CAR T Offers Hope for Challenging Gliomas

Behnam Badie, MD, and Christine Brown, PhD

While chimeric antigen receptor (CAR) T-cell therapy is an established treatment option for hematologic malignancies, it is also being applied in solid tumors, including brain tumors.

A phase 1 study (NCT02208362) conducted at City of Hope led by Behnam Badie, MD, and Christine Brown, PhD, investigated CAR T-cell therapy in recurrent glioblastoma and high-grade glioma. The study involved 65 patients and tested different delivery methods and manufacturing techniques for the CAR T cells. The treatment was found to be safe and well-tolerated with manageable adverse effects. Importantly, half of the patients showed stable disease or improvement, including complete tumor disappearance in a few cases.^1,2

Survival rates were also encouraging, with a median overall survival of 7.7 months for all patients and 10.2 months for those receiving a specific combination of delivery method and manufacturing process.

These results suggest that CART-cell therapy targeting interleukin-13 receptor alpha 2 (IL13Rα2) has promise for treating recurrent high-grade glioma. Further studies are warranted to refine the approach and improve outcomes for patients with this challenging cancer.

“It is an exciting time for the field in cell therapy and developing a cell therapy that can target glioblastoma and other high-grade gliomas is an important unmet need. We think we are moving closer to the goal of developing a meaningful therapy for this patient population,” said Brown in an interview with Targeted Oncology^TM.

In the interview, Badie and Brown delved into the study, its findings, and its implications for the brain cancer treatment landscape.

Targeted Oncology: What makes glioblastoma challenging to treat?

Badie: There are many reasons. One of the main problems is that these tumors are very invasive. When we do a surgical excision, it is impossible to remove all of the tumor. Also, they are very heterogeneous. Some of the drugs that target specific oncogenic pathways in other cancers do not work because [glioblastoma] can change over time and become more aggressive. The drugs that have been developed for other cancers also do not penetrate the margin of the tumor. It is difficult to target those invasive cells. Finally, and this relates to immunotherapy, is that the microenvironment [in glioblastoma] is different, and it is immunosuppressive. This is a major reason why immunotherapies have not been very effective against these tumors. 

What about glioblastoma allows CAR T-cell therapy to target it?

Badie: Targeting glioblastoma in general is very challenging. We have not made [many] strides. If you look at all the approved drugs over the past few decades, we have added maybe a few months to the average survival. No matter what you try to develop, it is a challenging cancer to target. But glioblastomas remain localized in the brain and rarely metastasize to other organs. This makes them attractive targets for local therapies such as CAR T cells.

Brown: Other therapies have gotten better at controlling systemic disease and cancer. But often, it is difficult for these therapies to cross the blood-brain barrier, so that leaves these cancers in the [central nervous system (CNS)] as nonresponsive to many other therapies. Using a cell therapy that can traffic through the CNS and locally delivering this therapy, we think provides an opportunity to have a therapeutic impact where other therapies have not.

Can you provide some background on what you were evaluating and how the study was designed?

Brown: This was a phase 1 study to evaluate the feasibility and safety of IL13Rα2-directed CAR T cells in heavily pretreated patient populations with recurrent glioblastoma or high-grade gliomas. As we mentioned, these are some of the most difficult to treat solid tumors, and a cancer that is typically refractory to immunotherapy. We knew when starting this trial [that] we were going after 1 of the most difficult-to-treat cancers.

The goal here was to understand how these cells can target glioblastoma and how they function in the CNS. Encouragingly, we showed that local regional delivery of these CAR T cells is both safe and feasible. Importantly, it showed that these CAR T cells can mediate meaningful clinical benefit in a subset of patients. We found that 50% of patients achieved stable disease or better, 2 patients had a partial response, and 2 patients had a complete response. While the majority of patients ultimately recurred, I think these early clinical findings are really encouraging.I think these are exciting the field [and] something to build on.

Badie: This clinical trial evolved over time. As we conducted the trial, we made new discoveries which resulted in changes to the protocol. That is why [the study] took a bit longer. But it set the foundation for future protocols that involve local delivery of CAR T cells.

Brown: To that point, I think it is really the close relationship of translational science, bench to bedside, and then bedside to bench. We have multiple examples throughout this trial where Dr. Badie would observe something clinically, and my lab would be studying that in preclinical models, and we would make a protocol change based on rigorous science that was leading us to these ideas.

One example of this is, in our meetings, Dr. Badie was discussing how the cells, when we delivered them into the resected tumor cavity, were locally controlling disease, but that some patients were recurring at distant sites. We were doing studies in animal models showing if we delivered the cells also to the cerebral spinal fluid, that potentially there was better trafficking to multifocal disease. This is why we looked at different routes of delivery, not only for safety, but looking hopefully to try to get these cells to these very invasive small malignant tumors.

What are the next steps of this research?

Brown: I think this trial has taught us a lot, not only for the safety, feasibility, and bioactivity, but also potentially giving insights [as to] why some patients responded better than others and why others progressed. As Dr. Badie mentioned previously, one of the challenges is heterogeneity. We saw in some patients’ tumors recurring with lower expression of the target antigen, and so we are moving forward and looking at multi-antigen targeting strategies where we target multiple receptors that are expressed by these heterogeneous tumors.

The other aspect we learned in this study was related to CD3 or T-cell infiltrates. Patients that have pretreatment tumors with higher T-cell levels seem to respond better to the therapy. This really drives a whole area of investigation of how we better engage the host immune system to help target this difficult-to-treat cancer. The last thing that we are learning is the suppressive pathways that are limiting the therapeutic function of the CAR T cells, and we're devising strategies to block these suppressive pathways to enhance the activity of the therapeutic cells.

Badie: I think one of the major learning points for me was the correlative studies that were done in Dr. Brown's lab. Because we were delivering the cells through catheters that had been implanted into the brain, we had access to spinal fluid, almost on a weekly basis. I think it was interesting to see that the patients’ immune systems get activated when we injected the cells into the brain. In addition to the CAR T cells, we detected other T-cell populations that trafficked from the body to the brain. Also, we saw that the CAR T cells migrated from the brain to the systemic vasculature. These were very novel findings.

REFERENCES:

1. Neith, K. City of Hope-developed chimeric antigen receptor (CAR) T cell therapy shows clinical activity in patients with aggressive brain tumors in phase 1 trial. News release. March 7, 2024. Accessed March 12, 2024. https://tinyurl.com/8m6kv8t5 

2. Brown CE, Hibbard JC, Alizadeh D. et al. Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat Med. Published online March 7, 2024. doi:10.1038/s41591-024-02875-1