Immunotherapy is a potential new therapeutic option in patients with high-grade gliomas (HGGs). Phase I/II trials have assessed the efficacy of increasing immune activity using vaccines made from lymphokine-activated killer cells, cytotoxic T cells, autologous tumor cells, or dendritic cells. Studies to decrease tumor immunoresistance have focused on cytokine modulation of known immunosuppressive factors in the tumor microenvironment. Several early studies have reported a survival benefit using different forms of immunotherapy. This article discusses past clinical trials using immunotherapy in HGGs, their efficacy, limits, and biologic and clinical design challenges that must be overcome to advance immunotherapy for patients with HGGs.
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Current strategies for immunotherapy against high-grade glioma include adoptive immunotherapy, active immunotherapy, and immunomodulation.
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Early clinical trials suggest that immunotherapy is safe and beneficial in a subset of patients.
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Major biologic challenges that must be overcome for immunotherapy to succeed include immune-editing, decreased antigen presentation by glioma cells, and decreased immune cell activation.
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The difficulty in predicting the success of immunotherapy trials as well as comparing the results across studies is the heterogeneous nature of immunotherapy trial design and reporting.
Introduction
High-grade gliomas (HGGs, World Health Organization [WHO] grade III and IV) make up most primary brain tumor diagnoses, with an incidence currently estimated at 14,000 new diagnoses per year. These tumors are associated with high morbidity and mortality and a median survival of 2 to 5 years for patients with anaplastic astrocytomas (WHO grade III) and 14.6 months for patients with glioblastoma multiforme (GBM, WHO grade IV).
The current standard of care for patients with HGGs is summarized in Table 1 , and includes maximal surgical resection followed by adjuvant chemotherapy and radiation therapy. In patients with anaplastic astrocytoma, a clear standard of care is lacking. The current treatment strategy typically includes maximal surgical resection in combination with adjuvant radiation with or without temozolomide (TMZ). Advances in imaging, neuronavigation, and fluoroscopic guidance have improved safety, decreased deficits associated with surgery, and allowed for more complete tumor resection, with more accurate surgical margins. Furthermore, medical treatment is often required to treat tumor-associated signs and symptoms, including seizures, edema, fatigue, and cognitive dysfunction. These treatments carry their own set of side effects, which must be managed alongside side effects from radiation and chemotherapy.
| Tumor | Treatment Paradigm |
|---|---|
| Anaplastic astrocytoma (WHO grade III) | Maximal surgical resection with the option of adjuvant radiation, TMZ, or combination radiation and TMZ |
| GBM (WHO grade IV) | Maximal surgical resection with adjuvant radiation therapy and TMZ or Gliadel (Eisai Inc, NC, USA) (implanted carmustine wafers) |
| Recurrent primary brain tumor | Resection of recurrent lesion, with adjuvant Gliadel placement, chemotherapy, or experimental treatments |
Despite advances in surgical and medical management of HGGs, there is no current treatment that specifically targets tumor cells and spares normal brain parenchyma. Recently, immunotherapy has emerged as a promising treatment strategy against intracranial tumors. Although the brain has historically been considered immune-privileged, more recent evidence suggests that the immune system is capable of effecting vigorous responses in the central nervous system (CNS). Microglia are considered the first line of defense in the brain and possess the ability to phagocytose foreign cellular material and synthesize proinflammatory cytokines and chemokines. Several groups have shown that lymphocytes and antigen-presenting cells (APCs), including macrophages and dendritic cells (DCs), are able to cross the blood-brain barrier and migrate to tumor within the brain parenchyma. However, despite the ability of immune cells to traffic into intracranial lesions, the cells are generally unable to eradicate the primary tumor, in part because of the presence of an immunosuppressive tumor milieu. The release of immunosuppressive cytokines into the tumor microenvironment, activation of immune checkpoints, and an enriched population of CD4+CD25+FoxP3+ T regulatory (T reg ) cells and T H 17 cells are implicated in preventing an aggressive antitumor immune response.
Despite these challenges, immunotherapy has the potential to be advantageous over other chemotherapeutic strategies because of the potential for cellular level specificity and long-term surveillance. The potential of immunotherapy against cancers has recently been highlighted with the approval by the US Food and Drug Administration (FDA) of sipuleucel-T for treatment of castration-resistant prostate cancer and ipilimumab for unresectable or metastatic melanoma. There is no FDA-approved immunotherapy for HGGs, but the clinical evidence, as described later, suggests that immunotherapy may be a useful strategy to combat HGGs. This article reviews several strategies, including adoptive immunotherapy, active immunotherapy, and immunomodulation, that have been tested or are currently being tested in clinical trials as of August, 2011.
Adoptive immunotherapy
Adoptive immunotherapy is a strategy in which immune cells are taken from the patient and activated ex vivo against tumor-specific antigens. The activated lymphocytes are then reintroduced into the patient, either directly into the tumor cavity or systemically.
Lymphokine-Activated Killer Cells
Lymphokine-activated killer (LAK) cells are peripheral lymphocytes that are cultured with interleukin 2 (IL-2) ex vivo. Once reintroduced, these cells possess cytotoxic abilities, but require activation against tumor cell antigens by host APCs. LAK cells have been studied in clinical trials and have been shown to be associated with varying levels of toxicity and antitumor activity. In a study by Hayes and colleagues, LAK cells were delivered via Ommaya reservoir 5 times every 2 weeks for 6 weeks, resulting in a median survival of 12.2 months compared with a median survival of 6.2 months in contemporary patients with recurrent GBM who were treated with surgery and chemotherapy. A similar trial in recurrent GBM showed a median survival of 9 months and a 1-year survival of 34%. The most recent clinical trial in primary GBM, reported by Dillman and colleagues, showed that introducing LAK cells into the tumor cavity in which patients who had undergone standard of care (radiation and TMZ) was safe and resulted in a median survival of 20.5 months with a 1-year survival rate of 75%. The use of corticosteroids was associated with lower total LAK count and worse survival. These trials are summarized in Table 2 .
| Reference | Number of Patients | Trial Results |
|---|---|---|
| 6 | No PR or SD No toxicity | |
| 9 | 1 CR, 2 PR Median survival: 53 wk | |
| 9 | Neurologic side effects in all patients 1 PR | |
| 20 | Median survival: 63 wk (36–201) Use of steroids did not influence in vitro generation of LAK or autologous stimulated lymphocytes | |
| 19 | 4 PR Median survival after therapy: 30 wk | |
| 5 | No survival benefit | |
| 9 | 1 CR, 2 PR, 4 stable disease Median survival: 18 mo | |
| 19 | 1 CR, 2 PR Median survival after therapy: 53 wk | |
| 9 | 2 PR Median survival: 78 wk | |
| 28 | 1 CR, 2 PR (GBM) Median survival: 53 wk (GBM) | |
| 40 | Median survival: 17.5 mo | |
| 33 | Median survival: 20.5 mo |
Cytotoxic T Cells
Other methods of adoptive immunotherapy for HGGs include infusion of cytotoxic T lymphocytes (CTL) that are isolated from a patient’s own tissues, including peripheral blood mononuclear cells (PBMC), tumor-infiltrating T lymphocytes (TILs), draining lymph nodes, or PBMCs after vaccination with irradiated autologous tumor cells (ATCs).
Five studies were completed using CTLs isolated from PBMCs and TILs. Results from these 5 phase I/pilot studies showed that this strategy was safe and associated with only minor toxicities, including isolated side effects of hemorrhage and fever, and transient cerebral edema in patients receiving TILs. In each of these studies, the CTLs that were activated ex vivo were injected directly to the tumor cavity.
Five other clinical trials studied the use of CTLs from draining lymph nodes or PBMCs after injection of ATCs. In these trials, all CTLs were injected intravenously. Similar to those studies that injected CTLs intracerebrally, the results from these studies showed acceptable safety with minimal toxicity. Isolated toxicities included delayed-type hypersensitivity (DTH) to the vaccine and fever and myalgias lasting 24 hours.
The clinical benefits of these studies have been generally promising. These trials are summarized in Table 3 . Despite each being only a phase I or pilot study with primary outcomes of safety and toxicity, all but one of these trials reported partial responses or stable disease. Despite this finding, Holladay and colleagues reported a time to recurrence of approximately 8 months, with 1 patient experiencing recurrence of GBM after more than 40 weeks and 7 patients experiencing recurrence after 8 or more months.
| Reference | Number of Patients | Trial Results |
|---|---|---|
| 5 | 2 PR 1 patient’s survival reported at 104 wk | |
| 4 | 3 PR | |
| 10 | 1 CR, 4 PR Median survival: 5 mo | |
| 5 | 3 SD | |
| 15 | No PR Time to recurrence >8 mo (n = 7) | |
| 10 | 3 PR, 1 SD Survival >1 y (n = 4) | |
| 10 | 3 PR | |
| 9 | 3 PR Survival >4 y (n = 2) | |
| 19 | 1 CR, 7 PR Median survival: 12 mo | |
| 6 | 1 CR, 2 PR |
In the 10 trials using LAK cells or CTLs, 2 variables consistently reported as significant were the total number of cells infused and the use of corticosteroids during treatment. In these trials, the number of CTLs injected ranged between 3 × 10 7 and 10 × 10 10 , with between 1 and 13 injections. Because the total number of CTLs as well as the method of delivery differed between studies, Kronik and colleagues sought to define the optimum dose using a mathematical model that incorporated data from in vitro and in vivo studies, interactions with CTLs and major histocompatibility complex (MHC) receptors, and the effect of transforming growth factor β (TGF-β) and interferon γ (IFN-γ) on the antitumor immune response. These investigators reported the optimum calculated dose of CTLs as 27 × 10 9 total CTLs. As a result, they concluded that many immunotherapy trials may not have been successful because the dose given to patients was often inadequate (sometimes 20-fold smaller than that predicted to be effective).
The use of corticosteroids to control peritumoral edema was another factor that varied between studies using LAKs or CTLs. Because of their immunosuppressive effect, corticosteroids were not used in 4 studies, suggesting that patients in these trials may have had a smaller tumor and potentially better outcomes compared with those patients who required steroid treatment. Evidence for better survival when using LAK cells without the use of corticosteroids was reported by Dillman and colleagues in their subset analyses. Other results point to the contrary, that corticosteroids did not have an effect on the number or functional activity of the infused effector cells.
Adoptive immunotherapy
Adoptive immunotherapy is a strategy in which immune cells are taken from the patient and activated ex vivo against tumor-specific antigens. The activated lymphocytes are then reintroduced into the patient, either directly into the tumor cavity or systemically.
Lymphokine-Activated Killer Cells
Lymphokine-activated killer (LAK) cells are peripheral lymphocytes that are cultured with interleukin 2 (IL-2) ex vivo. Once reintroduced, these cells possess cytotoxic abilities, but require activation against tumor cell antigens by host APCs. LAK cells have been studied in clinical trials and have been shown to be associated with varying levels of toxicity and antitumor activity. In a study by Hayes and colleagues, LAK cells were delivered via Ommaya reservoir 5 times every 2 weeks for 6 weeks, resulting in a median survival of 12.2 months compared with a median survival of 6.2 months in contemporary patients with recurrent GBM who were treated with surgery and chemotherapy. A similar trial in recurrent GBM showed a median survival of 9 months and a 1-year survival of 34%. The most recent clinical trial in primary GBM, reported by Dillman and colleagues, showed that introducing LAK cells into the tumor cavity in which patients who had undergone standard of care (radiation and TMZ) was safe and resulted in a median survival of 20.5 months with a 1-year survival rate of 75%. The use of corticosteroids was associated with lower total LAK count and worse survival. These trials are summarized in Table 2 .
| Reference | Number of Patients | Trial Results |
|---|---|---|
| 6 | No PR or SD No toxicity | |
| 9 | 1 CR, 2 PR Median survival: 53 wk | |
| 9 | Neurologic side effects in all patients 1 PR | |
| 20 | Median survival: 63 wk (36–201) Use of steroids did not influence in vitro generation of LAK or autologous stimulated lymphocytes | |
| 19 | 4 PR Median survival after therapy: 30 wk | |
| 5 | No survival benefit | |
| 9 | 1 CR, 2 PR, 4 stable disease Median survival: 18 mo | |
| 19 | 1 CR, 2 PR Median survival after therapy: 53 wk | |
| 9 | 2 PR Median survival: 78 wk | |
| 28 | 1 CR, 2 PR (GBM) Median survival: 53 wk (GBM) | |
| 40 | Median survival: 17.5 mo | |
| 33 | Median survival: 20.5 mo |
Cytotoxic T Cells
Other methods of adoptive immunotherapy for HGGs include infusion of cytotoxic T lymphocytes (CTL) that are isolated from a patient’s own tissues, including peripheral blood mononuclear cells (PBMC), tumor-infiltrating T lymphocytes (TILs), draining lymph nodes, or PBMCs after vaccination with irradiated autologous tumor cells (ATCs).
Five studies were completed using CTLs isolated from PBMCs and TILs. Results from these 5 phase I/pilot studies showed that this strategy was safe and associated with only minor toxicities, including isolated side effects of hemorrhage and fever, and transient cerebral edema in patients receiving TILs. In each of these studies, the CTLs that were activated ex vivo were injected directly to the tumor cavity.
Five other clinical trials studied the use of CTLs from draining lymph nodes or PBMCs after injection of ATCs. In these trials, all CTLs were injected intravenously. Similar to those studies that injected CTLs intracerebrally, the results from these studies showed acceptable safety with minimal toxicity. Isolated toxicities included delayed-type hypersensitivity (DTH) to the vaccine and fever and myalgias lasting 24 hours.
The clinical benefits of these studies have been generally promising. These trials are summarized in Table 3 . Despite each being only a phase I or pilot study with primary outcomes of safety and toxicity, all but one of these trials reported partial responses or stable disease. Despite this finding, Holladay and colleagues reported a time to recurrence of approximately 8 months, with 1 patient experiencing recurrence of GBM after more than 40 weeks and 7 patients experiencing recurrence after 8 or more months.
| Reference | Number of Patients | Trial Results |
|---|---|---|
| 5 | 2 PR 1 patient’s survival reported at 104 wk | |
| 4 | 3 PR | |
| 10 | 1 CR, 4 PR Median survival: 5 mo | |
| 5 | 3 SD | |
| 15 | No PR Time to recurrence >8 mo (n = 7) | |
| 10 | 3 PR, 1 SD Survival >1 y (n = 4) | |
| 10 | 3 PR | |
| 9 | 3 PR Survival >4 y (n = 2) | |
| 19 | 1 CR, 7 PR Median survival: 12 mo | |
| 6 | 1 CR, 2 PR |
In the 10 trials using LAK cells or CTLs, 2 variables consistently reported as significant were the total number of cells infused and the use of corticosteroids during treatment. In these trials, the number of CTLs injected ranged between 3 × 10 7 and 10 × 10 10 , with between 1 and 13 injections. Because the total number of CTLs as well as the method of delivery differed between studies, Kronik and colleagues sought to define the optimum dose using a mathematical model that incorporated data from in vitro and in vivo studies, interactions with CTLs and major histocompatibility complex (MHC) receptors, and the effect of transforming growth factor β (TGF-β) and interferon γ (IFN-γ) on the antitumor immune response. These investigators reported the optimum calculated dose of CTLs as 27 × 10 9 total CTLs. As a result, they concluded that many immunotherapy trials may not have been successful because the dose given to patients was often inadequate (sometimes 20-fold smaller than that predicted to be effective).
The use of corticosteroids to control peritumoral edema was another factor that varied between studies using LAKs or CTLs. Because of their immunosuppressive effect, corticosteroids were not used in 4 studies, suggesting that patients in these trials may have had a smaller tumor and potentially better outcomes compared with those patients who required steroid treatment. Evidence for better survival when using LAK cells without the use of corticosteroids was reported by Dillman and colleagues in their subset analyses. Other results point to the contrary, that corticosteroids did not have an effect on the number or functional activity of the infused effector cells.
Active immunotherapy
Active immunotherapy involves administration of tumor antigens to prime the patient’s endogenous immune system. Lysates of injected tumor antigens can be derived from irradiated tumor cells, nonspecific protein and mRNA lysates, and synthetic peptides. The delivery of these antigens is typically via vaccine, which often includes an immune adjuvant or the tumor antigen complexed to DCs, to increase the antitumor immune response. This strategy is considered advantageous because of the specificity afforded by directly injecting immunogenic tumor antigens and the long-term antitumor effect as a result of immunologic memory.
ATCs
ATCs have been studied in active immunotherapy strategies against HGG in 8 clinical trials and 2 case reports for a total of 71 patients treated ( Table 4 ). Of these studies, there was large heterogeneity in the number of cells infused, number of injections, and the use of immune adjuvants. The number of cells injected ranged from 10 6 to 10 11 total cells per patient and they were given in 1 to 13 vaccinations. Only 2 of the 8 studies used immune adjuvants such as IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF). Although toxicities were minimal, 2 studies (n = 10 newly diagnosed GBM and n = 1 recurrent GBM), showed that no survival benefit was associated with treatment.
| Reference | Number of Patients | Trial Results |
|---|---|---|
| 1 | No survival benefit | |
| 11 | Median survival: 46 wk | |
| 12 | 2 CR, 4 PR | |
| 1 | Survival: 10 mo | |
| 23 | Median progression-free survival: 40 wk Median survival: 100 wk | |
| 3 | Prolonged recurrence-free survival | |
| 12 | 1 CR, 1 PR, 2 minor response, 1 SD Median survival: 10.7 mo | |
| 5 | 3 SD |
Despite a large number of trials (n = 8), the available data do not show robust efficacy data despite most patients showing a strong immune response as assessed by ex vivo assays. Several studies reported a local skin reaction at the injection site. Sobol and colleagues reported an antitumor immune response mediated in part by CD8+ cytotoxic T cells, which were collected in the peripheral blood. Several groups reported significant increases of DTH reactions, numbers of tumor-reactive memory T cells, and numbers of CD8(+) TILs in recurrent tumors. Despite the presence of increased antitumor immune activity, most studies were unable to show a survival benefit in patients.
DCs
Glioma cells are poor APCs because of downregulation of costimulatory molecules and the release of immunoinhibitory cytokines. DCs are professional APCs that phagocytose foreign antigens and present them in the context of MHC to activate innate and adaptive immune cells. DC therapy is based on the concept that GBM cells are poor stimulants of the host’s immune system and thus require DCs, acting as APCs, to internalize GBM antigens and present them to activate antitumor immune cells. Nineteen studies have been published using DCs, with a total of 323 patients studied. The cellular material complexed with APCs included whole ATCs, tumor lysate, tumor peptides, including the epidermal growth factor vIII (EGFRvIII), or tumor mRNA.
DC vaccinations are typically prepared using GM-CSF and IL-4 as adjuvants, although several groups have reported stimulating DCs with other cytokines. These vaccines are typically injected intradermally or intranodally. Nishioka and colleagues reported delivering DCs that expressed IL-12 directly to the tumor cavity and found that these cells were able to traffic to draining lymph nodes and activate cytotoxic, antitumor immune cells. Phase I studies have reported that DC vaccines are safe and associated with only grade I and II vaccine site responses.
Results of these studies are summarized in Table 5 . In brief, immunologic, radiologic, and clinical benefits were seen in roughly 40% of patients. A peripheral immune response, as measured by ex vivo assays or DTH reactions, was present in more than half of patients. Clinically, 13 studies reported efficacy in terms of beneficial survival compared with historical controls. Two studies did not find a correlation between peripheral immune response and survival.
Related posts:
Modern Management of High Grade Glioma, Part II
Immunotherapy for Glioma
Molecular Characteristics and Pathways of Avastin for the Treatment of Glioblastoma Multiforme
Clinical Trials of Small Molecule Inhibitors in High-Grade Glioma
Use of Language Mapping to Aid in Resection of Gliomas in Eloquent Brain Regions
Quality of Life and Outcomes in Glioblastoma Management
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