Locally delivered CAR T cells exhibit therapeutic activity in aggressive brain tumors

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A phase 1 trial showed chimeric antigen receptor T-cell therapy may hold promise for the treatment of glioblastoma.

The study assessed engineered CAR T cells designed to target the tumor-associated antigen interleukin-13 receptor alpha 2 (IL-12Ra2), a product invented at City of Hope and licensed by Mustang Bio, a Fortress Biotech company.

Quote from Benham Badie, MD

A major obstacle to successful brain cancer treatment is the limited ability of medications to cross the blood-brain barrier. To overcome this, researchers administered CAR T cells directly into the brain tumor and cerebrospinal fluid.

Results showed 29 (50%) of 58 patients with recurrent high-grade gliomas — primarily glioblastoma — who received the CAR-T product attained stable disease for a minimum of 2 months. Two patients achieved partial responses and one achieved complete response.

Investigators reported a second complete response after additional administration of CAR T cells under a compassionate use protocol.

Christine E. Brown, PhD

Christine E. Brown

“When we started this study in 2015, this was the first second-generation CAR T cell to be delivered into the brain of patients with a high-grade brain tumor,” Christine E. Brown, PhD, Heritage Provider Network professor in immunotherapy and deputy director of the T Cell Therapeutics Research Laboratories at City of Hope, told Healio. “At the time, there was a lot of evidence for cytokine release syndrome and neurotoxicity with CD19 CAR T-cell therapies. This was a very important study to show that we can locally deliver engineered T cells, and that they can have therapeutic activity.”

Healio spoke with Brown and study senior author Behnam Badie, MD, Heritage Provider Network professor in gene therapy and chief of neurosurgery at City of Hope, about the potential of this therapeutic strategy and what it might mean for the future of glioblastoma treatment.

Healio: What inspired you to investigate CAR T-cell therapy in this patient population?

Badie: High-grade gliomas have very poor prognosis. They don’t respond to standard therapies. We do surgery followed by radiation and chemotherapy. These tumors are very invasive so it’s nearly impossible for surgeons to remove all of the tumor. Tumors migrate into surrounding brain tissue, and we often leave tumor cells that are far from the area of the surgery. Radiation and chemotherapy don’t work well for various reasons. There are glioma stem cells that are resistant to chemoradiation so, invariably, they come back within a month or a month and a half if nothing is done. With standard radiation and chemotherapy, the average survival is about 14 to 16 months.

CAR T-cell research for gliomas began at City of Hope nearly 20 years ago. The idea was to generate T cells that recognize specific receptors on gliomas. After they are generated, we deliver them intracranially, directly where the tumor is. We went through different phases of the trial and improved on the CAR T cells, and we are still working on that. The rationale was to deliver an effective immunotherapy right into the tumor.

Healio: How did you conduct the study?

Badie: The study was built on our knowledge from other phase 1 studies. We’ve learned that injecting some of the T cells directly into the surgical resection cavity was safe, but we modified the delivery over time. In a few cases, when we removed the tumor, we implanted catheters and delivered CAR T cells directly where the surgery had been performed. We noted there was a delay in tumor recurrence. In some cases, tumors didn’t recur in that area, but patients developed tumors in other parts of the brain. We modified the delivery to not only inject into the resection cavity, but also the ventricles where the cerebral spinal fluid is made.

Healio: What did you find?

Brown: We’ve shown that locally delivering engineered T cells can have therapeutic activity. Now, multiple groups are building on our experience with locoregional delivery and engineered cells because we’ve shown in a subset of patients that there truly is clinical benefit, even if it’s transient. There is still a lot of important translational medicine to build on, but our findings establish a very critical foundation.

The correlative studies have highlighted what we think are some key areas. We published a case report in 2016 in which an individual had a complete response to therapy. When his tumor came back again, it lost the antigen we were targeting. This highlights an important next step — targeting these heterogenous tumors with cell therapy that is engineered to recognize multiple antigens. Unexpectedly, our study showed that every time we infuse these T cells, there are not only increases in inflammatory cytokines, but also associations between the bioactivity of the cells and an interferon gamma signature. This can be used to assess the bioactivity of the therapy.

By being able to sample both the blood and cerebral spinal fluid, we were able to show that local delivery changes the microenvironment in the brain and in the tumor in distinct ways. We think that’s important. We see the trafficking of new immune cells into the brain after we infuse these cells.

Lastly, we talk about how the baseline tumor features can be a determinant of how well a patient responds. If the baseline tumor has more immune infiltrates — specifically T cells — those patients survive longer after treatment with CAR T-cell therapy. We’re interrogating this and trying to use it to make the next-generation therapy. We have a working hypothesis that there’s an interplay between the therapy and host immunity, but also tumors that have higher infiltration might suggest a different tumor microenvironment where the T cells are able to function with more potency. We are looking at both of these hypotheses as we build our next-generation therapy.

Healio: What do these findings suggest in terms of the potential role of CAR T-cell therapy for treatment of brain tumors?

Badie: We’ve learned a lot. A few other papers on this topic came out at the same time. It should be noted that we reported on 60 patients as opposed to just a few. Our paper stands out, not only because we have the longest history and experience with this technology, but also because of the reporting of these correlative studies, which is very unique. In college and medical school, they teach you that the brain is an immune-privileged organ — that immune cells don’t go to the brain or they don’t come out of it. However, we’ve shown in this trial that this is not the case. There is surveillance of the immune cells — they migrate to the brain — and we’ve also seen T cells go out of the brain into the blood. We think these are very important findings and something that can be educational for investigators in other fields of immunotherapy, such as multiple sclerosis. We know CAR T cells work for some patients — we just have to figure out why they don’t work in others.


For more information:

Benham Badie, MD, can be reached at bbadie@coh.org.

Christine E. Brown, PhD, can be reached at cbrown@coh.org.

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