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, Michael Barish, PhD, spoke about an investigational CAR T-cell therapy that he and colleagues are developing as a treatment for patients with glioblastoma. He and his team designed the agent to harness chlorotoxin, an amino acid peptide toxin component of scorpion venom, as a vehicle for intratumoral delivery of therapy for this patient population.

Barish, a chair in the Department of Neurosciences/Developmental & Stem Cell Biology at City of Hope, discussed the background and mechanisms surrounding this novel compound, which he and colleagues evaluated as part of a phase 1 trial (NCT04214392). Early findings published in 

 showed that among 4 patients with recurrent glioblastoma, 3 (75%) achieved a best response of stable disease. Additionally, the chlorotoxin-directed cellular therapy was found to be well-tolerated with no dose-limiting toxicities. Although responses were not as strong as Barish and colleagues had hoped, he described how the study nevertheless demonstrated the safety and feasibility of this CAR T-cell therapy formulation.

After establishing the safety of the novel agent in patients with recurrent glioblastoma, Barish highlighted how next steps for research included engineering different versions of the chlorotoxin and modifying the T cells that express the chimeric receptor. He stated these reconfigurations may help yield additional power and efficacy of the cellular therapy in future studies. Overall, Barish noted how the potential therapeutic application of the neurotoxin represented a “proof of principle.”

“[V]enoms of many invertebrates are, in fact, very powerful biologically. In a sense, evolution has honed them to be relatively specific. Neurobiology is very much driven by the specificity of different toxins for different ion channels,” Barish stated. “This idea—that one could use biological products efficiently this way for something as heterogeneous as glioblastoma—might be an example of how it could be more efficacious for other solid tumors as well.”

Barish ME, Aftabizadeh M, Hibbard J, et al. Chlorotoxin-directed CAR T cell therapy for recurrent glioblastoma: interim clinical experience demonstrating feasibility and safety. Cell Rep Med. 2025;6(8):102302. doi:10.1016/j.xcrm.2025.102302.

Michael Barish, PhD, discusses a novel cellular therapy for patients with glioblastoma that harnesses chlorotoxin, a peptide found in scorpion venom.

How Can Chlorotoxin-Directed CAR T-Cell Therapy Impact Glioblastoma Care?

Shewetal Mehta, PhD, spoke about her research team’s focuses

 in moving novel brain cancer therapies down the pipeline as part of an early phase clinical trials program at the Ivy Brain Tumor Center.

Mehta, the deputy director and pre-clinical core leader at the Ivy Brain Tumor Center of Barrow Neurological Institute in Phoenix, Arizona, underscored a scientifically rigorous, patient-driven philosophy that drives her team members to deliver timely answers to those with brain cancer via work in a clinical lab and a pre-clinical arm. This collaboration helps identify therapeutic agents that may demonstrate activity in the brain while determining patient populations who are suitable to enroll on clinical trials.

As part of her institution’s early phase trial program, Mehta specifically highlighted work associated with a phase 0/1 clinical trial (NCT06072586) evaluating BDTX-1535, a brain-penetrant fourth-generation EGFR inhibitor, for those with recurrent high-grade glioma harboring oncogenic 

 Investigators are incorporating liquid biopsy, sampling cerebrospinal fluid from patients on treatment to monitor potential evolutions or changes in brain tumors.

Regarding biomarker testing, Mehta described the roles that gene sequencing and immunohistochemistry can play in identifying targetable alterations in patients with brain cancer. She described vorasidenib (Voranigo), which 

received approval from the FDA in August 2024

, as an example of a targeted therapy that may be suitable for use in patients who are found to have actionable 

“Over the last year, we’ve seen that we were capable of not just doing these early phase clinical trials [but of entering] this phase of moving drugs into phase 3 [studies]. That’s exciting,” Mehta stated regarding her outlook on the current state of brain cancer treatment. “Right now, we are excited about these new classes of agents that are within the space, like the proteolysis targeting chimeras, protein degraders, and antibody-drug conjugates, which have shown amazing promise in the rest of the oncology space.”

Study of BDTX-1535 in recurrent high-grade glioma (HGG) participants with EGFR alterations or fusions. ClinicalTrials.gov. Updated January 15, 2025. Accessed January 15, 2025. https://tinyurl.com/m6kwr2b3

FDA approves vorasidenib for grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. News release. FDA. August 6, 2024. Accessed January 20, 2025. https://tinyurl.com/25r9fkvy

Ivy Brain Tumor Center

Shwetal Mehta, PhD, emphasizes her institution’s patient-focused and scientifically rigorous philosophy when developing new therapies in brain cancer.

Conducting Early Phase Trials of Promising Treatments in Neuro-Oncology

, Yoshie Umemura, MD, offered various perspectives on progressing in the brain cancer treatment field. In addition to detailing institution-level advances in delivering multidisciplinary care, she highlighted her personal growth as she advanced in the neuro-oncology field while giving key advice to aspiring researchers who are in the early stages of their careers.

Umemura, the chief medical officer of the Ivy Brain Tumor Center, division chief of Neuro-Oncology, and the William and Joan Shapiro chair of Neuro-Oncology at Barrow Neurological Institute, first described what drew her to studying neurology and eventually specializing in neuro-oncology, emphasizing the potential to form close connections with patients during treatment. Additionally, her collaborative approach to care and her institution’s emphasis on multidisciplinary practice have helped in yielding various accomplishments, which included expediting the development of an investigator-initiated trial during the COVID-19 pandemic.

The conversation also focused on the personal aspects of Umemura’s neuro-oncology career. Delving into her experiences with immigrating to the United States when she was a high school student, she recalled feeling like an outsider as she learned to speak English and began to study neurology. However, she noted how several role models and mentors in the field have offered her guidance, which helped her grow and take on more leadership positions over time.

Continuing to build upon the theme of collaboration in brain cancer research, Umemura emphasized the necessity of finding mentors even outside of one’s institution to advance in the field. Additionally, as part of paying it forward to a new generation of neuro-oncologists, researchers should also become open to guiding others once they have gained enough experience.

“When you are at a conference and you meet someone you think you might click with, you’re intrigued about, or you’re impressed with, you can shoot an email and ask them if they would be open to chatting with you about a question or mentoring you,” Umemura said. “[You should also] pay it forward. Always be open to mentoring others; I think that’s the only way to move forward….It [speaks] to the collaborative aspect and how to operate as an outsider. You’re not an outsider as long as you make the connection; you can just wedge yourself in.”

The only way forward in the brain cancer field is to be open to mentoring others, according to Yoshie Umemura, MD.

Forming Connections and Making a Difference in the Brain Cancer Field

, Nader Sanai, MD discussed the current state of the glioblastoma field, highlighting ongoing research efforts to help improve outcomes among patients with this disease.

Sanai is the director of the Ivy Brain Tumor Center and J.N Harber Professor of Neurological Surgery, Francis and Dionne Najafi chair for Neurosurgical Oncology, and chief of neurological oncology at Barrow Neurological Institute.

Specifically, Sanai described plans to assess treatment with niraparib (Zejula) compared with temozolomide (Temodar) in a population of patients with newly diagnosed MGMT unmethylated glioblastoma as part of the phase 3 Gliofocus study (NCT06388733).

 He contextualized the rationale for conducting this study by focusing on findings from a proof-of-concept hybrid study (NCT05076513) and detailing how they supported additional investigation into the utility of niraparib.

According to findings from this proof-of-concept study presented at the 

2024 American Society of Clinical Oncology (ASCO) Annual Meeting,

 the median overall survival (OS) was 20.3 months among patients who received niraparib in combination with radiotherapy.

 Additionally, data showed that niraparib reached drug concentrations in Gadolinium-nonenhancing newly diagnosed glioblastoma tissue exceeding those of any other evaluated PARP inhibitors; investigators identified no new safety signals after combining niraparib with radiotherapy in this population.

With the Gliofocus trial, Sanai and co-investigators aim to provide a clinically meaningful quality of life benefit with niraparib-based therapy beyond a marginally valuable statistical advantage. By evaluating treatment with niraparib, investigators look to improve historical survival rates reported with standard-of-care options among patients with unmethylated disease.

“What we’re looking to do with this trial is set a benchmark that’s clinically relevant for patients and providers. The [OS] target for the study is 18 months, which is to effectively convert [a] 12-month natural history to a natural history closer to the methylated glioblastoma population,” Sanai said. “We think that is a meaningful transformation of a difficult patient population, a significant chunk of survival time that would be beneficial to patients, providers, and caregivers. Importantly, [it may also mean] an advantage for quality of life, which is of paramount importance for this patient population.”

A study comparing niraparib with temozolomide in adult participants with newly-diagnosed, MGMT unmethylated glioblastoma. ClinicalTrials.gov. Updated June 24, 2024. Accessed September 16, 2024. https://tinyurl.com/y25er8p9

Sanai N, Umemura Y, Margaryan T, et al. Niraparib efficacy in patients with newly-diagnosed glioblastoma: Clinical readout of a phase 0/2 "trigger" trial. 

 2024;42(suppl 16):2002. doi:10.1200/JCO.2024.42.16_suppl.2002

Investigators of the Gliofocus trial look to set a clinically relevant “benchmark” in the glioblastoma field, according to Nader Sanai, MD.

Advancing Glioblastoma Research Through a Phase 3 Niraparib Trial

 at John Theurer Cancer Center, Timothy Chen, MD, highlighted various novel treatment strategies that have impacted his care of patients with brain tumors and other types of cancer.

Chen, a board-certified radiation oncologist and medical director of the Central Nervous System Program at Jersey Shore University Medical Center and the director of Proton Therapy in the Department of Radiation Oncology at Hackensack Meridian Health, first discussed his use of the novel stereotactic radiosurgery modality ZAP-X for patients with brain tumors. According to Chen, this tool may allow for practices to administer radiation at submillimeter precision, which can spare normal tissue from receiving excess radiation.

Another technology that Chen highlighted included GammaTile, a radiation treatment that was developed for the management of brain tumors. He said that this collagen tile may help with administering strong radiation to precisely where the tumor is located, while also protecting healthy tissues to minimize the adverse effects from radiation therapy. Specifically, Chen stated that GammaTile may be beneficial for those with larger, difficult-to-treat tumors.

Finally, Chen discussed the potential applications of proton therapy and how it may improve outcomes in patients compared with standard radiotherapy. According to Chen, proton therapy serves a “great purpose” with what he described as a precise depth charge that can minimize toxicity during treatment.

Additionally, Chen described how proton therapy may help reduce the probability of developing mutations or secondary cancers among pediatric patients. He highlighted the potential benefit of this modality based on a specific case in which a pediatric patient with myxopapillary ependymoma experienced improvements in pain and urinary control following proton therapy.

Regarding these novel forms of therapy, Chen emphasized the notion of multidisciplinary care and said that practices should “work together as a team” when operating these technologies.

“[With] all this technology, it's not just used as it is; the technology brings us to work together,” Chen said. “I think multidisciplinary care is the future. People are no longer siloed…. We all work together.”

Timothy Chen, MD, highlights how technologies such as ZAP-X and proton therapy may improve outcomes for patients with cancer.


Applying Novel Radiotherapy Technology for Brain Tumors and Other Cancers

Javier Orozco-Mera, MD, FACS, MSc, a neurosurgeon in the Department of Neurosurgery at Hospital Universitario del Valle “Evaristo García,” University of Valle, spoke with CancerNetwork

Signaling Pathways in the Relapse of Glioblastoma,

In his study, Orozco-Mera and his colleagues identified a several signaling pathways and molecular processes that are involved in glioblastoma relapse, including markers such as O-6-methylguanine-DNA methyltransferase, micro-RNA, EGFR, and P53.

Don’t forget to subscribe to the “Oncology On-The-Go” podcast on 

Javier Orozco-Mera, MD, FACS, MSc, discusses signaling pathways and molecular mechanisms involved in the relapse of glioblastoma.

Oncology-On-The-Go Podcast: Signaling Pathways in Glioblastoma Relapse

Today we are discussing glioma therapy options with Dr. James Perry, MD, FRCPC, a neuro-oncologist at the Sunnybrook Health Sciences Centre in Toronto, Canada who specializes in the care of patients with central nervous system cancers. 

 Can you talk about the difference between gliomas and glioblastomas? Do both types of brain tumors tend to be malignant when they are found and what are the differences in prognosis for these two tumor types?

I’d be very happy to and thank you for the opportunity to communicate with this great audience. One thing that is not well appreciated is that glioma represents a family of tumors and in the recent World Health classification of brain tumors in 2016, there were no less than 36 different subtypes of glioma identified based on histology and various biomarkers.

Glioma refers to a primary brain tumor rather than a metastatic brain cancer and refers to tumors that have started growing within the brain, usually from glial cells. The predominant ones are astrocytes, which [are] for the astrocytomas and they are graded 2–4 with a grade 4 astrocytoma being a glioblastoma (GBM) [which] is by far the most common form of brain tumor.

Gliomas can also come from oligodendrocytes.  Those form oligodendrogliomas which are significantly more favorable in terms of their biological behavior and their prognosis for patients and can have survivorship measured of decades for folks with these tumors that have the most favorable biomarker profiles.

What are the main initial therapies for malignant gliomas and for glioblastomas?

These tumors are usually identified by imaging, usually following a neurological symptom such as a seizure and usually patients are evaluated in a surgical center by a surgeon. Although the imaging appearance can be fairly typical for most of the gliomas, especially, glioblastoma, it is relatively uncommon to begin treatment without tissues through an operation.

Typically patients will have a biopsy or surgical resection. But that said, we’ve learned in the past 5–10 years that so-called maximal resection, meaning removal of as much of a brain tumor as can be done safely within the confines of not causing neurological morbidity, is beneficial to patients. Patients that have an excellent resection tend to tolerate subsequent treatment much better and their overall prognosis is better.

Patients will typically start with a craniotomy and surgical resection and these days the technology has improved quite a bit so a lot of these patients will have pre-op and intra-operative imaging, awake craniotomies or real-time monitoring of neurological condition, and some neuro techniques using fluorescence imaging where pre-operatively, a patient is given a fluorescent compound that actually tags tumor cells because at surgery, especially with lower grade gliomas, it is very difficult to distinguish abnormal cancer tissue from the normal brain and this technique can really help.

Then the tissue sample goes to a pathologist and a name and histology [is given] for the tumor and a grade. The most important thing these days are the biomarkers that not only help classify tumors, but also are predictive of response to certain therapies. Treatment is tailored, as much as it can be, to the particular type of glioma but most patients will go on to receive external beam radiation therapy. Patients with many of the tumor types will receive the radiation combined with the oral, alkylating agent temozolomide.

You mentioned temozolamide so could you talk about its role in the treatment of these tumor types and subtypes? Are there other chemotherapies that are often used on their own or in conjunction with the radiotherapy?

Historically, the field of neuro-oncology, from the perspective of chemotherapy, started with drugs such as carmustine and thereafter, PCV (procarbazine, lomustine and vincristine). PCV was a very commonly adopted strategy until what we call the temozolamide era emerged. Temozolamide was developed in the 1980s and 1990s and the clinical trials started in the late 1990s. [It] is an oral alkylating agent that is much better tolerated than PCV chemotherapies or the nitrosoureas used historically like carmustine.

A real change in the field happened in 2005 with the publication of the so-called Stupp protocol based on our colleague Roger Stupp who led an international trial testing the role of temozolamide chemotherapy given concurrent with radiation and followed by adjuvant or maintenance oral temozolomide. The field shifted at that point because we had not really had a positive clinical trial for decades prior to that, so there was finally a standard drug therapy. From that success in glioblastoma, multiple groups around the world have tested temozolomide in a variety of other glioma subtypes, including anaplastic astrocytoma and oligodendrogliomas.

All of these tend to be quite sensitive to temozolomides, and oligodendrogliomas in particular are one of the most chemo-sensitive human, solid malignancies. One of the downsides of temozolomide is that its activity is very dependent on a DNA repair enzyme, MGMT [O

-methylguanine DNA methyltransferase], so patients that have high expression of MGMT don’t do well because the alkylating damage induced by temozolomide is quickly repaired.

About 40% of patients with glioblastoma have random hyper-methylation of the 

gene promoter region, effectively shutting off the gene, and diminishing MGMT expression in the tumor cells. Those folks, the 40% or so with this 

 promoter methylation, have much better prognosis and response. So a sort of hole in our field that remains are the 60% of patients with GBM that don’t harbor the 

 promoter methylation which is a very easily determined biomarker in the lab and is routinely done these days.

Essentially 60% of patients receive no benefit from the drug and there really is not an effective chemotherapy agent in standard practice at this point for this unmethylated 

Lastly, are there novel therapies in development or novel combinations for either of these tumor types that are particularly interesting or promising that you could highlight?

Sure, the first caveat is that our field is, unfortunately, lagging behind other cancers in that regard. We all went through the era of targeted therapies and the promise of targeted therapies and we’ve seen those evolve. For example, EGFR inhibitors for lung cancer. The issue for us as neuro-oncologists is the presence of the blood brain barrier and the way our clinical trials were designed were insufficient at detecting that the vast majority of these compounds were not brain-penetrant.  We had a huge number of negative phase II and phase III clinical trials testing these approaches. They never had a chance because they were not getting into the brain in sufficient concentrations.

I mention that because we are in the midst of the newest revolution with immunotherapies including oncolytic viruses and vaccine approaches and we are facing the same kinds of challenges compared to other cancer types. What seems to be promising now is the combination of immunotherapy strategies with anti-angiogenic strategies. So, bevacizumab is fully FDA approved and is routinely used for recurrent gliomas, especially glioblastoma, and it has excellent symptomatic effects although has never really been shown to enhance survival. The immunotherapies have been a challenge on their own.

All of the published vaccine trials have not shown much promise and the checkpoint inhibitors, when used as single agents essentially have no activity. When combined, they have some activity but a lot of toxicity. Newer trials that have shown promise have combined those approaches, whether it's vaccine-based, or checkpoint inhibitor based combined with bevacizumab or other experimental anti-VEGF [Vascular endothelial growth factor] treatments. That is one of the major areas of focus for those of us involved in cooperative group and other trials, trying to find the optimal combination approaches and there have been some exciting early results as there always are when you are trying new things and it remains to be seen how things evolve over the next couple of years.

Thank you so much for joining us today Dr. Perry.

Dr. James Perry speaks with Cancer Network about glioma therapy options and the future of brain cancer treatment.

Promising Glioma Therapy Options

As part of our coverage of the 19th Annual Scientific Meeting and Education Day of the 

, we are speaking today with Mary K. Hughes, MS, RN, clinical nurse specialist in the department of psychiatry at the University of Texas MD Anderson Cancer Center. At this year’s meeting, Hughes is taking part in an education session discussing quality of life and neurologic rehabilitation of patients with neuro-oncologic diseases. 

 Ms. Hughes, why is quality of life an important topic to discuss in patients with neuro-oncologic diseases? 

 Quality of life is what most people focus on. They don’t want to just be alive, they want to be able to enjoy their lives, feel like they have meaningful lives, and feel like they are productive in their family and in society. Sometimes neuro-oncological disease can affect a person’s ability to function, not only doing intimate activities of daily living, but function in their family and in their job, if they choose to work.

 When in the course of disease management should providers address issues of quality of life?

 I think when the person is first seen, their provider should ask them about quality of life and how important it is. How is the disease affecting their life? During the treatment process, how is this affecting your quality of life? At some point, people are not able to eat like they used to or they are not able to drive, and that certainly affects their quality of life. It is an ongoing process across the continuum of care, from diagnosis through survivorship.

 Your portion of the session discusses intimacy and sexual dysfunction. Are these issues common among patients with these diseases?

 Yes they are. Often people mistake sexual dysfunction occurring in only people that have cancer of the genitals. Any time people are treated for cancer of any type, it can affect their sexuality. By discussing their sexuality, this shows the patient that you are interested in treating the whole person, not just the diseased body part. By bringing it up, it legitimizes the topic for discussion. When the practitioner talks about it, the patient says, “I can talk about it too. I am not the only one that has these issues.” It also emphasizes the importance of trying to maintain normal activities and relationships during and after treatment.

 What are some of the specific problems patients may face with sexual dysfunction or intimacy?

 One would be low libido, the person is not very interested in sex and that can be for a variety of reasons, maybe from fatigue or the medicines they are taking. The male may have erectile dysfunction. The female may have difficulty lubricating. That is arousal-they are not able to be aroused. For some people, they are not able to have an orgasm or the orgasm happens too fast or it takes too long to have an orgasm.

 Are these issues something that should be addressed in every patient?

 Absolutely. It does show that you are interested in the person as a whole, not just their diseased part. One of the things that happens in people with brain tumors, they may not recognize visual clues like they used to. For example, how they knew their partner was interested in sex. They also have physical changes because of steroids, so they may have a poor self-image. Sometimes they may be more disinhibited and, at other times, more inhibited. Also, they might not remember the last time they had sex. Their partner might have to remind them-“It has been awhile” or “We just had sex yesterday, don’t you remember?” Those are some specific sexual effects of brain tumor treatment.

 This was all very helpful information about a topic that is not frequently discussed. Thank you again for taking a few minutes to preview this topic for us. 

 You’re welcome. It has been my pleasure.

Society for Neuro-Oncology Annual Meeting (SNO)

As part of our Society of Neuro-Oncology annual meeting coverage, we discuss quality of life issues and neurologic rehabilitation in patients with neuro-oncologic diseases. 

Brain Cancer

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