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| REVIEW |
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| Year : 2018 | Volume
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| Issue : 4 | Page : 125-131 |
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Engineered T Cells for glioblastoma therapy
Junjie Zhong, Jianhong Zhu
Department of Neurosurgery, Fudan University Huashan Hospital, National Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| Date of Web Publication | 30-Aug-2018 |
Correspondence Address:
Dr. Jianhong Zhu
Department of Neurosurgery, Fudan University Huashan Hospital, National Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, No.12 Urumqi Mid Road, Shanghai 200040
China
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/glioma.glioma_26_18
Engineered T cells therapy holds promise for glioblastoma (GBM) therapy. Genetic modification of T-lymphocytes, using T cell receptors, chimeric antigen receptors, and others, is an attractive antitumor strategy, especially in large solid tumors. Recently, several clinical trials have shown an impressive tumor regression in GBM patients, demonstrating the therapeutic potential of this approach. Still, major challenges, such as antigen specificity, tumor trafficking, hostile immunosuppressive microenvironment, proliferation and persistence of T cells and unexpected adverse effects, may hinder the clinical benefit of this approach. In the present review, we summarize recent developments of engineered T cells therapy against GBM, its challenges and future.
Keywords: Adoptive cell therapy, engineered T cells, glioblastoma, immunotherapy
How to cite this article:
Zhong J, Zhu J. Engineered T Cells for glioblastoma therapy. Glioma 2018;1:125-31 |
| Introduction | |  |
Glioblastoma (GBM) remains the most common and aggressive primary brain tumor.[1] Despite the combined therapeutic approach, including surgery, chemotherapy, and radiotherapy, the median overall survival of GBM patients is as low as 14.6 months, with the 5-year survival rate of <10%.[1],[2] This dismal prognosis coupled with limited therapeutic options underscores the urgent need for novel therapies.
With the development of medicine and basic science, number of innovative therapies are being developed utilizing cells from the immune system, which are modified with specific disease targets. This is particular widely used in cancer treatments. With the immune response obtained by utilizing or enhancing the function of specific immune cells, it is possible to achieve long-term cancer regression. Over the past decade, autologous or allogeneic immune cells, including natural killer cell, dendritic cell, and T cell, have been widely tested in preclinical and clinical studies.[3],[4],[5],[6] Engineered T cells therapy has emerged as a tremendous promising anticancer approach. The concept underpinning the new personalized and targeted therapy is based on the following three long-stand therapeutic strategies: antibodies, transplants, and vaccines. In the past decade, clinical trials using engineered T cells have been successfully tested in treating other malignancies, such as melanoma, sarcoma, lymphoma, and leukemia.[7],[8],[9],[10],[11],[12],[13] Recently, the FDA has approved two chimeric antigen receptor (CAR)-T commercial products for the treatment of acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), respectively.
However, the experience in treating solid malignancies remains limited. Currently, engineered T cell therapy is being extended to target solid tumors such as GBM.[14],[15],[16] While presenting as a potential therapeutic option, engineered T cells remains unclear by concerns about efficacy, safety, and off-target toxicity. Given to the increasing importance as a potential treatment for GBM patients, we conducted this review to highlight some of the latest and promising preclinical and clinical results using engineered T cells immunotherapy approaches.
| Brain and Glioblastoma Immune Status | | |
Historically, the brain has been seen as an immunologically privileged tissue,[17] due to several physiological characteristics of the central nervous system (CNS) such as separation through the blood-brain barrier (BBB), absence of professional antigen-presenting cells (APCs), low major histocompatibility complex (MHC) Class I and II expression, anti-inflammatory soluble modulators, and lack of obvious connections with the lymphatic system.[18],[19] However, substantial progress has also been made in understanding the immune function of the CNS system. Initial studies demonstrated that: (i) the presence of microglia and its interaction with APCs; (ii) peripheral immune cells can cross the intact BBB; and (iii) the transportation of T lymphocytes to the CNS through BBB after activation in the cervical lymph node.[20],[21],[22] Furthermore, multiple CNS disorders such as stroke, Alzheimer's disease, Parkinson's disease, and autism have also shown evidence that the CNS cannot be considered immunologically privileged. It is now clear that the CNS is an immunologically distinct site and not an immune-privileged site.[23],[24] Moreover, multiple factors are contributed to the mechanism of immunosuppression in GBM. Immune cells, including tumor-associated macrophages, microglia, and T cells, are recruited to the GBM microenvironment, but their immune-rejection activities are suppressed.[25],[26] Immune-suppressive cytokines, including interleukin (IL)-1, transforming growth factor β-1, prostaglandin E, and IL10 can inhibit immune response on GBM.[27],[28],[29],[30]
| History of Adoptive T Cell Therapy | | |
Historically, surgery, chemotherapy, and radiotherapy were the three pillars of cancer treatment. In recent years, immunotherapy has emerged as the fourth pillar. Adoptive T cell therapy is a personalized cancer therapy where autologous or allogeneic tumor-specific T cells are engineered to direct their antitumor ability against specific cancer cells and then transfused into the patient. Rosenberg et al.[31] pioneered tumor-infiltrating lymphocytes (TILs) which were isolated from resected tumors, cultivated, activated, and expanded ex vivo, and reinfused to treat melanoma patients. The promising clinical results supported the potential therapeutic use of TILs. Schuessler et al.[16] conducted a phase I clinical trial using autologous cytomegalovirus-specific T cell for the treatment of recurrent GBM patients, resulting in an encouraging median overall survival of 403 days. Despite the promising results, the widespread use of TILs was limited by its complicated manufacturing and the availability of tumor-specific lymphocytes. To overcome this limitation, gene modification, retroviral delivery, and other synthetic biology tools have been developed to enhance the efficacy and specificity of adoptive T cell therapy. Engineered T cells with T cell receptor (TCR), CARs, and other receptors have produced unprecedented preclinical and clinical results.
| T Cell Receptor Gene Therapy | | |
As an alternative to TILs, engineering T cells to express a tumor-specific αβ chains TCR can mediate antitumor immunity. Based on this concept, Morgan et al.[32] conducted the first clinical trial using TCR targeting MART-1 in metastatic melanoma patients, with promising results. Lately, various clinical trials involving TCRs have vastly expanded the range of cancers being targeted, including metastatic colorectal cancer,[33] multiple myeloma,[13] synovial cell sarcoma,[34] and others. Despite the clinical benefits, there remain significant limitations in TCR gene therapy. For example, the induced α and β chains can miss pair with the endogenous β and α chains, respectively. Such mispairing can possibly cause inefficacy,[35] lead autoreactivity in TCR-transduced human T cells in vitro[36] and mediate lethal graft versus host disease, which was proved in mice administered with TCR-transduced T cells following a protocol simulating human clinical trials.[37] Moreover, the affinity of TCR to target cells is also critical for exerting antitumor effects, which is determined by several contributing factors including the number of TCRs on the surface, the density of homologous antigens on the target cells and the presence of co-receptors such as CD4 or CD8.[38] While TCRs can target a wide range of tumor antigens, primarily, it is limited to human leukocyte antigen (HLA), meaning the target cells must share an HLA allele.[39] Overall, TCR-transduced T cells provide the ability to target a variety of self and non-self targets through the normal biology of T cells. To date, TCR therapy has demonstrated a successful clinical response in several cancers;[13],[32],[33],[34],[40],[41] however, no clinical trial has been performed for GBM.
| Chimeric Antigen Receptor T Cell Therapy | | |
In contrast to TCRs, CARs provide a more universal approach to target tumor antigens that are expressed on the membrane of tumor cells, without the need for HLA formation. This is particularly important for GBM treatment due to the frequent down-regulation of MHC Class I in GBM tumor cells.[42]
In general, a CAR is composed of an extracellular single chain variable fragment (scFv) derived from a specific tumor-targeted monoclonal antibody, joined to a molecular hinge peptide, and a transmembrane domain, which is further linked to one or more intracellular costimulatory domains. According to different combination strategy of costimulatory domains, the current CARs can be grouped into four generations. The first-generation CARs lacks costimulatory domain, resulting in a limited clinical response. The second-generation CARs are composed of a single costimulatory domain while the third-generation CARs are combined with two signaling domains. These costimulatory domains such as CD28, 4-1BB, and OX40 can efficiently sustain proliferation, survival, and persistence of infused engineered T cells.[43],[44],[45],[46] The fourth-generation CARs, also known as “TRUCKs,” are additionally modified with a constitutive or inducible expression cassette for a transgenic protein, such as cytokines released by CAR-T cells to modulate T cell responses.[47]
CAR-T cell therapy has shown tremendous promising antitumor effects against a variety of cancers and FDA has approved two commercial CAR-T products.[8],[48],[49],[50],[51] In the context of GBM, CAR-T cell therapy is also being studied and has yielded promising results. Sampson et al.[15] demonstrated that CAR-T cell targeting EGFRvIII (epidermal growth factor receptor variant III), the expression of which is found in approximately 30% of cases of GBMs, can significantly prolong survival in glioma-bearing mice. Recently, Morgan et al.[52] at NCI successfully engineered EGFRvIII-targeted CAR-T cells, using T cells obtained from GBM patients, and validated it against glioma stem cell lines, in vitro. And more recently, Duke University and Beijing Sanbo Brain Hospital have conducted EGFRvIII-targeted CAR-T Clinical Trial for GBM, the results of which are pending in ClinicalTrials.gov [Table 1]. IL13Rα2 is highly expressed in GBMs, in about 44%–100% cases, while the same is low or even absent in normal tissues.[54] Brown et al.[55] reported positive results in the first-in-human clinical trial using IL13Rα2-targeted CAR-T cells on three patients with recurrent or refractory GBM. Engineered T cells targeting IL13Rα2, which is overexpressed in greater than one-half of the GBMs, were directly infused into the resected tumor cavity. More recently, a single patient trial showed successful clinical response by infusion of IL13Rα2-targeted CAR-T into the resected tumor cavity followed by infusion into ventricular system.[14] The current ongoing CAR-T clinical trials targeting GBM are summarized in [Table 1]. These studies are critically important to define the safety and efficacy of CAR-T cell therapy for GBM. | Table 1: Current epidermal growth factor receptor variant III-targeted chimeric antigen receptor-T clinical trials for glioblastoma
Click here to view |
| Other Receptors | | |
While engineered TCRs and CARs have been well studied, other ongoing modified receptor types for engineered T cells are also showing encouraging advantages and clinical potential. Other strategies include inhibitory CARs, in which the surface antigen recognition domain is modified with PD-1 or CTLA-4 as an acute inhibitory signaling domain to limit T cell responsiveness despite concurrent engagement of an activating receptor.[56] This switch-receptor provide a dynamic, self-regulating safety switch to prevent the consequences of T cell specificity rather than to treat. Other studies also reported the switch receptor strategy, by introducing a truncated extracellular domain of PD-1 and the transmembrane and cytoplasmic costimulatory signaling domains of CD28 into CAR-T cells.[57] Instead of improving the safety, this switch-receptors offered a potential way to enhance the antitumor effect by delivering second-generation CAR-T cells with more potent third-generation activation turned on specifically within the immunosuppressive tumor microenvironment.[57] More recently, Cho et al.[58] developed a split, universal, and programmable (SUPRA) CAR system which is composed of a zip-CAR containing a leucine zipper as the extracellular portion of the CAR, and a zip-Fv fused to a cognate leucine zipper that can bind to the leucine zipper on the zipCAR. The SUPRA CAR system can switch to respond to multiple antigens, prevent relapse, reduce over-activation, and enhance specificity. This preclinical study provided a novel strategy that multiple advanced logic and control functions can be implemented in a single integrated system.[58] Still, there is an urgent demand to find more novel, specific and effective antigens, and more intelligent combining CAR system for engineered T cell therapy.
| Challenges in Engineered T Cell | | |
Recent engineered T cell clinical trials toward other malignancy have revealed promising results; however, there also remain major challenges towards their safety and efficacy. Thus, efforts have been made to improve the function of engineered T cells which involves multiple challenges, including antigen specificity, tumor trafficking, hostile immunosuppressive microenvironment, proliferation and persistence of T cells, and unexpected adverse effects.
Antigen specificity and glioma cancer stem cells
To perform an effective and targeted immune response, engineered T cells must be able to recognize and target-specific antigens presented in the context of MHC proteins on the tumor. The tumor heterogeneity increases the complex of antigen selection. Hence, selecting suitable tumor-targeted antigens can be challenging. The ideal antigen is widely expressed in tumor while completely absent in normal tissue. However, most tumor-targeted antigens are expressed both in tumor and some normal tissue. Consequently, the expression on normal tissue may inherently induce the on-target, off-tumor adverse effect. Cancer-testis antigens are potentially safer candidate antigens for engineered T cells therapy due to their high expression in a wide range of malignancies and limited expression in normal tissues other than testis. To date, most tumor-targeted antigen relies on overexpression in tumor and are relatively nonspecific, including HER2, IL13Rα2, and GD2.
However, the wider application is limited by the availability of cell surface tumor-associated antigens specific for the tumor, while sparing normal cells. Intracellular antigens have a diverse array that acts as disease-driven factors, such as oncogene products or are expressed only in tumor cells or in very specific tissues.[59] Recent clinical trials explored the potential of posttransfer vaccination to enhance the clinical efficacy of adoptively transferred T cells expressing TCR specific for an intracellular tumor antigen in the context of MHC Class I.[60],[61],[62] However, the posttransfer vaccine is hardly applicable for current CAR-T therapy due to the inability to recognize peptide antigen in the context of MHC. Grada et al.[63] used tandem CARs, which contain extracellular domains with two scFvs, to increase the specificity of effector cells and to offset antigen escape.
Accumulating evidence have suggested that the cancer stem cells (CSCs) are responsible for the relapse by virtue of their greater resistance to therapy compared with that of their progeny in glioma.[64] The CSCs display many characteristics of normal stem cells, such as the potential for sustained self-renewal.[65],[66] Due to their resistance to conventional therapies, it has been hypothesized that immunotherapies targeting CSCs may eliminate this therapeutically resistant CSC population. Recent studies have shown promising results in eradicating the CSCs by engineered T cells in preclinical models and clinical trials.[52],[67],[68],[69]
Immune cells trafficking
Once engineered T cells were generated and infused to the patient, they must traffic and infiltrate to the tumor site and efficiently exert antitumor effects. Comparing to blood cancer, it is likely a major problem in solid tumors such as GBM. GBM is thought to be more difficult to physically penetrate because of BBB. Therefore, better strategies are needed to promote T cell trafficking into GBM tumors and enhance the antitumor effect of engineered cells. In general, CAR-T cells can be delivered to the brain by both intravenous and intracranial routes. Brown et al.[14] infused CAR-T cells to a GBM patient through two intracranial routes: the resected tumor cavity and the ventricular system. Both routes had similar low toxicity, with the ventricular system route showing stronger ability to eliminate distal tumor growth. These results indicate that the routes of infusion play an important role in antitumor effects. One potential approach is to take advantage of chemokine and chemokine receptors, which are critical in regulating immune cells trafficking and positioning.[70] Thus, CAR-T cells may be modified to express chemokine receptors to enhance trafficking to tumor sites and homing to tumor cells. Previous studies have shown that co-expression of chemokine receptors with CAR T cells improve tumor trafficking and immune response either targeting GD2 or HER2, in mice models.[71]
Hostile immunosuppressive microenvironment
The hostile tumor microenvironment can also directly inhibit potential antitumor immune responses. The presence of a tumor is defined as a result of some degree of evasion or inhibition of endogenous immune control. Multiple mechanisms are involved to evade immune response, including impairment of immune cell signaling, nutrient starvation, abnormal antigen presentation, and release of soluble cytokines.[72],[73],[74] Importantly, as with the endogenous immune system, adoptive engineered T cells are also susceptible to the tumor-mediated destruction of the immune system.[75] The refractory of tumors may be attributed to immune escape or hostile immunosuppressive microenvironment that can limit the efficiency and potency of engineered T cells. In addition, chronic T cells activation induces up-regulation of inhibitory ligands on activated T cells, possibly contributing to T cell exhaustion.[76]
To overcome these obstacles, numerous approaches are under investigation. One approach is to use alternative homeostatic cytokines, which are critical regulators of immunity and possess both overlapping and distinctive functions. A recent preclinical study has demonstrated that activating cytokines such as IL-2, IL-12, and IL-15 mitigated the effect of immunosuppressive factors in the tumor microenvironment and showed remarkable enhancement of CAR-T efficacy.[77] Under in vitro assessments, these cytokines maintained T cell accumulation in response to repeated antigen stimulation but did not promote long-term T cell persistence in vivo. Although there is extensive work done on the tumor microenvironment, to date, the relation with the function of engineered T cells and the immunosuppressive nature of endogenous cells have not been studied well.
Monitoring proliferation and persistence of T cells
Through preclinical and clinical results, Dudley et al.[78] first reported that the persistence and antitumor activity of transferred T cells in vivo was greatly increased with nonmyeloablative lymphodepleting treatment before transfer. However, several clinical trials noted the failure of engineered T cell therapy.[79],[80],[81] One potential reason is the reduction of functional T cells due to immune recognition of exogenous peptides and subsequent immune-mediated destruction of modified T cells.
Once engineered T cells were adoptive transferred to the tumor site, monitoring their biological activity and mechanism of action is essential to understand the molecular basis of both success and failure of the treatment. In addition, a critical goal is to maintain the long-term antitumor effect of infused CAR-T cells. One of many approaches is to focus on the selection of specific T cell subsets to optimize antitumor efficacy. In a recent study, Christine et al.[82] reported the antitumor differences between CD4+ and CD8+ CAR-T cells in GBM models, demonstrating that CD4+ group outperformed CD8+ CAR-T cells, specifically with respect to long-term antitumor response.
Emerging platforms and strategies to interrogate and modulate the activity of engineered T cells are extensively discussed in the previous review.[83] New technologies for high-throughput and multiplex analysis, including TCR sequencing to track clonal T cell populations, gene expression platforms, mass cytometry methodologies for comprehensive multichannel phenotyping and multiplexing microbead immunoassay to simultaneously detect cytokines, are being developed. As these platforms and strategies become standardized in engineered T cell therapy, the monitoring information will help to drive the field forward.
Adverse effects
Early TCRs and CARs clinical trials have revealed encouraging efficacy, however, also showed adverse events. In general, adverse effects associated with engineered T cells therapy can be broadly categorized as autoimmune toxicity and cytokine-associated toxicity.[84] Autoimmune toxicity, also known as on target, off-tumor toxicity, results from targeting specific antigens that are expressed not only in tumors but also in normal tissues. The on target, off-tumor toxicity is a major challenge in treating solid tumors because the target antigen may be not tumor specific. This may lead to the destruction of normal cells expressing the target antigen and substantially limiting the clinical application. One approach to prevent these toxicities is a suicide switch, modified into the vectors in engineered T cells, providing an additional safety net when infused T cells cause unexpected toxicities. In recent years, a number of suicide switches have been developed, and caspase switches have been shown to efficiently eliminate T cells in patients.[85],[86]
The most common and severe adverse effect is cytokine-associated toxicity, also known as cytokine release syndrome (CRS), a nonantigen-specific condition that occurs as a result of high-level immune activation and manifests as a constellation of clinical features, including fever, rash, nausea, vomiting, tachypnea, hypotension, azotemia, and headache.[84] CRS usually occurs within days of T cell infusion and at the peak of CAR-T cell expansion. According to previous clinical trials in patients with ALL, CRS is most common and severe in patients with high tumor burden.[49],[87],[88] Consequently, CRS toxicity and its medical management costs, hamper the broad use of CAR-T cell therapy. Recently, Giavridis et al.[89] revealed that the severity of CRS is not mediated by CAR-T cell derived cytokines, but by IL-6, IL-1, and nitric oxide produced by recipient macrophages. These findings suggest that CAR-T cells may be designed to mitigate these burdens without requiring exogenous intervention.[89]
Overall, both autoimmune toxicity and CRS are serious and life-threatening side effects. Monitoring and identifying these potentially life-threatening side effects is critical for the broad clinical acceptance in future.
| Future Prospects and Conclusions | | |
GBM is the most common malignant primary brain tumor in adults. Engineered T cells therapy for solid tumors including GBM is under rapid growth, both at bench and bedside. However, no engineered T cells therapy for GBM has reached FDA approval, reflecting its infancy. Although earlier trials of engineered T cells for GBM have not shown the same success as seen in the ALL and NHL, a better understanding of multiple hurdles found in GBM will advance the design of engineered T cell therapy and clinical trials.
We look forward to the availability of varies of genetically modified tools to overcome current challenges and improve the safety and efficacy of this promising approach. With the sheer extent of preclinical and clinical trials, we hope that the engineered T cells therapy may provide formidable opportunities for future GBM treatment.
Financial support and sponsorship
This work was supported by grants (2018YFA0107900, 31771491, 2013CB967400 and 2017YFC0110304) from the National Nature Science Foundation and Ministry of Science and Technology of China.
Conflicts of interest
There are no conflicts of interest.
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