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The future of rindopepimut seems to be bright in 2015. The results of three clinical trials have shown that this peptide tumor therapeutic vaccine can elicit an immune response and delay polymorphic glioblastoma multiforme (GBM). The disease progression of the patient.

GBM is the most malignant brain cancer. The vaccine manufacturing company Celldex Therapeutics hopes to persuade the FDA to speed up the approval of the drug based on Phase II clinical data. However, the FDA did not agree to ask them to wait for the results of the Phase III clinical trial.

Unfortunately, Phase III clinical trials have not been successful. Interim data analysis at the beginning of 2016 found that GBM patients receiving this vaccine did not have a survival benefit, and Celldex also terminated the development of the vaccine.

In the face of such a result, patients and doctors are very disappointed. But in fact, from another perspective, such a result is not surprising. “Maybe it’s not surprising because I’m used to the failure of too many drugs in the field,” said E. Antonio Chiocca, chief neurosurgeon at Bregen and Women’s Hospital.

GBM is also the most common type of brain cancer, accounting for approximately 50% of primary brain cancer. And such tumors are usually always fatal. Surgery, chemotherapy, and radiation have a very limited impact on patient survival.

Tumor immunotherapy has revolutionized many other difficult-to-treat cancers, including melanoma. Checkpoint inhibitors can abolish the immunosuppressive state of the tumor against the immune system, reducing the risk of disease progression and death in melanoma patients by nearly 50%. But unfortunately, such changes have not appeared in the treatment of GBM, nivolumab Phase III clinical only added a failed study in this field.

But despite the constant setbacks in clinical research over the past few decades, researchers in the field of neurooncology are optimistic because they believe in the potential of cancer immunotherapy and believe that immunotherapy can eventually defeat such cancers.

Immune reactivation

Glioma cells (blue) protect themselves from immune cells such as macrophages (green), including inhibition of macrophage function through signaling pathways involving PD-L1 (red). Checkpoint inhibitors such as Pembrolizumab block this pathway, allowing macrophages to attack tumor cells. Researchers are becoming more and more aware of GBM’s strategy against the immune system. “This type of cancer is always smarter than the corresponding treatment, and immunotherapy is probably the only exception,” said Linda Liau, a neurosurgeon at the UCLA Medical Center.

 

Unprivilege

The central nervous system can be independent of other parts of the body by forming a blood-brain barrier. The blood-brain barrier prevents some macromolecular substances, small molecule drugs, and cells from entering the brain and affecting the function of the nervous system. But the brain is not exactly an occlusion fortress. Although people have long thought that human brains lack immune surveillance, some studies in recent years have found that this is not the case.

In 2015, Antoine Louveau, Jonathan Kipnis of the University of Virginia and their colleagues had a surprising discovery that they found lymphatic vessels in the brain that allowed T cells to enter the circulatory system. This also indicates that there is an intersection between the brain and the immune function outside the brain.

Other studies have shown that circulating immune cells can enter the brain in other ways. Inflammation and autoimmune diseases are the best examples, and such phenomena can be observed in the brains of cancer patients.

And even the blood-brain barrier itself is not completely insurmountable. Although macromolecules usually do not cross the blood-brain barrier, monoclonal antibodies, including checkpoint inhibitors, can cross the barrier to some extent and enter the brain.

John Sampson of Duke University School of Medicine predicts that approximately 1% of drugs will enter the brain after intravenous drug use. Although this number sounds low, in fact this amount has already led to clinical efficacy.

“If you use checkpoint inhibitors in patients with melanoma or lung cancer brain metastases, you can also see that there is a potential for remission of brain metastases in patients,” said Donald O’Rourke, a neurosurgeon at Perelman School of Medicine at the University of Pennsylvania. These findings also suggest that the use of such immunotherapy to fight cancer in the brain is feasible.

However, O’Rourke also reminded that although such checkpoint inhibitors are effective in treating brain metastases, they do not have much therapeutic effect on primary brain cancer. This actually shows that the immune system is very difficult to harm GBM, not simply because of the lack of immune surveillance in the brain. “This is definitely related to the intrinsic characteristics of glioma,” O’Rourke said.

GBM has many layers of self-protection mechanisms. Firstly, the genetic heterogeneity of GBM is extremely strong, that is to say, the genetic mutations that drive the survival of tumor cells within the same tumor are extremely different. “A tumor cell in GBM can have 50-60 mutations in difference with another tumor cell nearby,” Chiocca said. “This makes it extremely difficult to develop targeted drugs because it is difficult to find a targeted drug. Completely remove all tumor cells.”

This may also be a reason for the phase III clinical failure of rindopepimut. This vaccine can trigger the immune system’s immune response to EGFRvIII. EGFRvIII is a tumor-specific protein that drives disease progression in GBM and other cancers. However, even if the vaccine can clear tumor cells expressing EGFRvIII, it is difficult to affect the part of tumor cells that do not express EGFRvIII.

In addition, GBM tumor cells also release chemical signals to surrounding tissues, inhibiting the function of immune cells. PD-1/L1 is also one of the mechanisms. However, even with the PD-1/L1 inhibitor, the presence of other immunosuppressive mechanisms other than PD-L1 will also keep the immune cells in a state of inhibition. And the paradox is that many immune cells can actually promote the formation of such immunosuppression.

 

Know your enemy

Despite this, some of the immunotherapies currently under development have given people some new hope. “The immune response to brain tumors is there, but these immune responses are not efficient enough,” says Valérie Dutoit of the University of Geneva, Switzerland. “We need to further strengthen this immune response.”

The failure of clinical trials over the years has also provided us with some experience and lessons. For example, some tumor therapeutic vaccines currently under development can reduce the possibility of antigen escape by mutating specific antigens in vaccines. Some vaccines rely on adjuvants to strengthen the immune response, and some vaccines are based on dendritic cells.

Dendritic cells obtained from a patient are manipulated in vitro to enable recognition of a particular antigen. Sampson and his colleagues designed a dendritic cell-based vaccine that elicits a durable immune response against tumors.

The core difficulty in vaccine development is to find an antigen that is widely expressed in tumor cells but not expressed in normal tissues and that is capable of eliciting an immune response. The antigen studied by the team is a protein expressed by cytomegalovirus.

The genetic material of macrophages can be integrated into the human genome, and most adults are infected with this virus at some point in their lives. “The virus is usually dormant, but it can be activated in an immunosuppressed state,” Sampson said. “When the virus is activated, there are also a large number of T cells corresponding to it.”

Studies have found that GBM-induced immunosuppression is sufficient to activate the virus, which allows immuno-trained macrophages to elicit a strong immune response against such tumor cells.

In a 2017 clinical trial of vaccines, the Sampson team found that 11 patients with GBM had a median survival of more than 41 months, while patients treated with conventional therapy had a survival of only 15 months. More importantly, the GBM of 4 subjects still did not progress after 5 years.

In addition to the Sampson team, other teams are also investigating another treatment strategy that uses individualized vaccines to target tumor-specific antigens obtained from patient tumor tissue sample analysis. For example, the GAPVAC organization in Europe is establishing a collection of immuno-activated functional peptides obtained from tumor cell surface proteins.

“During two to three months after a patient receives standard therapy, the researchers are able to analyze the acquired antigen and vaccinate it and apply it to the patient, which is a good way forward for individualized cancer vaccine research. Dutoit said.

Another treatment has also been found in clinical trials to prolong the survival of patients, and the study of this individualized vaccine has also caused a lot of repercussions.

Northwest Biotherapeutics’ DCVax-L therapy uses patient-derived proteins to train dendritic cells. The company’s Phase III clinical study found that 100 of the 331 treated patients survived after 40 months of treatment.

Research on antigens is not only beneficial for the development of therapeutic vaccines, but also for CAR-T therapy. O’Rourke’s early exploration in this field, the first clinical study of human GBM CAR-T found that after intravenous injection of EGFRvIII-targeted CAR-T cells, cells can safely penetrate gliomas and trigger A localized degree of immune response. O’Rourke said that one of the 10 patients treated was still alive after nearly three years of treatment.

However, similar to previous tumor vaccines targeting EGFRvIII, targeting a single antigen is not sufficient to target all tumor cells. Therefore, Dutoit and Dietrich hope to establish a partnership with Carl June of the University of Pennsylvania based on their experience in the classification and classification of GBM antigens. Individualized therapies developed based on this collaboration enable doctors to develop a combination of two or three CARs for their specific antigens for GBM patients.

 

Awaken sleeping immune cells

In fact, these tumor-specific immunotherapy is not enough to relieve the strong inhibition of tumors in the brain, and it is not a tumor-specific protein that can trigger an effective immune response. Heimberger of the MD Anderson Cancer Research Center believes that it is necessary to find a way to specifically activate immune cells, rather than being limited to finding antigens in tumors.

Accordingly, some clinical studies are also exploring the value of combination of tumor vaccines or CAR-T therapies with checkpoint inhibitors such as nivolumab. However, it is still unclear whether this combination strategy is sufficient to overcome the suppression of the immune system by the tumor microenvironment of GBM.

In addition to checkpoint inhibitors, Heimberger’s team is exploring another strategy. STAT3 regulates gene expression and not only produces immunosuppressive effects, but also affects cancer progression.

“Almost all of the tumor-mediated immunosuppression you can think of is related to STAT3,” Heimberger said. Her team has worked with other researchers to find a STAT3 inhibitor that crosses the blood-brain barrier and is preparing for clinical research.

Oncolytic viruses are also a relatively promising way to relieve immunosuppression. Oncolytic viruses kill tumor cells and also trigger a strong immune response. The potential power of oncolytic viruses is based on a feature of the human immune system: the human immune system is better at attacking pathogens than tumor cells.

Oncolytic virus therapy uses the virus to activate the immune system, but the immune system can also act on tumors while fighting the virus.

In addition to these explorations, researchers are also trying to use viral vectors to improve the sensitivity of tumor cells to chemotherapeutic drugs through gene therapy.

Liau has worked with Tocagen on several clinical trials to convert tumor cells to cytosine deaminase and 5-fluorocytosine to 5-fluorouracil by gene therapy. One of the Phase I clinical studies found that the therapy can remove detectable tumors in the brain of 20% of patients.

Liau said that although this combination can only kill tumor cells by cytotoxicity, the effect of the therapy on the immune system is the key to long-term control of tumor growth, as the vector virus appears to be the result of preclinical studies. Can induce immune memory against tumors.

 

Increasing conflict

These early clinical studies have shown that the possibility of disrupting GBM immunosuppression does exist. The task now is to conduct more in-depth research and confirm whether it can be demonstrated in large randomized controlled phase III clinical studies that these treatments can prolong patient survival and generate patient benefit.

However, the current clinical trial research environment is not very beneficial to researchers. For example, many patients enrolled in many clinical studies are GBM patients who have failed multiple treatments, and they have been unable to respond to multiple therapies.

“Temozolomide not only kills tumor cells, it also kills T cells and other lymphocytes,” Chiocca said. Regular use of sterols in the treatment of GBM to reduce brain edema in patients also exacerbates this immunosuppressive effect.

But on the other hand, even if such patients with obvious inhibition of immune function can trigger an immune response by using these therapies, this should be a great thing. More and more clinical trials have begun to study whether the treatment of earlier immunotherapies will improve the efficacy of the drug.

But Liau also said that it is not easy to recruit patients who still have alternative treatment options. At the same time, however, more and more patients are beginning to understand that the prognosis of patients undergoing traditional therapy is often very high, which prompted them to start experimenting with immunotherapy.

More importantly, although immunotherapy has the risk of over-activation of the brain’s immune response, many immunotherapies have been found to be very safe in clinical trials. O’Rourke said that patients receiving CAR-T therapy did not experience a cytokine release storm. Adverse reactions in checkpoint inhibitors and clinical trials of vaccines are also generally controllable.

Chiocca said: “We have spent too much energy on research on targeted therapies, but it is clear that you can’t expect to destroy all enemies with precision-guided missiles, especially when faced with enemies like GBM. .”

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