technology The first is the physical barrier, namely, the blood-brain bar - Department of Neurosurgery, Chinese of China, Chengdu, Sichuan Province, c rier (BBB), which is formed by endothelial and mural cells. The Institute of Pathology People’s Liberation Army (PLA) General Hospital, Beijing, tight junctional construction of the BBB supports maintenance & Southwest Cancer Center, Southwest Hospital, Third Military Medical University Integrative Cancer Center & Cancer (Army Medical University), Chongqing, of central nervous system (CNS) homeostasis, separating the Clinical Research Center, Sichuan Cancer Hospital & Institute Sichuan Cancer blood components, pathogens, and circulating immune cells in Center, School of Medicine University of Electronic Science and Technology, [6] the CNS from the peripheral environment. The second imped- Chengdu, Sichuan Province, China iment is reduced tumor immunogenicity, which is commonly * Corresponding authors: Xiuwu Bian, Institute of Pathology & Southwest Cancer found in almost all solid tumors. A low tumor mutation burden Center, Southwest Hospital, Third Military Medical University (Army Medical or the absence of antigen presentation machinery is responsi- University), Chongqing 400038, China. E-mail: bianxiuwu@263.net; Chuan Xu, Department of Oncology, Sichuan Academy of Medical Sciences, Sichuan ble for the paucity of effective antigen targets; this conceals Provincial People’s Hospital, University of Electronic Science and Technology of tumor characteristics, making it invisible to the immune sys- China, Chengdu 610072, Sichuan Province, China. E-mail: xuchuan100@163.com [7] tem. T cell dysfunction is the third hindrance; effective T cells Copyright © 2022 The Chinese Medical Association, Published by Wolters are exhausted by persistent activation, which is manifested by Kluwer Health, Inc. This is an open-access article distributed under the terms of the loss of cytotoxic products including interleukin-2 and inter- the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 feron (IFN)-γ. Therapeutic options including radiation or TMZ (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially have also been reported to reduce lymphocyte count; this is without permission from the journal. [8] associated with shorter survival time in patients with glioma. Journal of Bio-X Research (2022) 5:151–162 Therefore, switching of the immune environment from “cold” Received: 7 August 2022; Accepted: 17 October 2022 to “hot” status is a prerequisite for overcoming the state of http://dx.doi.org/10.1097/JBR.0000000000000135 immune silence. 151 REVIEW ARTICLE Journal of Bio-X Research Figure 1. Immunosuppressive environment of glioma. There are three main obstacles contributing to immune suppression in glioma: existence of blood-brain barrier prevents infiltration of immune cell into intracranial position; low tumor mutation burden or the absence of antigen presentation machinery are responsible for reduced tumor immunogenicity; infiltrated T cell become dysfunctional under persistent activation. Created with BioRender.com. CTL=cytotoxic T lympho- cyte, IFN-γ=interferon gamma, IL-2=interleukin-2. Various therapeutic strategies targeting different aspects of neoantigen; DC vaccine; immune checkpoint inhibitor; chimeric immunosuppression have been proposed to address this issue; antigen receptor-T; tumor-treating fields. Most of the selected their clinical potential is being fully evaluated (Fig. 2). Tumor studies (80% of all references) were published form 2012 to vaccines have been utilized to address the low immunogenic- 2022. An ancient publication (1991) was included in consider- ity of gliomas; they supplement immunogenic neoantigens or ation to its relevance in the mast cell field. Information of clin- enhance antigen presentation (in the case of dendritic cell [DC] ical trials included in this review was retrieved in ClinicalTrial. vaccines). Adoptive cell therapies such as chimeric antigen gov (https://clinicaltrials.gov). receptor (CAR)-T or CAR-natural killer (NK) cells are designed to address the issue of inadequate immune cell infiltration, while Tumor vaccines inhibitors targeting immune checkpoints are used to recover functionally exhausted T cells. Although high response rates are The genomes of cancer cells contain nonsynonymous somatic achieved in almost all tumors, outcomes remain unsatisfactory mutations, which are entirely absent in their healthy counter- in patients who undergo immunotherapy. It is believed that this parts. These mutation-derived immunogenic neo-nonself epitopes may be overcome by combining immunotherapy with standard (neoantigens) can be presented by major histocompatibility com- therapy or by other innovative strategies such as tumor-treat- plexes (MHCs) to distinct T cell receptors (TCRs) to trigger an ing fields (TTFields). In this review, we illustrate the principles antitumor T cell response. Patients with a higher tumor mutation of current immunotherapies and related combined therapies burden tend to be capable of producing neoantigens more fre- in patients with glioma. Updated information regarding the quently; this becomes a prognostic factor for immunotherapeutic [9] advances and limitations of these therapies has been summa- response. However, silenced expression of effective tumor anti- rized after a thorough search of related clinical trials. Further gens is a universal phenomenon in gliomas. These altered antigens challenges in the development of immunotherapy have also are potentially labeled as mismatched production and are cleaved been discussed. by protease or metalloproteinase systems; this deprives their access to MHC molecules. Gliomas also evolve to reduce MHC diversity by loss of major MHC encoding-components (eg, human Retrieval strategy leukocyte antigen loss of heterozygosity) or epigenetic regulation; [10] Literature review was electronically performed using PubMed this minimizes their immunogenicity. Advancements in antigen database. The following combinations of key words were used discovery and vaccine development have led to the use of multiple for initial literature retrieval: glioma and immunotherapy; vaccine approaches aimed at supplementing immunogenic tumor 152 Journal of Bio-X Research REVIEW ARTICLE Figure 2. Landscape of immune cells and components in glioma. Glioma microenvironment is composed of highly heterogeneous tumor cells and various immune cells, such as macrophage and lymphocytes. Under different stimulation or pathological condition, these cells play different immune modulatory func- tion by expressing distinct markers or releasing cytokines. Created with BioRender.com. AIM2=absent in melanoma, CCL17=C-C Motif Chemokine Ligand 17, CCL20=C-C Motif Chemokine Ligand 20, CCL22=C-C Motif Chemokine Ligand 22, CTLA-4=cytotoxic T lymphocyte-associated antigen 4, DC=dendritic cell, DC-SIGN=dendritic cell-specific ICAM-3-grabbing nonintegrin, EGFRvIII=epidermal growth factor receptor variant III, EphA2=ephrin type-A receptor 2, FN=fibronectin, GARP=glycoprotein-A repetitions predominant, gp100=glycoprotein 100, HA=hyaluronic acid, HER2=human epidermal growth factor receptor 2, HLA-E=HLA class I histocompatibility antigen, alpha chain E, IDH1=isocitrate dehydrogenase (NADP(+)) 1, IDO1=indoleamine 2,3-Dioxygenase 1, IFN- γ=interferon gamma, IL-10=interleukin 10, IL13Rα2=interleukin 13 receptor α2, IL-2=interleukin 2, IL-4/13=interleukin 4/13, IL-6=interleukin 6, ITGB1=integrin subunit beta 1, ITGB2=integrin subunit beta 2, LOXL2=lysyl oxidase like 2, Mac-1=macrophage-1 antigen, MAGE-A1=MAGE family member A1, MHC I/ II=major histocompatibility complex I/II, MICA=MHC class I polypeptide–related sequence A, NCR=natural cytotoxicity receptor, NCR-L=natural cytotoxic- ity receptor-ligand, NK=natural killer, NKG2A=NK cell Group 2 isoform A, NKG2C=NK cell Group 2 isoform C, NKG2D=natural killer group 2, member D, PD-1=programmed cell death 1, PGE2=prostaglandin E2, Qa-1=MHC class Ib molecule, SOX11=SRY-Box transcription factor 11, SOX2=SRY-Box tran- scription factor 2, TGF-β=transforming growth factor beta, Th1=T helper type 1, Th2=T helper type 2, TNF-α=tumor necrosis factor α, Treg=regulatory T cell, TRP2=tyrosinase-related protein 2, VACN=versican, WT1=Wilms tumor 1. antigens; (pre-) clinical assessments are ongoing (Additional EGFRvIII-free cells may be responsible for resistance to the [15] Table 1, http://links.lww.com/JR9/A43). drug. Mutations on critical arginine residues of IDH (R132H) are rarely found in healthy cells; however, these are enriched in gli- Single neoantigen vaccines omas, which produce the oncometabolite 2-hydroxyglutarate [16] and demonstrate genomic hypermethylation. In a first-in- Ideal neoantigens, which can either be distinct mutated pro- humans phase I trial (NCT02454634), peptide vaccines using teins or related nucleic elements, are expected to elicit suffi- mutated IDH demonstrated successful presentation by MHC II; cient tumor-specific immune responses. Cancer-specific mutant this induced mutation-specific T cell responses with interferon-γ antigens are the leading type of tumor vaccine material; they [17] production. The lysine (K) to methionine (M) mutation at are generally peptide(s) (usually 10–30 amino acids long) that [11] position 27 of histone H3 (H3.3K27M) is another characteris- are encoded by candidate neoantigen-encoding genes. The tic of gliomas and is harbored by approximately 70% of these detailed landscape of glioma-specific antigens has been expanded patients. H3.3K27M-targeted peptide vaccines show immuno- using sequencing technology and computational algorithms; the [18] genicity and good tolerance in patients with GBM. Patients antigens include epidermal growth factor receptor variant III with H3.3K27M-specific immunological CD8 T cell responses (EGFRvIII), IDH-1/2, interleukin-13 receptor (IL13R) α2, and [12] demonstrate prolonged overall survival (OS) compared with survivin. [19] non-responders. Mutations of the EGFR gene are distinctive of glioblastoma multiforme (GBM) and multiple tumors and are accompanied by aberrant activation of the EGFR cascade. EGFRvIII is the Mixed antigen vaccines most common variant of EGFR (deletion of exons 2–7) found in GBM, with 31% of GBMs overexpressing both wildtype Compared to single-neoantigen cancer vaccines, mixed antigen [13] (wt)-EGFR and EGFRvIII. Tumoral specificity and mem- peptide vaccines demonstrate greater antitumor efficacy. IMA950 brane localization of EGFRvIII makes it a practicable target is a novel GBM-specific therapeutic vaccine, which contains 11 for antibody-based drugs, such as depatuxizumab mafodotin tumor-associated peptides with high binding affinity for human [20] (Depatux-M) and AMG595. Rindopepimut (also known as leukocyte antigen (HLA). Injected IMA950 can be presented CDX-110), a vaccine consisting of an EGFRvIII-specific pep- on tumor surfaces, eliciting spontaneous T cell responses in a [21] tide conjugated to keyhole limpet hemocyanin, has shown majority of patients with GBM. In patients with astrocytoma, + + good tolerance and immunogenicity in patients with GBM. sustained CD8 and CD4 T cell responses have been found to [14] However, rindopepimut offers limited clinical benefit. Loss appear after vaccination with IMA950 and adjuvant polyinos- [22] of EGFRvIII expression is prevalent in patients who expe- inic-polycytidylic acid. Aborted loading of tumor epitopes rience recurrence following treatment with rindopepimut; to HLA receptors lead to unfavorable responses to exogenous 153 REVIEW ARTICLE Journal of Bio-X Research tumor-associated antigen (TAA) vaccines. This issue may be HLA-A*2402-restricted peptide, WYEGLDHAL (the peptide addressed by personalizing neoantigens; this may be achieved by sequence), enables positive CTL responses in patients with recur- [34] removal of identifiable tumor-associated peptides using endog- rent gliomas. In a phase I clinical trial, the injection of pep- [23] enous antigen-processors. In the notable glioma actively tide cocktail (Wilms tumor-1, human epidermal growth factor personalized vaccine consortium-101 trial (NCT02149225), receptor 2 [HER2], melanoma-associated antigen 3, and mela- vaccination strategies of mutated peptides derived from the noma-associated antigen 1 or gp100) pulsed-DCs contributed to GBM library (APVAC1) or personalized mutated neoepitopes a positive immunological response and long-term recurrence-free [35] (APVAC2) were assessed to be safe and functional, with sus- survival in GBM. In a subsequent phase II clinical trial, positive tained immunogenic T cell responses in patients treated with CTL responses were elicited in most patients, and were accom- [24] [36] APVAC1 or APVAC2 neoepitopes. In another phase Ib trial panied by prolonged survival. Certain pathogenic antigens (NCT02287428), neoantigens were predicted and designed by manifest particularly valuable immunogenic ability. The human comparing surgically resected tumors and matched normal cells. cytomegalovirus (HCMV) is a carcinogenic virus, which infects After vaccination with those personalized peptides, a subset of nearly half of the adult population; HCMV antigens or nucleic [25] T cells was induced within resected GBM tumors. In addition acids have been preferentially found in GBM cells rather than in to those protein antigens, particular antigen-encoding deoxyri- adjacent healthy tissue. Vaccination with DCs loaded with GBM [37] bonucleic acid (DNA) or ribonucleic acid were selectively taken lysate therefore elicits a HCMV-specific immune response. up by resident antigen processing cells (APCs) to allow efficient Compared to glioma-associated antigen-DC vaccina- [26] expansion and activation of antigen-specific T cells. In this tion, ATL-DC vaccination is more precise and well-tolerated. context, the intraperitoneally injected SOX6 DNA vaccine has Autologous glioma cells are irradiated to release tumor anti- successfully induced SOX6-specific cytotoxic T lymphocyte gens, which are fused with DCs in distinct ratios and condition- [27] (CTL) responses, effectively restricting tumor growth. ally cultured before administration. Integrating autologous DC vaccines with radio/chemo/immunotherapy can potentiate their [38] anti-tumor activity. DCVax-L (Northwest Biotherapeutics, Oncolytic virus-based vaccines Inc., Bethesda, MD) is one of the earliest ATL-DC vaccines used Oncolytic viruses represent a new class of immunotherapy for in glioma. Results from a phase 3 trial demonstrated the safety reviving tumor immunogenicity, which is dually accomplished and efficacy of adding DCVax-L to standard therapy; it also [28] [39] by specifically recognizing and infecting tumor cells. The extended survival duration to a certain extent. Combining viral contents effectively recruit immune cells, while tumor cells DCVax-L with a neoantigen-based peptide vaccine even pro- [40] are lysed during the release of viral progeny; massive TAAs are longed OS to 21 months in 1 patient with GBM. released to serve as “in situ vaccines,” attracting nearby or distal The function of DC vaccines may be hindered by distinct immune cells and inducing a systemic immune response. Human immune cell subsets and cytokines, such as IL-10, that lead herpes simplex virus (eg, HSV-1 C134, HSV-1 rQNestin34.5v.2, to ineffective T cell responses. In patients with glioma who HSV-1 G207, and HSV-1 M032), adenovirus (eg, DNX-2401, receive DC vaccines, elevated T regulatory (Treg) cell counts DNX-2440, and CRAd8-S-pk7-loaded neural stem cells), and and expression of negative co-stimulatory molecules are asso- [41] parvovirus (eg, ParvOryx) are the leading types of oncolytic ciated with poor prognosis. Decreased post/pre-vaccination viruses being engineered for virotherapy. Present evidence sug- Treg, to activated NK cell ratios are associated with prolonged [42] gests that their use is feasible and safe, with minimal dose-limit- survival. Administration of immune stimulators such as poly- [29,30] ing toxic effects or serious adverse events. inosinic-polycytidylic acid or tetanus toxoid enhances the effec- tiveness of DC vaccines, promotes tumor antigen presentation, [43] and significantly improves survival in patients with GBM. DC vaccines APC-mediated tumoral antigen processing and uptake is nec- Immune checkpoint blockade essary for initiation of T cell responses. This is implemented by abundant antigen processing and presenting molecules (eg, Once an MHC presented tumor antigen is recognized by TCRs MHC), co-stimulatory factors (eg, CD80, CD86, and CD40), (ie, the first signal), a second signal is launched on binding of T and adhesion molecules (eg, intercellular adhesion molecule 1 cell co-stimulatory receptors with corresponding ligands on and lymphocyte function-associated antigen 1). DCs normally APCs. CD28 represents the major co-stimulator in almost all serve as the most potent APC population in different can- solid tumors, playing a crucial role in regulation of T cell activa- [44] cers; however, the quantity or capacity of DC antigen uptake tion and sensitivity. Using the MYPPPY motif within its extra- [31] is impaired in glioma. This phenomenon is associated with cellular immunoglobulin (Ig)-V-like domain, CD28 can combine TMZ treatment, indicating the feasibility of DC vaccine use in with members of the B7 family, which are highly expressed on [32] patients with glioma receiving TMZ. Direct supplementation APCs; these include B7-1 (CD80) and B7-2 (CD86). Once CD28 of DC may address this dilemma through sensitization of anti- engages with CD80 and CD86, nearby membrane lipid rafts are gen-reacting T cells. rearranged to augment TCR signaling and cytokine production. In Notably, immature DCs need to be educated to recognize spe- addition to the co-stimulatory process, a set of co-inhibitory factors cific tumor antigens before injection. Both, general glioma-as- can competitively bind with similar homo-ligands to functionally [45] sociated antigen peptides and personalized autologous tumor exhaust T cells and impair tumoricidal ability. These co-inhibi- lysate (ATL) can be used to pulse DCs and recover their tumor- tory factors target different mediators of the exhaustion process, icidal activity. Similar to neoantigens, satisfactory antigens are such as programmed death 1 (PD-1/B7-H1/CD279), PD-L1 (B7- more glioma-specific and encode HLA-restricted T cell antigen H4/CD274), PD-L2 (B7-DC/CD273), CD276 (B7-H3), cytotoxic epitopes. Interleukin 13 receptor α2 (IL13Rα2) is a glioma-as- T-lymphocyte–associated antigen 4 (CTLA4 [CD152]), lympho- sociated antigen, which can offer better induction of specific and cyte-activation gene 3, T cell immunoglobulin and mucin-domain [33] tumor-reactive CTLs. DC pulsed with an IL13Rα2-derived containing-3 (HAVCR2/CD366), and T cell immunoglobulin and 154 Journal of Bio-X Research REVIEW ARTICLE immunoreceptor tyrosine-based inhibitory motif domain, among lymphocyte-activation gene 3. In a study, multitarget combined [46] others. therapy (eg, PD-1, CTLA-4, and B and T lymphocyte attenua- PD-1, in conjunction with its ligands (PD-L1 or PD-L2), are tor-monoclonal antibodies) synergistically increased the effec- the most well-known co-inhibitory couples in various tumors. tive cure rate in GBM; it also markedly improved systematic [61] PD-1 is commonly enriched in myeloid lineage cells such as immunologic memory and prevented recurrence. Notably, macrophages and dendritic cells, while PD-L1 is abundantly anti-antibody reactions to these animal-derived antibodies [47] found in glioma and microglial cells. After combining with and treatment-related adverse events are additional challenges PD-L1 or PD-L2, PD-1 is phosphorylated at the tyrosine-based encountered in ICI therapy. inhibitory motifs, providing docking sites for Src homology region 2 domain-containing phosphatase (SHP)-1 and SHP-2. Activation of SHP-1 and SHP-2 dephosphorylates the TCR– Augmentation of tumor-killing lymphocytes CD3ζ complex, blocking proximal CD28 co-stimulation and CAR-T cells [48] TCR signaling. PD-1 or PD-L1-targeted monoclonal antibod- ies have been previously used to counteract their immune-in- Dysfunction or loss of CD8 T cells is a universal phenomenon hibitory effect; some of these are already clinically approved in glioma, and is more common in the tumor core than the per- [62] by the United States Food and Drug Administration (FDA). itumoral zones. The major objective of current immunother- Nivolumab (Opdivo) and pembrolizumab (Keytruda) are the apy is to prime the response of tumor-killing lymphocytes; this most well investigated PD-1 antibodies. The safety and feasi- can be achieved by adoptive cell therapy (ACT). Two types of bility of nivolumab therapy has been demonstrated in patients cells are usually employed to reinforce defective CD8 T cells [49] with relapsed GBM (NCT02550249). Patients receiving neo- in ACT: tumor-specific CTLs and nonspecific NK cells. CAR-T adjuvant pembrolizumab (which is continued in the adjuvant therapy supplements CTLs by transfusion of autologous or setting) have also demonstrated significantly longer OS than xenogenous T cells loaded with specific TAA-recognition TCRs. [50] those receiving adjuvant PD-1 alone. As with other immuno- The fourth-generation of CAR-Ts are armed with co-stimula- therapy agents, response to anti-PD-1 inhibitors is highly asso- tory molecules and suicide genes, and are demonstrating good [63] ciated with basic immunological status and tumor conditions, safety and specificity in current clinical studies. [51] such as hyper tumor mutation burden. The essential steps of CAR-T preparation include the design CTLA-4 is another key co-inhibitor, which combines directly of single-chain variable fragments of cell-surface receptors and with CD3-ζ to inhibit tyrosine phosphorylation-mediated T cell loading of the coding sequence onto T cells for expression of activation. CTLA-4 can mediate trans-endocytosis and degrade engineered TAA-specific receptors. As described previously, CD80 and CD86 from opposing cells, irretrievably terminating TAAs can be classified into unique or shared tumor antigen [52] co-stimulation of CD28. Blocking CTLA-4 with specific anti- categories based on their varied distribution in normal or neo- [64] bodies therefore reactivates T cells and improves the anti-tumor plastic tissues. Similar to neoantigens, an ideal TAA selected [53] response. Previous literature has demonstrated that CTLA-4 for CAR-T construction must be detectable and tumor-spe- and PD-1 act separately and in an orderly manner to inhibit T cific. CAR-Ts targeting IL13Rα2 (NCT2208362), CD276 cell activation or drive T cell exhaustion; this is suggestive of (NCT04385173 and NCT04077866), HER2 (NCT03500991), the synergistic antitumor effect of combined anti-CTLA-4 and ephrin type-A receptor 2 (EphA2) (NCT03423992), and disia- [54] anti-PD-1 therapy. This was validated by the findings of the loganglioside 2 (NCT04196413), among others, are currently [65] CheckMate (name of the clinical trial series)-143 study, in which under evaluation in glioma. patients with recurrent GBM were administered nivolumab plus As mentioned previously, EGFRvIII amplification occurs in ipilimumab, the first humanized anti-CTLA-4 monoclonal anti- ~50% of patients with GBM; this makes it a promising target [55] body. CTLA-4 blockade also restricts disease progression and for CAR-T therapy. In the NCT02209376 study, patients with leads to acquisition of immune responses in patients with brain GBM demonstrated detectable transient expansion of CAR- metastases; the intracranial response is more prolonged with EGFRvIII T cells in their peripheral blood after being injected combined nivolumab and ipilimumab therapy than with either with CAR-EGFRvIII T cells; the T cells were successfully traf- [56] [66] agent alone. ficked across the BBB into active GBM sites. However, inevi- Although immune checkpoint inhibitors (ICIs) are widely table immune escape or exhaustion is also observed in internal used in other cancers, gliomas demonstrate higher tolerance, CAR-T cells. Trafficking of CART cells to regions of active which may be attributed to insufficient immune cell infiltra- GBM is rapidly followed by a decrease in antigen levels in dis- [57] tion. Expression of immune checkpoints and T-cell hypo-re- tinct areas; this leads to off-target effects and tumor relapse. In sponsiveness are prominently upregulated in glioma; this results patients who recur following IL13Rα2-redirected CAR-T ther- [58] in more severe immune exhaustion than in other malignancies. apy, the overall levels of IL13Rα2 in recurrent tumor tissues The dynamic process of T cell activity interference is mediated are lower compared to pre-therapeutic levels; this is especially by numerous immune checkpoint molecules, which render the observed adjacent to the injection site of CAR-T cells (as in the [67] exhaustion process reversible in early stages; however, it pro- NCT00730613 study). This issue has been partially addressed [59] gresses rapidly in later phases due to dysfunction. PD-1 pro- in a subsequent study by fusing a 4-1BB co-stimulatory domain motes cell proliferation and self-renewal in glioma stem cells to the EGFR-specific CAR, thereby avoiding tumor escape of - [68] without participation of PD-L1; therapeutic antibodies that EGFRvIII tumor cells. inhibit PD-1/PD-L1 interactions therefore fail to diminish the CD276, a homologue of PD-L1, is expressed in a wide range of [60] [69] growth advantage of PD-1 in tumor cells. The identification of malignancies including GBM and neuroblastoma. Increasing new immune checkpoint molecules may provide a solution. An evidence suggests that CD276 negatively regulates T cell acti- increasing number of immune checkpoint molecules are being vation and proliferation and effector cytokine production in explored and evaluated by ongoing clinical trials, such as those patients with glioma; CD276-redirected CAR-T cells there- [70] on T cell immunoglobulin and mucin-domain containing-3 and fore effectively control tumor growth. Pathogenic antigens 155 REVIEW ARTICLE Journal of Bio-X Research are also thought to compensate for immunosuppression and CAR-NK cells increase T cell responses based on their special immunogenicity. Although the anti-tumor ability of CAR-T cell therapy has been In a phase I clinical trial, the co-stimulatory effect of TAA and confirmed, several limitations persist; these include possible dis- latent viral antigens were measured using HER2-specific CAR- ease progression during preparation (which is time-consuming) modified virus-specific T cells. Autologous HER2-specific CAR- and off-target effects. CAR-NK based therapy is regarded as a modified virus-specific T cell infusions were found to be safe more secure alternative. CARs targeting tumor specific antigens [71] and offered clinical benefit in patients with progressive GBM. can be loaded onto NK cells to exert considerable antitumor In this context, treatment with HCMV-specific ACT has been activity. Notably, the anti-tumor cytotoxic function of NK cells found to trigger evident CMV-specific T cell immunity; it is safe is MHC-independent. NK-cells may therefore be derived from [72] and improves OS in GBM. healthy donors, reducing the likelihood of toxicities or cytokine Multi-target strategies have been adopted to overcome the [78] release syndrome. off-target effect. Bivalent CAR-T (HER-2 and IL13Rα2), tri- CAR-NK cells targeting HER2 are currently under evaluation valent CAR-T (HER-2, IL13Rα2, and EphA2), and bispecif- in patients with recurrent HER2-positive GBM (NCT03383978); ic-CAR-T (EGFR and EGFRvIII) significantly mitigate tumor [79] no dose-limiting toxicities have been reported to date. Several antigen escape and overcome antigenic heterogeneity in preclinical studies have also highlighted the antitumor activity GBM models. In this context, EGFR-directed bispecific T-cell of infused CAR-NK cells. In a study, intravenous infusion of engager technology is a dual-targeted platform engineered onto DAP12.CD3/CAR-NK EGFRvIII-directed YTS cells with CXCR4 receptor EGFRvIII-CAR T cells; it has been found to minimize immune overexpression inhibited tumor growth and prolonged survival – + [73] escape in EGFRvIII /wtEGFR tumors. In a trial, an innova- [80] in xenograft mouse models. Bispecific CAR-NK cells targeting tive synthetic Notch (synNotch) CAR circuit was designed to both wt- and mutated EGFR (dual-specific EGFR- and EGFRvIII- recognize EGFRvIII and sequentially produce CAR targets on directed CD28.CD3ζ.CAR-NK-92) have been constructed to other antigens, including EphA2 and IL13Rα2. The SynNotch- reduce antigen loss. The bispecific structure has been found to based CAR-T approach elicited thorough but controlled tumor outperform monospecific EGFRvIII-directed CAR-NK in terms [74] cell killing, and averted persistent immune exhaustion. [81] of survival prolongation and reduction of antigen escape. In recent years, the fifth generation of CAR-T, namely univer - sal CAR-T, is under investigation. Functional elements such as the interleukin-2 receptor, which allows Janus kinase/signal transducers Immunotherapy-based combination therapies and activators of transcription pathway activation in an antigen-de- Although immunotherapies have shown efficacy in almost all pendent manner, are loaded to optimize the antigen-specificity and solid tumors, current data suggest that they are only effective [75] scalability of CAR-T cells. Appropriate doses and techniques in specific biomarker-identified subgroups of patients. As suf- for CAR-T injection are under investigation for improving safety ficient immune infiltration is a prerequisite of immunotherapy and persistent activity issues. Engineered CAR-T cells are usually efficacy, combining immunotherapy with other immune-stimu- derived from autologous peripheral blood mononuclear cells to lating strategies may exert a synergistic effect (Additional Table protect patients from immune rejection. Lymphodepletion chemo- 2, http://links.lww.com/JR9/A44). therapy is initially used to eliminate competition from growth-pro- moting cytokines and remove immune suppressive cells (eg, Tregs Immunotherapy + standard therapy or myeloid suppressive cells). Patients are then infused with CAR-T 7 8 cells at doses of 1 × 10 to 10 cells per cycle by intravenous or intra- Data from studies are increasingly demonstrating the associa- cranial injection, to lower the risks of cytokine release syndrome or tion between anti-tumor therapy and immunogenic cell death. [76] organ toxicity, especially neurotoxicity. Intraventricular injection Radiotherapy and TMZ can affect immune cell infiltration in is an effective strategy for directing CAR-T cells into intracranial gliomas via three different mechanisms: increased expression of regions. Active CTLs cloned from CAR-T have been detected after adhesion molecules, chemokine secretion, and changes in vascular being administered directly into the resection cavity via an indwell- structure. However, in the CheckMate-498/NCT02617589 and [67] ing catheter. However, this technique may result in insufficient CheckMate-548/NCT02667587 studies, the addition of ICI to CAR-T cell counts in extracranial regions, thereby impairing the radiotherapy or TMZ did not provide superior efficacy compared [73] [82,83] ability to eradicate metastatic tumors. Intravenous injection is to radiotherapy plus TMZ treatment in patients with GBM. more convenient and is associated with a reduced risk of complica- These findings also underline the importance of predictive bio- tions, including increased intracranial pressure. Increasing evidence marker-based patient stratification prior to administration of suggests that intravenously injected T cells can also cross the BBB immunotherapy plus standard therapy. In this context, baseline and travel to the brain, addressing concerns regarding homing to tumor genomic or gut microbiotas such as Ruminococcus are glioma tissue. reported to be associated with OS and response to treatment. NK-T cells represent a distinct lymphocyte subset, in which In many patients with cancer, adjuvant therapy aids in the TCR and NK lineage markers are co-expressed. They may be elimination of residual cancer cells after standard treatment, classified into three types: type I (invariant NKT [iNKT]), effectively preventing metastasis and reducing recurrence risks. type II (nonclassical NKT), and NKT-like cells. In anti-tumor A number of clinical trials have demonstrated the clinical benefit immunity, iNKT cells express invariant Vα24-Jα18 TCRα of adjuvant (after surgery and radiotherapy) TMZ in patients [84] and Vβ11 TCRβ chains, which can be activated by recog- with glioma. In this context, an immune inhibitory environ- nition of CD1d presented antigens such as α-galactosylcer- ment can be formed after surgery, radiotherapy, or TMZ treat- amide. Treating GBM cells with retinoic acid upregulates ment, with an increase in immune-suppressive lymphocytes and [85] CD1d expression, assisting the induction of iNKT cell-me- genetic markers. Gliomas recurring after surgery show sig- [77] diated cytotoxicity. Nevertheless, the potential of NKT- nificantly increased levels of PD-1 and PD-L1 compared to pre- based immunotherapy remains unused due to limited clinical surgical lesions; this reflects the abundance of anti-PD-1/PD-L1 evidence. targets in unresectable gliomas. Adjuvant immune strategies, 156 Journal of Bio-X Research REVIEW ARTICLE such as adjuvant DC vaccines or CMV-specific T cells, are control is not achieved. Tolerance to bevacizumab partly results therefore expected to reduce the risks of operation-induced from vasotropic factors other than VEGF (including hepatocyte [72,86] micro-metastases and postoperative recurrence. growth factor and fibroblast growth factor, among others); these Neoadjuvant immunotherapy can also generate enhanced and factors reinitiate vascular formation when VEGF is blocked. The [87] sustained antitumor immune responses. The immunoenhanc- anti-angiogenic function of bevacizumab can be replenished by ing effect reduces tumor burden and reactivates systemic immu- plerixafor, a small molecular inhibitor of CXCR4. Treatment [49] nity, thereby improving survival over standard monotherapy. with plerixafor transiently decreases plasma levels of free VEGF In patients with glioma, neoadjuvant vaccination with GBM stem (unbound to bevacizumab) and proangiogenic markers (angiopo- [93] cell lysate upregulates the secretion of cytokines and chemokines, etin-2 and basic fibroblast growth factor). with an increase in both peripheral and glioma-infiltrated CD8 Hypoxia hijacks immune tolerance by directly suppressing [88] T cells. In this context, immune-related genes were found to immune effector cells or augmenting immune inhibitory cells; this [94] be upregulated while proliferative genes were downregulated issue cannot be effectively addressed by radiotherapy or TMZ. in glioma tissue from patients who received neoadjuvant PD-1. Based on these findings, the combination of anti-angiogenic ther - Neoadjuvant and continued adjuvant pembrolizumab therapy has apy and immunotherapy (especially ICIs) may be a valid ther- been found to significantly extend OS compared to adjuvant PD-1 apeutic option for enhancing cancer immunity. Treatment with blockade alone; this indicates synergetic benefit with neoadjuvant angiogenic agents remodels the immune system by altering popu- [50] [95] immunotherapy and surgery. However, before this becomes the lations of immune cells and multiple cytokines. VEGF-induced standard of care in patients with glioma, the schedule needs to be inhibitory checkpoints (eg, PD1 and T-cell immunoglobulin and optimized based on genetic subtypes and individual responses. mucin domain 3) on DCs or CD8 T cells are found to revert [96] once the VEGF-VEGFR interaction is blocked. Under antian- giogenic therapy, normalized tumor blood vessels demonstrate Immunotherapy A + immunotherapy B restored ability of drug penetration; drug uptake by tumor cells The immune suppressive microenvironment in glioma is col- is also improved, resolving the issue of effectiveness of chemother- lectively influenced by multiple factors or immune related pro- apy drugs. In the ReACT study (NCT01123291), patients received cesses, which are difficult to resolve using mono-immunotherapy bevacizumab with rindopepimut, an injectable peptide vaccine or therapies aimed at a single target. Combining different targeting EGFRvII; robust anti-EGFRvIII titers (≥1:12,800) were types of immunotherapeutic treatments may stimulate distinct achieved and survival was prolonged compared to that of rin- [97] immune compartments, thereby enhancing antitumor immunity dopepimut-naive patients. Tumor vascular normalization can and overcoming resistance. In a study presented at the American also improve tumor tissue perfusion and immune cell infiltration, Society of Clinical Oncology annual meeting, 2022, T cell-en- thereby enhancing the effectiveness of immunotherapy; activated abling therapy including INO (synthetic DNA plasmid)-5401 or reprogrammed immune cells can also normalize tumor blood (synthetic DNA plasmid encoding human telomerase reverse vessels. In a study, patients with high CD8 T-cell infiltration expe- transcriptase, WT-1, and prostate specific membrane antigen) rienced significant benefit from combination therapy with bevaci- [98] and INO-9012 (synthetic DNA plasmid encoding IL-12) was zumab and lomustine. In another study, triple blockade of VEGF, administered in combination with cemiplimab, an inhibitor of angiopoetin-2, and PD-1 significantly extended survival duration in PD-1, in patients with newly diagnosed GBM. INO-5401 pro- orthotopic GBM models compared with vascular targeting alone. moted infiltration of antigen-specific T cells in GBM, turning In the GBM microenvironment, triple therapy induced an increase “cold” microenvironments “hot,” thereby generating synergis- in CTL counts and decreased myeloid-derived suppressor cells and [89] [99] tic effects with cemiplimab. In another right-to-try program, Tregs; it also offered higher global vascular normalization. a tumor vaccine (SITOIGANAP) administered in combination However, results from other clinical trials are less satisfactory. with cyclophosphamide/granulocyte-macrophage colony-stim- In a study, patients who received bevacizumab plus PD1 blockade ulating factor/bevacizumab/nivolumab (or pembrolizumab) for glioma did not demonstrate a better prognosis compared to the offered significant benefit. The OS in these patients was twice bevacizumab-naive group; in addition, some patients discontinued [100] that of the average in patients with recurrent GBM; however, the study treatment due to adverse effects. As shown in the GliAvAx [90] toxicity was minimal compared to that with current therapy. clinical trial (NCT03291314), the combination of avelumab (anti- PD-L1 IgG1 antibody) plus axitinib (VEGFR 1-3 inhibitor) is well tolerated; however, no obvious synergistic efficacy was observed in Immunotherapy + antiangiogenic therapy [101] patients with GBM. The immunosuppressive character, toxic Hypoxia-associated neovascularization is the hallmark of almost side effects, and multiple patterns of angiogenesis considerably limit all solid tumors, and supplies oxygen and nutrition for fast-grow- the efficacy of combined approaches in GBM. ing and invasive tumor cells. Vascular endothelial growth factor (VEGF)-mediated vasculogenesis and angiogenesis are primarily Immunotherapy + TTFields responsible for tumor-vessel formation. The extreme hypoxic conditions found in glioma additionally stimulate other inter-re- In 2011, the FDA approved a device for the treatment of patients [3] lated patterns of neovascularization such as vascular mimicry and with GBM, namely, TTFields. It delivers intermediate frequency [91] GBM-endothelial cell transdifferentiation. Current anti-angio- (200 kHz in humans) and low intensity (1–3 V/cm) electric fields genic agents include antibodies or peptides that target potent to the human body through transducer arrays. Under alternating angiogenic factors (eg, bevacizumab, aflibercept, and thalido- electrical fields, the uniform electrical field within dividing cells is mide) and tyrosine kinase inhibitors (eg, axitinib and sorafenib). disrupted; this breaks the alignment of tubulin subunits and hin- Bevacizumab, a humanized monoclonal IgG1 VEGF antibody, ders normal microtubule spindle formation. These disruptive events [92] has been approved by the FDA for the treatment of GBM. preferentially occur in rapidly growing tumor cells than in normal [102] Although patients with glioma show superior responses with cells, and disintegrate their daughter cells. In addition to the bevacizumab than other anti-vascular therapy, durable tumor direct anti-mitotic effect, the anti-tumor effect of TTFields may be 157 REVIEW ARTICLE Journal of Bio-X Research Figure 3. Mechanism of anti-tumor activity and immune activation by TTFields. Through delivering intermediate frequency (200 kHz in humans) and low intensity (1–3 V/cm) electric field, TTFields disrupt proliferation of glioma cells directly. Meanwhile, cell debris is immunogenic to promote immune activity. The structure of the BBB can also be transiently broken to increase infiltration of immune cells. Created with BioRender.com. ATP=adenosine triphosphate, BBB=blood-brain barrier, GBM=glioblastoma multiforme, HMGB1=high mobility group box 1, IL-1β=interleukin 1 beta, IL-6=interleukin 6, MHC=major histocompatibility complex, NO=nitric oxide, ROS=reactive oxygen species, TNF-α=tumor necrosis factor α, TTFields=tumor treating fields. [112,113] mediated by diverse mechanisms. It may also transiently disrupt Chen et al showed that the use of TTFields could upregulate the structure of the BBB, increase membrane permeability in GBM expression levels of proinflammatory cytokines, thereby increasing [103,104] cells, and elevate cellular concentrations of anti-tumor drugs. the immune infiltration of activated DCs, macrophages, and T cells In the NCT00916409 study, the addition of TTFields significantly and turning the “cold” GBM “hot.” Changes in the quantity and improved progression free survival and OS compared to TMZ activity of CD8 T cells in the TTFields-stimulated tumors suggest a [105] or radiotherapy alone. TTFields-related toxicities and adverse significant shift from a pro-tumoral to anti-tumoral immune signa- events are milder than those of chemotherapy; this corresponded ture. This indicates that the integration of TTFields with ICIs may [106] with a better quality of life in the NCT00379470 study. Safety provide superior efficacy in patients with glioma. concerns have been adequately addressed based on a safety surveil- Limitations lance analysis among >11,000 patients with GBM who underwent [107] TTFields-based treatment. This review described immunotherapy in glioma and sum- TTFields-mediated cell death and immunogenic pyroptotic cell marized clinical advances. Different types of immunothera- death can activate robust innate immunity pathways, priming effec- pies have been tested against glioma, whereas current results tive responses to immunotherapy (Fig. 3). TTFields-treated can- are less satisfactory. Identifying new therapeutic targets and cer cells release more damage-associated molecule patterns such investigating combined therapeutic strategies are valuable for as high mobility group box protein 1 and adenosine triphosphate further exploration, which are also summarized in this review. and demonstrate calreticulin exposure; this promotes DC matura- However, there is still some limitation due to insufficient reports [108] tion and engulfment of tumor cells. In a study, positive T cell and incomplete retrieval of updating research. responses were observed in TTFields-treated tumor areas with + + abundant CD45 T cells; however, CD45 T cells had spread dis- Conclusions [109] cretely in tumors of controls. Notably, TTFields have the abil- ity to trigger an adaptive anticancer immune response targeting Growing evidence indicates the feasibility of immunotherapy in residual cancer cells. CTLs isolated from TTFields-treated tumors patients with glioma. Based on growing recognition of the spe- demonstrate increased production of interferon-γ and enhanced cial immune landscape of glioma, the dismal response rates to anti-tumoral T cell function; this supports the use of combined traditional therapy may be surpassed by multipronged immu- [110,111] TTFields and T-cell based immunotherapeutic approaches. notherapy and innovative immunotherapeutic strategies (Fig. 4). 158 Journal of Bio-X Research REVIEW ARTICLE Figure 4. Graphic summary of current therapeutic options in glioma. Since last century, different strategies were innovated including chemotherapy, radiother- apy, immune therapy and tumor treating fields. As illustrated, current immunotherapy in glioma are comprised of immune regulator, chimeric antigen receptor T/ NK cell, immune checkpoint inhibitor, oncolytic virus, and tumor vaccine. Created with BioRender.com. CIK-DC=cytokine-induced killer-dendritic cells, CTLA- 4=cytotoxic T lymphocyte-associated antigen 4, EGFRvIII=epidermal growth factor receptor variant III, EphA2=ephrin type-A receptor 2, GD2=disialoganglioside 2, HER2=human epidermal growth factor receptor 2, IFN-γ=interferon gamma, IL13Rα2=interleukin 13 receptor α2, PD-1=programmed cell death 1, TAA=tumor associated antigen, TNF-α=tumor necrosis factor α, VEGFα=vascular endothelial growth factor α. However, existence of BBB and inadequate immune cells result in Conflicts of interest unique immune-suppression in glioma and restricting infiltration The authors declare that there are no conflicts of interest. of immune cells. High heterogeneity and invasiveness of glioma Editor note: XB is an Editorial Board member of Journal of result in off-target of adoptive immune cells, which also con- Bio-X Research. He was blinded from reviewing or making deci- tributes to limited response to routine immune therapy. Further sions on the manuscript. The article was subject to the journal’s investigations regarding safe and effective targets and synthetic standard procedures, with peer review handled independently of methods are warranted for developing future immunotherapeutic this Editorial Board member and their research groups. strategies. References Acknowledgments [1] Ostrom QT, Bauchet L, Davis FG, et al. The epidemiology of glioma in None. adults: a “state of the science” review. Neuro Oncol 2014;16:896–913. [2] Louis DN, Perry A, Wesseling P, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 2021;23:1231–1251. Author contributions [3] Fisher JP, Adamson DC. Current FDA-approved therapies for high- YS, MW, YL, LC, XB, and CX participated in the writing of grade malignant gliomas. Biomedicines 2021;9:324. the article. XB and CX reviewed and modified the article. All [4] Ma DJ, Galanis E, Anderson SK, et al. 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Journal
Journal of Bio-X Research – Wolters Kluwer Health
Published: Dec 31, 2022