November 29, 2021

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The clinical prospects of immunotherapy for glioblastoma

The clinical prospects of immunotherapy for glioblastoma



 

The clinical prospects of immunotherapy for glioblastoma.

 

Preface

Glioblastoma multiforme ( GBM ) is the most common primary central nervous system ( CNS ) malignant tumor in adults . All current standard care treatments are not effective, and the prognosis is poor. The 5-year overall survival rate is only 6.8%.

 

The treatment criteria for GBM include maximum safe tumor resection, followed by radiotherapy ( RT ) and temozolomide ( TMZ ) combined chemotherapy. Compared with radiotherapy alone, the median overall survival (OS) of combination therapy was 14.6 months and 12.1 months, respectively. In 2015, the FDA approved a new electrophysical therapy model, namely, tumor treatment fields ( TTFields ) for GBM patients . The phase III ( NCT00916409 ) clinical trial proved that the median progression-free survival ( PFS ) of TTFields treatment increased to 6.7 months, while that of the temozolomide group was 4.0 months. The median OS also improved significantly, at 20.9 months and 16.0 months, respectively ( p<0.001 ).

 

However, almost all GBM will relapse. Available treatment options include second-line surgery, radiotherapy, alkylating agent chemotherapy, and bevacizumab therapy. Unfortunately, the median OS range is only 6 to 9 months from the first progression or relapse. Therefore, there is an urgent need for new treatment strategies to treat recurrent GBM.

 

Immunotherapy is a new type of therapy that uses the patient’s own immune system to fight tumors. It has completely changed the treatment of a variety of cancers. Although so far, immunotherapy has not made a breakthrough in the treatment of GBM, it is worth noting that the previous Recurrent GBM treated with radiotherapy and chemotherapy usually has a higher mutation load and is expected to have higher immunogenicity than untreated GBM patients, which enhances people’s confidence and optimism towards immunotherapy. A further understanding of its biology, immune microenvironment and the emergence of new therapeutic combinations may change the current dilemma of immunotherapy in GBM.

 

 


Immune privileges of the central nervous system

 

For a long time, the central nervous system has been considered an immune privileged system: because the blood-brain barrier ( BBB ) blocks pathogens, the CNS has far fewer chances of contact with pathogens than any other organ. From an evolutionary perspective, since there is no need to frequently launch immune attacks, and because of the consequences of autoimmune brain cells, it may be beneficial to inhibit the immune system of the central nervous system.

 

Until 2015, it was generally believed that the central nervous system lacked functional lymphatic vessels. Since these are important components of the immune response, it is difficult to understand how antigen presentation occurs. In addition, the BBB itself is also considered a limiting factor for effective immune response, because its tight junction physically prevents the entry of immune participants ( such as lymphocytes or antibodies ).

 

A key difference between the central nervous system and other organs is that there are almost no dendritic cells used for antigen presentation in the brain. In the central nervous system, microglia are considered to be the main antigen presenting population, which is mainly an anti-inflammatory phenotype, which makes T cells prone to immunosuppressive Th2 phenotype.

 

However, there are now many definite evidences that active immune surveillance does occur in the central nervous system and produces an effective immune response against infection. In addition, autoimmune diseases such as multiple sclerosis also show that immunogenic antigens can be processed in the central nervous system and trigger a powerful immune response. In 2015, the discovery of the lymphatic pathway along the dural venous sinuses to the deep cervical lymph nodes greatly changed our concept of the immune environment of the brain. Today, although the central nervous system is considered an immunologically distinctive part, it is believed that its immune microenvironment provides suitable conditions for immunotherapy against brain tumors.

 

The clinical prospects of immunotherapy for glioblastoma

 

 


GBM’s immune evasion mechanism

GBM is the deadliest brain cancer, with rapid growth and frequent recurrence. This fact can be attributed to multiple factors, including high proliferation rate, high tissue invasion ability, treatment-resistant cancer stem cells, and difficulty for drugs to enter the central nervous system. In addition, immune evasion also plays a key role in the poor prognosis of GBM.

 

Many immune evasion mechanisms are involved, including blocking the entry of immune cells through the complete blood-brain barrier, immunosuppression of the tumor microenvironment, or hijacking key immune pathways and participants, such as immune checkpoint receptor expression, regulatory T cells, tumors Regulation of related macrophages.

 

GBM has a high intrinsic resistance mechanism to immune attacks and excellent adaptability. A study on PD-1 blockade in GBM showed that only a few patients had an initial response, and all patients relapsed. The pathology of recurrent tumor biopsy is characterized by new expression of immunosuppressive molecules and loss of expression of neoantigens.

 

First, GBM acquires immunosuppressive properties from its location in the central nervous system. Secondly, GBM benefits from the complex heterogeneity of tumor tissues. In addition, GBM also benefits from a favorable microenvironment, even further making it immunosuppressive.

A study showed that CD8+ T cells targeting central nervous system antigens were quickly cleared after entering the central nervous system, proving the tolerance of the central nervous system microenvironment.

In an inflammatory environment, interferon-induced chemokines activate endothelial cells and allow peripheral immune cells to pass through the BBB.

GBM evades immunity by up-regulating chemoattractive proteins in the matrix and recruiting inhibitory monocytes such as MDSC and TAM from the periphery.

 

Finally, one obstacle to GBM immunotherapy is iatrogenic immunosuppression. In GBM, radiotherapy combined with temozolomide chemotherapy is the standard treatment.

A study showed that this treatment caused the CD4+ T cell count of 3/4 of the patients to drop below 300 cells/mm3. In addition, temozolomide prevented the induction of memory T cells in preclinical trials of PD-1 blockade.

 

 


Tumor vaccine treatment

 

Like preventive vaccines used to prevent infectious diseases, anti-cancer vaccines consist of adjuvanted tumor antigens to trigger and enhance immune responses. Three main methods are considered in GBM: (1) peptide/DNA vaccine; (2) DC vaccine; (3) mRNA vaccine.

 

The clinical prospects of immunotherapy for glioblastoma

 

One of the earliest and most evaluated vaccine methods involves alternative splicing variant III ( vIII ) of EGFR , which is a tumor-specific antigen produced by alternative splicing of exons 2 to 7. EGFRvIII is expressed in 25-30% of GBM tumors.

Rindopepimut ( CDX-110 ) is the most widely studied EGFRvIII peptide vaccine. It uses the immunomodulatory protein KLH as an adjuvant, which was recognized by the FDA as a “breakthrough therapy” for GBM in February 2015. Phase II data shows that compared with the control, both PFS and OS have improved.

 

In order to increase the probability of an effective immune response to GBM, people combine multiple tumor-specific antigens into a vaccine. IMA950 is a peptide vaccine that combines 11 GBM-derived antigens.

The vaccine has been shown to induce T cell responses to single and multiple antigens.

However, no randomized clinical trials have been conducted yet, so whether this immune response actually leads to improved clinical outcomes remains to be proven.

 

Dendritic cells are a powerful antigen presenting cell that can induce antigen-specific T cell responses.

To date, two randomized trials have evaluated the efficacy of DC vaccines. ICT-107 is an autologous DC immunotherapy targeting six antigens of tumor and cancer stem cells, including MAGE-1, AIM-2, HER2/neu, TRP-2, gp-100 and ILRa2. In a double-blind, placebo-controlled trial involving 124 patients, 75 patients received ICT-107 after RT and concomitant TMZ.

The results showed that the median PFS of the treatment group was slightly higher than that of the control group ( 11.2 months vs 9 months; HR: 57, p=0.011 ), but there was no difference in OS ( 17.0 months vs 15 months; HR: 0.87, p=0.580 ).

Interestingly, patients with immune responses showed improved PFS and OS compared to non-responders. The results of another large-scale, randomized and controlled phase III trial ( NCT00045968 ) of DC vaccine DCVax-L showed that compared with historical control data, the median OS reached 23.1 months.

 

In addition, there are many candidate vaccines still in development: NCT02287428 clinical trials are testing personalized neoantigen peptide vaccines containing up to 20 long peptides.

The NCT03422094 trial is studying the combination of NeoVax and ipilimumab or nivolumab. GAPVAC-101 is a personalized vaccine based on 30 GBM overexpression antigens in Phase 1 clinical trials ( NCT02149225 ).

 

 


Oncolytic virus

 

Several OV therapies have been studied in GBM, including adenovirus, measles virus, polio virus, HSV, parvovirus and retroviral vectors, and the feasibility and safety of this method have been demonstrated.

Recently, a phase 1/2 clinical trial of GBM has shown significant efficacy of the new OVs, and the survival period of the patient subgroup is more than 3 years.

These include adenovirus DNX-2401 ( Ad5-delta24-RGD ), measles virus MV-CEA, parvovirus H-1 ( ParvOryx ), polio rhinovirus chimera ( PVSRIPO ) and retroviral vector Toca 511 ( vocimagene Amirepreprevec) And Toca FC ).

 

The clinical prospects of immunotherapy for glioblastoma

 

Toca 511 is a retroviral vector based on mouse leukemia virus, encoding yeast cytosine deaminase that transforms 5-fluorocytosine ( 5-FC ). In a phase I trial ( NCT01470794 ), the efficacy of Toca 511 was tested in 56 patients with relapsed glioblastoma.

The median OS was 14.4 months, and the 1-year and 2-year OS rates were 65.2% and 65.2%, respectively. 34.8%. Five patients showed complete remission. The Toca5 trial is another multicenter, randomized, open-label Phase II/III clinical trial comparing standard treatments, but the trial was terminated in 2020 due to lack of efficacy ( NCT02414165 ).

 

DNX-2401 ( Ad5-Delta-24-RGD; tasadenoturev ) is a tumor-selective oncolytic adenovirus vector. Tumor cell targeting is achieved by deleting 24 base pairs in the E1A protein and inserting the Arg-Gly-Asp ( RGD ) motif in the viral capsid protein , thereby increasing the affinity for αV integrins.

In a phase 1 dose escalation trial of 37 patients with recurrent malignant glioma, 20% of patients survived more than 3 years after treatment, and 3 patients had PFS more than 3 years.

Biopsy after treatment showed that DNX-2401 can replicate in tumors and induce effective CD8+ and T-bet+ T cell infiltration in tumors. Another phase II combined trial is underway, which aims to study 48 cases of recurrent GBM The efficacy of intratumor injection of DNX-2401 and systemic administration of pembrolizumab ( CAPTIVE/KEYNOTE-192, NCT02798406 ).

The mid-term results showed that the median OS was 12 months, the 6-month OS rate was 91%, and 47% of patients showed clinical benefit ( stable or regression ). Four patients had PR, and three of them survived >20 months.

 

Other adenovirus vectors are also under study. Phase I clinical trials ( NCT02026271 and NCT03330197 ) are testing intratumoral injection of Ad-RTS-hIL-12, an inducible adenovirus vector that expresses human IL-12 in the presence of the activating ligand veledimex.

The NCT02026271 trial is a dose-escalation trial, conducted in 38 adult patients with recurrent or progressive glioma, showing good safety and survival ( median OS is 12.7 months ).

The NCT03330197 trial is an unfinished pediatric trial, which is still being recruited.

 

The measles virus Edmonston vaccine strain is a safe and specific oncolytic virus. It can express human carcinoembryonic antigen ( CEA ) as a reporter gene after genetic modification to monitor virus replication in vivo.

MV-CEA OV has been tested in a phase I clinical trial ( NCT00390299 ) of 23 GBM patients, and was given before and after surgery.

The median OS of the two was 11.4 and 11.8 months, respectively, and the median OS was within 6 months. The bit PFS rate was 22–23%.

 

ParvOryx is a modified rat parvovirus that was tested in 18 patients with recurrent GBM in a phase I/IIa dose escalation trial ( NCT01301430 ).

The median OS after ParvOryx treatment was 15.5 months, 8 patients survived> 12 months, and 3 patients survived> 24 months. Analysis of tumor biopsy showed that 6 patients had strong CD8+ and CD4+ T lymphocytes infiltration.

 

PVSRIPO is an engineered Sabin 1 attenuated polio virus. In May 2016, it received the FDA’s breakthrough therapy designation.

In the phase I dose escalation trial ( NCT01491893 ) of 61 patients with recurrent grade IV malignant glioma , the median OS of all 61 patients was 12.5 months, but the safety was controversial, because 19% of patients had Adverse events of grade 3 or higher. In addition, about 20% of patients can survive 57-70 months after PVSRIPO administration.

A randomized phase II trial of PVSRIPO alone or in combination with lomustine in patients with recurrent grade IV malignant glioma is currently underway ( NCT02986178 ).

 

Several other clinical trials for adult patients with recurrent glioblastoma/glioma are underway, such as the phase I/II trial of vaccinia-based OV TG6002 combined with 5-FC ( ONCOVIRAC, NCT03294486 ); expression of immune stimulation OX40 Phase I trial of adenovirus OVDNX-2440 with ligand ( OX40-L ) ( NCT03714334 ); a phase I trial of genetically engineered herpes simplex virus ( HSV-1 ) expressing IL-12 named M032 ( NCT02062827 ) ; Phase I trial of genetically engineered HSV-1rQNestin34.5v.2 combined with cyclophosphamide ( NCT03152318 ).

 

In general, these early clinical trials have shown that OVs can improve the survival rate of some subgroups of patients.

 

 


Immune checkpoint inhibitor

 

88% of newly diagnosed glioblastomas and 72% of recurrent glioblastomas showed PD-L1 overexpression, although overall levels were low. Therefore, anti-PD-1 ICI in recurrent GBM is the subject of many phase I clinical trials ( NCT02017717, NCT02336165, NCT02337491, NCT02054806 ).

The overall response rate of anti-PD-1 or anti-PD-L1 monotherapy ranges from 2.5% to 2.5%. Between 13.3%. The 6-month PFS rate is between 16% and 44%, and the OS rate is between 7 and 14 months.

 

The clinical prospects of immunotherapy for glioblastoma

 

The CheckMate-143 ( NCT02017717 ) trial investigated the efficacy of nivolumab monotherapy and ipilimumab in combination for patients with first-time GBM recurrence.

The results showed that nivolumab alone showed a higher median OS (10.4 months vs 9.2 months) and lower toxicity than the combination regimen.

Dual checkpoint suppression causes serious adverse events in more than 50% of patients, so this method is no longer used.

 

The third phase of the CheckMate-143 trial compared nivolumab 3 and bevacizumab, but was terminated early due to lack of efficacy.

There was no statistical difference between the two groups in terms of median OS and toxicity.

Currently, two ongoing phase III trials are investigating the treatment of newly diagnosed GBM with nivolumab: The CheckMate-548 trial ( NCT02667587 ) is testing temozolomide plus radiotherapy combined with nivolumab in the treatment of newly diagnosed MGMT methylated GBM patients, ( NCT02617589 ) is investigating the combination Comparison of nivolumab and temozolomide after radiotherapy.

However, the information obtained so far suggests that neither of these two trials may reach their primary endpoint.

 

The Keynote-028 trial ( NCT02054806 ) studied the efficacy of another anti-PD1 antibody, pembrolizumab, on several advanced solid tumors, including 26 patients with glioblastoma. Among them, one case of PR ( 4% ), 12 cases ( 48% ) of SD, the median PFS was 2.8 months, and the median OS was 14.4 months.

 

Another phase II trial investigated the efficacy of durvalumab as a monotherapy or in combination with bevacizumab or radiotherapy in the treatment of 30 patients with recurrent glioblastoma. 4 cases of PR ( 13.3% ), 14 cases of SD ( 46.7% ), the PFS rate at 6 months was 20%.

 

 


Adoptive cell therapy

 

In GBM, a pilot trial studied autologous TIL infusions in six glioma patients. 3 cases were anaplastic astrocytoma and 3 cases were GBM. Of the 3 GBM patients, 2 patients showed PR.

In another clinical trial ( NCT00331526 ), lymphokine activated killer ( LAK ) cells were used to treat GBM.

LAK cells are a heterogeneous cell population, mainly composed of natural killer cells ( NK ) and natural killer T cells ( NKT ) Composition, showing unrestricted MHC anti-tumor activity. A total of 33 patients received auxiliary LAK cell infusion in the tumor resection cavity, and the average OS was 20.5 months.

 

 

CAR-T is currently a hot field of tumor immunotherapy, and some CAR-T therapies for glioblastoma are under development. Common targets include the neoantigen IL-13R-α2, EGFRvIII, cytomegalovirus ( CMV ) bispecific receptor and HER2.

 

In a pilot trial ( NCT02209376 ), 10 patients with recurrent EGFRvIII-positive GBM were treated with a single dose of EGFRvIII-specific CAR-T cells. However, this trial did not show any clinical benefit, but interestingly, biopsy after treatment showed that the glioblastoma lesions were infiltrated by CAR-T cells, proving that they can pass through the BBB.

 

GBM CAR-T cell research is very hot: ongoing GBM CAR-T cell clinical trials include EGFRvIII ( NCT01454596, NCT02209376, NCT02844062 and NCT03283631 ), EphA2 ( NCT02575261 ), HER2 ( NCT02442297, NCT01109095 and NCT03389230 ), IL-13Rα2 ( NCT02208362 ) and PD-L1 ( NCT02937844) . In addition, new potential targets are emerging in preclinical models, such as CD70, IL-7 receptor and PDPN.

 

Clinical trials published so far have shown that CAR-T cells can indeed infiltrate GBM tumors and can eliminate significant tumor volume, but they also prove the strong adaptability of GBM to enable it to evade immune attack. Heterogeneous antigen expression, immunosuppressive tumor microenvironment and immunoediting are the main obstacles that need to be overcome for the effectiveness of CAR-T cells.

These obstacles are not limited to GBM. In fact, the efficacy of CAR-T cells in solid tumors has not been proven. It is possible to overcome these challenges by enhancing the design of CAR-T cells.

Recently, a trivalent CAR-T cell targeting three glioma antigens ( IL13Rα2, HER2 and EphA2 ) was designed , which can recognize almost 100% of GBM.

These advances in CAR-T cell design, combined with immunotherapy strategies such as checkpoint inhibitors or oncolytic viruses, may be the key to the success of GBM immunotherapy.

 

 


Challenges and prospects

So far, there has not been any immunotherapy method that can convincingly show significant clinical benefits in a randomized phase III trial.

This may be related to many factors, including tumor limiting factors: for example, GBMs have a lower mutation load and provide fewer therapeutic targets for the immune system; antigen targets are selectively down-regulated in cancer cells; in addition, GBM may be in its developmental process It is subject to significant immune editing, resulting in highly immune avoidant and suppressive tumors.

The tumor microenvironment of GBM is particularly immunosuppressive. Research has been conducted on the inhibition and reprogramming of CSF-1 ( NCT02526017 ), TGF-β ( NCT02423343 ) and IDO ( NCT02052648 ), but so far there is no clinical benefit.

 

In addition, the normal function of the immune system in GBM patients may be hindered by the toxic effects of required supportive treatments ( such as steroids ) or chemotherapy.

The selection of patients who do not require steroids for clinical studies, at least in the first stage of treatment, may be crucial. In newly diagnosed GBM patients, it may be critical to consider neoadjuvant immunotherapy before radiotherapy and temozolomide treatment, and even before neurosurgical resection of the lesion.

It was observed in a phase II randomized trial that taking pembrolizumab before resection can significantly improve OS compared with patients treated only in an adjuvant setting.

 

Considering subsequent immunotherapy, the choice of local treatment strategy may also be important: preclinical data shows that local treatment methods, especially stereotactic radiotherapy, do synergistically interact with immunotherapy by releasing tumor antigens.

This theory is based on two ongoing clinical trials ( NCT02648633 and NCT02866747 ), combining stereotactic radiotherapy with GBM PD-1 inhibition, and a series of local treatments that combine the release of different antigens ( NCT02311582, NCT01811992, NCT02197169, NCT02798406) And NCT02576665 ).

 

Finally, a single immunotherapy method is probably not enough to elicit a strong enough response. Therefore, the combination therapy is being actively studied, hoping to overcome the immunosuppressive environment and tumor escape mechanism in GBM.

 

 


Summary

 

Immunotherapy has completely changed the mode of cancer treatment.

However, GBM has proven to have a strong resistance mechanism to all stages of tumor immune attack.

Many factors can explain the negative results obtained so far.

In the process of tumor development, GBM may be significantly immunoedited, leading to a high degree of immunosuppression and escape phenotype.

 

So far, little is known about GBM’s immunotherapy resistance or the inherent characteristics of tumors. Further research on the molecular factors that determine the response of immunotherapy in GBM tumors and its microenvironment is essential, and it is necessary to reconsider the design of clinical trials evaluating immunotherapy methods in order to quickly obtain information about the potential clinical impact of these methods. At present, judging from the latest data, the combined application of immunotherapy methods may be the ultimate breakthrough in GBM immunotherapy.

 

 

 

References:

1. Immunotherapy in Glioblastoma: A Clinical Perspective. Cancers (Basel). 2021 Aug; 13(15): 3721.

The clinical prospects of immunotherapy for glioblastoma

(source:internet, reference only)


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