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Human CAR-T Cell Glioblastoma Trial Generates Clues for Improving Treatment

A chimeric antigen receptor T-cell (CAR-T) therapy for glioblastoma (GBM) successfully crossed the blood–brain barrier to reach tumors in the brain, appeared safe, and diminished levels of its epidermal growth factor variant III (EGFRvIII) tumor target in GBM cells, in a first-in-man trial carried out by researchers at the University of Pennsylvania. The explore also found that broad variation in EGFRvIII expression among patients, coupled with active immunosuppressive switches in the tumor in response to CAR T-cell infusion, may represent barriers to the clinical utility of the CAR-T therapy on its own.

The autologous EGFRvIII-directed CAR-T therapy has been developed through an ongoing collaboration inbetween researchers at the University of Pennsylvania and Novartis. The partnership has already resulted in the development of Novartis` CAR-T therapy CTL019 (tisagenlecleucel), which just last week was unanimously recommended for approval by FDA`s Oncologics Drug Advisory Committee for treating relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) in children and youthfull adults.

EGFRvIII is voiced in about 30% of freshly diagnosed GBM cases; however, in patients who get through for a year or longer, EGFRvIII expression is thought to be associated with poorer prognosis. The reported pilot investigate with the CART-EGFRvIII candidate involved ten powerfully treated patients with refractory, recurrent GBM, who received a single infusion of the CAR T cells. Three of the patients did not fall under surgery following CAR-T therapy infusion, three patients, respectively, underwent late surgery at 34, 55, or one hundred four days after infusion, and four early surgery patients had clear symptomatic progression and underwent a combined regimen of CAR T-cell infusion followed by clinically indicated surgery.

Tests on tumors from patients who underwent surgery soon after therapy found CART-EGFRvIII cells and signs of activation within the very first two weeks after CAR T-cell infusion. Circulating CAR T cells were also found in the blood of all patients receiving the infusion. Blood levels of the CART-EGFRvIII cells began to decline after two weeks and were undetectable after a month. Tumors from five patients who underwent surgery following therapy also exhibited lower levels of the target antigen EGFRvIII.

The primary endpoint of the Phase I investigate was safety, rather than efficacy, and it wasn`t possible to identify definitive clinical benefit of CART-EGFRvIII therapy. However, one patient achieved stable disease at eighteen month follow-up and was still alive when the examine data was published. Another two patients also survived, but demonstrated disease progression. The remaining seven patients lived incrementally longer than would be predicted based on their treatment history and multifocal tumor recurrence.

While the trial demonstrated that treatment was associated with on-target activity in the brain, it also found that there was a broad variation in EGFRvIII expression among patients over time and in different areas of their tumors. CAR-T therapy also triggered the production of immunosuppressive regulatory T cells that migrated into the tumor, and led to upregulation of extra immunosuppressive pathways. Both EGFRvIII variability and inhibitory responses in the tumor microenvironment will represent potential barriers to therapy, the authors point out.

«Albeit the former will require targeting extra antigens, the latter may be overcome with existing drugs that target immunosuppressive molecules,» they write in their published paper describing the explore. «Our initial practice with CAR T cells in recurrent GBM suggests that albeit intravenous infusion results in on-target activity in the brain, overcoming the adaptive switches in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM.» The paper, titled «A Single Dose of Peripherally Infused EGFRvIII-Directed CAR T Cells Mediates Antigen Loss and Induces Adaptive Resistance in Patients with Recurrent Glioblastoma,» is released today in Science Translational Medicine.

“There is a dramatic expansion of inhibitory T cells in the tumors after the infusion, much more significant than what you see without the CAR T cells,” notes trial leader, Donald M. O`Rourke, M.D., associate professor of neurosurgery at University of Pennsylvania`s Perelman School of Medicine. “This tells us that we need to begin to modulate the microenvironment to make it more favorable. . There may be a synergy inbetween CAR T cells and inhibition of these pathways with small-molecule drugs or checkpoint blocking antibodies.”

Albeit the immunosuppressive nature of GBM is well recognized, «the adaptive environment is a fresh finding,» professor O`Rourke told GEN. «This investigate represents the very first exploration of the microenvironment in depth. . We are ultimately going to get some clues about the tumor microenvironment both before and after CAR T-cell administration, and maybe begin to develop approaches to modify that, and to peak the balance in favor of clinical efficacy.»

«One of the titillating things about this investigate is the number of T cell clones that get into the brain after CAR T-cell infusion,» Dr. O’ Rourke stressed. «If we can devise strategies to get more in, and combine that with modifying the tumor microenvironment, we might see better clinical results.” One possibility may be to combine CAR-T therapy with checkpoint inhibition, potentially using programmed cell death protein one (PD-1) or programmed death-ligand one (PD-L1) inhibitors, he suggests. A number of groups at Penn University are also actively carrying out research on the GBM tumor microenvironment, both in preclinical models and in patients.

Safety was a potential concern, but the trial didn’t highlight an issues, Dr. O’Rourke stressed. «At the beginning of this investigate we were worried that providing this very active product would cause a lot of brain inflammation,» he commented to GEN. «The fact that we are not witnessing any clinically adverse problems is something on which we can build, and we are very encouraged by the safety profile.» These early indications of safety are particularly encouraging, in light of patient deaths in Juno`s JCAR015 CAR-T therapy trial last year. Earlier this year Juno confirmed that it was ditching further development of JCAR015 for treating adult r/r ALL.

«As far as I know, this is the very first time that the tumor microenvironment has been characterized and its influence on resistance has been noted in a solid tumor after CAR-T therapy,» added senior probe author Marcela Maus, Ph.D., M.D., a former Penn faculty member who is now the director of cellular immunotherapy at the Massachusetts General Hospital (MGH) Cancer Center and an assistant professor of medicine at Harvard Medical School. «We were able to demonstrate that this CAR T-cell product is safe and that the CAR T cells infiltrated the brain tumors,» she reiterated to GEN. «There are several potential next steps, including providing more doses, and combining it with other drugs to increase the potency of the CAR T cells in GBM – candidate drugs could include chemotherapy, checkpoint blockade like anti-PD1 to make the CAR T cells more resistant to the tumor microenvironment, or small-molecule drugs that switch the tumor microenvironment. . My fresh laboratory at MGH is exploring preclinical models to prioritize combinations that can be given with CAR T cells in solid tumors, including engineering the CAR T cells to modify or switch the tumor microenvironment, and address the heterogeneity of the target expression.»

Novartis and the University of Pennsylvania established their global collaboration and license agreement to research, develop, and commercialize CAR-T therapies for cancer in 2012. The EGFRvIII CAR-T therapy uses a construct that was jointly developed under the agreement, and to which Novartis has sensational rights, a Novartis spokesperson explained to GEN. The stiff is now considering combination strategies that may increase the function of EGFRvIII-directed CAR T cells against GBM tumors.

Novartis and the University of Pennsylvania are working to develop numerous candidates. «As part of our ongoing research and development collaboration with the University of Pennsylvania, researchers are generating a pipeline targeting hematological malignancies as well as solid tumors with CAR-T therapies. CTL119 is a humanized anti-CD19 CAR in initial clinical development for numerous B-cell malignancies. CART-BCMA is a novel, fully human CAR targeting B-cell maturation antigen (BCMA) under evaluation in numerous myeloma. A novel, fully human antimesothelin CAR (huCART-Meso) recently began clinical testing in solid tumors.»

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