Scientists have identified a new molecular target for CAR T-cell immunotherapy to attack both glioblastoma cells and tumor-supporting macrophages at once. A study published today in Nature shows promising preclinical results that could allow this approach to overcome the limitations of previous attempts to target glioblastoma with CAR T cells.
“Our approach targets both the tumor and the environment that allows it to thrive,” said Sheila K. Singh, MD, PhD, professor of neuro-oncology and neurosurgery at King’s College London and McMaster University. “Instead of treating glioblastoma as only a mass of cancer cells, we need to think of it as a connected tumor-immune ecosystem. By going beyond the cancer cells alone, we are also targeting immune cells that help shield the tumor from treatment.”
Glioblastoma is an aggressive and lethal form of brain cancer where current treatments, including surgery, radiation and chemotherapy, only provide temporary benefits and are rarely able to prevent recurrence. Past attempts to develop CAR T therapies for glioblastoma have failed to produce sustained responses due to a number of challenges such as heterogeneous antigen expression, antigen loss, and microenvironmental barriers that treatments solely focusing on targeting the tumor cells have not been able to surmount.
In particular, tumor-associated macrophages have been shown to be key contributors to glioblastoma progression. While macrophages normally play an important role in the immune response against infections, glioblastoma can recruit and reprogram these immune cells to promote tumor growth, suppress the immune system, and resist treatment.
“CAR T therapy has been effective in some blood cancers, but translating that success to brain tumors has been difficult,” said Shan Grewal, an MD/PhD candidate at McMaster and co-lead author of the study. “Most approaches have focused on killing cancer cells alone. Our work suggests we may also need to dismantle the immune support system that helps glioblastoma survive.”
Using patient tumor samples, Singh’s team conducted multi-omic profiling studies that led to the identification of a promising target present both in glioblastoma cells and tumor-associated macrophages, called glycoprotein non-metastatic melanoma protein B (GPNMB). By engineering CAR T cells to target GPNMB, the researchers were able to attack glioblastoma tumors on two fronts and show potent antitumor activity in several preclinical models including patient-derived xenografts.
While more work will be needed before this strategy can be evaluated in clinical trials, the study introduces a new framework to identify immunotherapy targets that could potentially be applied to a wide range of solid tumors beyond glioblastoma.
Supporting this concept, a team at the University of Calgary has simultaneously published results in Nature Cancer from a first-in-human study using a similar approach in relapsed alveolar soft-part sarcoma (ASPS) and translocation renal cell carcinoma, two types of cancer that stably express GPNMB. In these patients, a CAR T-cell therapy directed against GPNMB was found to be safe and induced stable disease for up to three months, providing early clinical evidence supporting the feasibility of this therapeutic approach.
The post CAR T Cells Simultaneously Target Glioblastoma and Immune Cells appeared first on Inside Precision Medicine.