Challenge deadly brain tumors: gene therapy, CAR-T, DC vaccine, PD-1 on the same stage, who is better in the end
Release date: 2017-11-24
Glioblastoma (GBM) is the most malignant brain cancer in gliomas, with more than 75% of patients dying within five years, and for the most common childhood gliomas, this number can exceed 99%! Even with the most aggressive treatment, the median survival is still less than 15 months. After surgery, radiotherapy, and chemotherapy, 70% of patients will have further tumor spread, accompanied by side effects such as cognitive decline and stroke.
The median overall survival (mOS) of patients with recurrent glioblastoma (rGBM) was 6-7 months. In patients with temozolomide, bevacizumab, or salvage chemotherapy failure, the overall survival OS was only 3- 5 months. In the face of such shocking figures, in addition to standard surgery, chemotherapy, radiotherapy, patients urgently need safe and effective treatment!
1. Ad-RTS-hIL-12 gene therapy
Recently, ZIOPHARM, a cancer drug company with a new immunotherapy development, announced a positive clinical study at the 22nd American Society of Neuro-oncology (SNO), its gene therapy star drug candidate Ad-RTS-hIL-12 + veledimex In the Phase I clinical trial for recurrent glioblastoma (rGBM), the survival benefit was good, and the company's share price rose 13% on the day. Prior to this, the FDA has granted the orphan drug qualification for the treatment of glioma by "injecting Ad-RTS-hIL-12 + oral veledimex".
Mechanism of action (image source ZIOPHARM)
Ad-RTS-hIL-12 is an adenoviral vector that is expressed by a single intratumoral injection and engineered to express hIL-12, while hIL-12 has been shown to be a powerful cell that stimulates a targeted anti-tumor immune response. factor. The expression of hIL-12 is regulated by the RheoSwitch therapeutic system (RTS) and is regulated by the oral small molecule veledimex, an activator ligand that has been shown to cross the blood-brain barrier.
RheoSwitch Therapeutic System (Source ZIOPHARM)
The latest clinical data were as of October 18, 2017, with a mean follow-up of 11.1 months, and the median overall survival (mOS) of patients treated with Ad-RTS-hIL-12 +20 mg veledimex (n = 15). It is 12.5 months. Compared to historical controls, patients with rGBM had a significant benefit from 5 to 8 months of survival. In addition, 4 patients with rGBM who received low-dose steroids maintained a 100% survival rate during an average follow-up of 11.1 months. Concentrated examination of magnetic resonance imaging (MRI) showed that brain tumor shrinkage in some patients demonstrated the anti-tumor effectiveness of this gene therapy.
The median overall survival was 12.5 months (Source ZIOPHARM)
Overall survival improved with ≤10 mg of dexamethasone in the first 15 days of treatment (image source ZIOPHARM)
Dr. Francois Lebel, Chief Medical Officer of ZIOPHARM, also presented data on the intratumoral production of hIL-12 associated with overall patient survival:
Francois Lebel (Source ZIOPHARM)
After completion of veledimex treatment, immunohistochemical analysis of biopsies from three patients demonstrated that IL-12 activates and maintains an immune response in rGBM tumors.
Three biopsies of rGBM lesions confirmed the anti-tumor response of extensive infiltration of CD8+ T cells into rGBM
Biopsy showed sustained (greater than 4 months) IFN-γ production, a cytokine essential for armed immune responses in the tumor microenvironment
Peripheral blood CD8 + / FOXP3 consistently showed a correlation with survival 14 to 28 days after virus injection: 20, 30, 40 mg cohort (image source ZIOPHARM)
The ratio of circulating killer CD8 + T cells to inhibitory FOXP3 + T cells is associated with survival benefit
At the time of biopsy, IFN-γ is undetectable in the blood, further demonstrating the targeted response
Picture source ZIOPHARM
The expression levels of PD-1 and PD-L1 were up-regulated in all biopsies, suggesting a potential synergistic effect of Ad-RTS-hIL-12+ veledimex in combination with immunological checkpoint inhibitors.
The treatment regimen of Ad-RTS-hIL-12+ veledimex is safe and well tolerated, and the adverse events (AE) that occur are predictable and reversible. The nerve AEs are relatively warm and transient, and have not occurred and treated. Related death events.
Antonio Chiocca (Image by bostonherald.com)
Based on the results of the above study, Dr. Antonio Chiocca of Neurosurgery at Harvard Medical School said: "The prolonged overall median survival of patients is promising, further validating that IL-12 control can safely cause the body's own immune system to produce T cells against rGBM. Response. We are pleased to see more and more evidence that targeted, localized immune responses can turn brain tumors into "hot tumors" and how this immunotherapy can help patients survive."
Picture source ZIOPHARM
In addition, Dr. Stewart Goldman presented the “Phase I clinical study of Ad-RTS-hIL-12 in combination with Veledimex needle in children with brain tumorsâ€. Prior to this, the company has announced the first patient to undergo this open-label study to evaluate the safety and tolerability of a single intratumoral injection of Ad-RTS-hIL-12 plus veledimex in the treatment of childhood brain tumors.
R&D pipeline for GBM (picture source ZIOPHARM)
Dr. Lebel said: "The safety and tolerability of intratumoral injection of Ad-RTS-hIL-12 plus oral veledimex have been proven. At present, the persistence of overall survival results and the persistence of sustained immune activation Evidence supports our approach to providing new treatments for patients with recurrent glioblastoma. We will continue to work with regulatory agencies and research leaders to initiate key research on Ad-RTS-hIL-12 + veledimex by the end of the year. Immunohistochemical analysis revealed extensive and sustained immune cell infiltration and up-regulation of immunological checkpoint biomarkers in brain tumors, which will support our study of Ad-RTS-hIL-12+ veledimex + anti-PD-1 drugs this year. .
2. EGFRvIII CAR-T therapy
On July 20, 2017, the University of Pennsylvania and Novartis jointly developed a CAR-T therapy targeting glioblastoma (GBM) targeting EGFRvIII, in a recent clinical trial led by Dr. Donald M. O'Rourke. (NCT02209376), successfully crossed the blood-brain barrier to reach brain tumors, and also showed the safety of the therapy. (Approximately 30% of GBM is highly expressed in EGFRVIII, and EGFRvIII expression is thought to be associated with poor prognosis)
CART-EGFRvIII (picture source curetoday.com)
The new study of CART-EGFRvIII included the results of the first 10 patients with severe refractory GBM who were treated. These patients have received a single infusion of CAR-T cells, three of whom did not undergo surgery after CAR-T treatment, and three patients underwent advanced surgery 34, 55 or 104 days after infusion, with the remaining four Patients with early surgery had significant progression of symptoms and received a combination of CAR-T infusions.
Effect of CART-EGFRvIII on radiological and/or pathological assessment of two subjects (Source: Science)
In the tumor test of patients who underwent surgery shortly after treatment, CART-EGFRvIII cells and signs of activation were detected in the first two weeks after CAR-T cell infusion, and circulation was also found in the blood of all patients receiving CAR-T treatment. CAR-T cells. Two weeks later, the level of CART-EGFRvIII cells in the blood began to decline and was not detected after one month. At the same time, tumors from 5 patients who underwent surgery also showed lower levels of the target antigen EGFRvIII.
As a Phase I study, the primary endpoint of the trial was safety, not efficacy, and certainly not a clear clinical benefit of CART-EGFRvIII treatment. However, at 18 months of follow-up, one of the patients was found to have stable disease and survived when the study data was published. Two other patients survived, but the disease progressed. The remaining 7 patients survived longer than predicted based on treatment history and multifocal tumor recurrence.
The first phase clinical trial of solid tumor CAR-T technology jointly developed by Novartis and Penn is safe and effective, and also proposes a new concept and solution for tumor microenvironment.
3. IL13Rα2-CAR T therapy
On December 29, 2016, a study published in the top journal of the clinical journal New England Journal of Medicine showed that CAR-T therapy, previously only available for the treatment of hematologic malignancies, in a glioblastoma with spinal metastases All solid tumors were successfully eliminated in the patient's body. And this is the first time that CAR-T therapy has achieved a major breakthrough in solid tumor treatment!
This clinical trial (NCT02208362) was conducted at the City of Hope Cancer Center using the IL13Rα2-CAR T cell product (MB-101) developed in collaboration with Mustang Bio.
Richard Grady (image source nationalrighttolifenews.org)
He was treated with a 50-year-old male patient, Richard Grady, who had recurrent multifocal glioblastoma who had undergone tumor resection and chemotherapy/radiation before. There are 5 tumor foci in the brain of the patient, which are called T1, T2, T3, T4 and T5. T2 and T3 have undergone incomplete resection before, and after the start of this treatment, two tumors T6 and T7 appeared in the vicinity.
Picture from NEJM
In this trial, patients were treated with IL13Rα2-CAR T therapy, and the IL13Rα2 target was first seen in the CAR-T study. More notably, the researchers used intraventricular injection. The injection site was located near T1. The first treatment lasted for 6 weeks. Although the tumor did not become large, it still existed, but T4, T5, The four tumor lesions of T6 and T7 all showed a small increase. At the same time, the researchers found that the patient's tumor showed spinal metastases.
In the second treatment, the researchers performed 10 injections in the right ventricle. After the injection was carried out for the third time (day 133), all the tumors in the brain and in the spine of the patient became smaller! After the 5th injection (day 190), some of the tumors disappeared and the remaining part was reduced by 77%. After the remaining five injections, the researchers found that the tumors in the patients all disappeared! After rigorous examination, no signs of tumor were found in the patient. And there are almost no serious side effects in the treatment.
The team that first killed the deadly brain tumor by intraventricular injection of CAR-T, this time "pointed" to the brain metastasis of breast cancer (publishing the complete preclinical results)
4, CD70 CAR-T therapy
In August 2017, two papers published in the journals Neuro-oncology and International Journal of Cancer showed that researchers at the University of Florida used CAR-T therapy targeting CD70 in human cancer cells and animal models. A strong anti-tumor response was produced during the experiment.
Huang Jianping (picture source ufl.edu)
As the first author of the two studies, Dr. Huang Jianping of the University of Florida neurosurgery said: "We believe that this discovery shows the great potential of immunotherapy and has new hopes for the treatment of glioblastoma."
In glioma models, mCAR-T cells induce complete response and prolong survival (Source IJC)
Success was also achieved in a group of mouse models treated with CAR-T cells, with 38% of the mice completely eradicated and the survival of other mice significantly extended. At the same time, the researchers said that no side effects were found in the experiment, indicating that the treatment is both effective and safe.
The ultimate goal of the study is of course to translate the therapy into clinical applications, so next, Dr. Huang Jianping will lead his team to study the effects of CAR-T treatment combined with other anti-tumor therapies. She said preliminary data from the mouse model showed that local radiation can improve the homing and anti-tumor activity of CAR-T cells.
Dr. Huang noted that approximately 35% of newly diagnosed glioblastoma patients and a higher percentage of patients with recurrent tumors carry CD70. Therefore, targeted immunotherapy with CD70 as a target will inevitably become a revolutionary breakthrough in the field of glioma treatment in the future.
For the first time, Chinese scientists have used the CAR-T therapy targeting CD70 to treat glioblastoma, and there is another option for fatal brain cancer.
5, DC vaccine combined with temozolomide
On April 14, 2017, a Phase I clinical study of 11 patients with glioblastoma found that patients who received a combination of DC vaccine and temozolomide had a survival period of more than five years. Quite rare, relevant trial results were published in the journal Clinical Cancer Research.
Kristen Batich
Dr. Kristen Batich of the Duke Cancer Institute, the leader of the study, said: "Although the scale of the trial is small, the results are surprising. If the vaccine is combined with a more intense chemotherapy regimen, it may further promote joint The effect of medication."
Batich and colleagues, including Dr. John Sampson, director of neurosurgery at the Duke Institute, further tested 11 patients as a one-armed study after dendritic cell vaccine (selective targeting of cytomegalovirus (CMV)) The safety of the trial of increasing doses of temozolomide. CMV proteins are abundant in glioblastoma but not in peripheral brain cells. In previous clinical trials, researchers used dendritic cell vaccines to induce T cells to attack tumor cells, and their data suggest that vaccine potency is further enhanced when activated by the immune system booster. In an independent clinical trial, it was found that a higher than standard dose of temozolomide in combination with immunostimulatory factors also activates the immune system, thereby enhancing response to different vaccine targets.
When the patient's lymphocytes are exhausted, it is the best time to introduce vaccine treatment. By placing a march command on the immune system and integrating resources to attack the tumor, the therapy significantly slows the patient's tumor progression. Typically, glioblastoma tumors re-grow at eight months after standard treatment, but participants in the study had a median of 25 months of recurrence.
Latest research: DC vaccine enables patients with malignant brain tumors to survive for more than 5 years
6, PD-1 inhibitor combination therapy
Picture from Inovio
On November 1, 2017, Inovio Pharmaceuticals announced a Phase 1b/2a immuno-oncology trial for newly diagnosed glioblastoma (GBM) patients to evaluate Regeneron's PD-1 inhibitor cemiplimab The effect of the combination with the company's INO-5401 and INO-9012.
Among them, INO-5401 is a T cell activation immunotherapy encoding a plurality of antigens, and INO-9012 is an immunoagonist encoding interleukin-12 (IL-12).
Cemiplimab (REGN2810) is a PD-1 inhibitor developed by Sanofi and Regeneron. In September 2017, the US FDA has awarded cemiplimab breakthrough therapy for metastatic skin. Squamous cell carcinoma (CSCC) and adult patients with locally advanced, unresectable CSCC. And the FDA has issued a fast track qualification, and the two companies plan to submit a biologics license application for cemiplimab in early 2018.
The open clinical trial of the cemiplimab, INO-5401, and INO-9012 combination includes 50 patients and will be performed at approximately 30 locations in the United States. The primary end point of the trial is safety and tolerability. In addition, the study will assess the effects of combination therapy on immune function, progression-free survival (PFS), and overall survival (OS).
The latest clinical progress: breakthrough results of PD-1/PD-L1 immunotherapy in various cancer treatments
7, the conclusion
Although the development of new drugs is similar to a “gambleâ€, it faces many uncertain factors such as long cycle, high cost and high risk. Whether we can overcome brain cancer, we can't conclude now, but more and more new treatments can prolong the lives of patients and improve their quality of life. We still have to hope, maybe the turn is in the next moment. So, gene therapy, CAR-T, DC vaccine, and PD-1 combination therapy, which one do you prefer?
Reference source
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http://ir.ziopharm.com/releasedetail.cfm?ReleaseID=1049290
Source: Medical Maike (WeChat emedclub_com)
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