Interneurons That BiTE: A Novel Cell-Based Therapy for NF1-Associated Brain Tumors
Abstract
Neurofibromatosis Type 1 (NF1) patients develop an array of both benign and malignant tumors. Of these, Malignant Peripheral Nerve Sheath Tumors (MPNST) and High-Grade Gliomas (HGGs) have the most dismal prognosis. About 15-20% of NF1 patients develop brain tumors; a third of these occur outside of the optic nervous tract. Importantly, these non-optic pathway gliomas are more likely to progress to malignancy, especially in adults. Even though the frequency of HGG is low, they have a disproportional effect on the morbidity of NF1 patients. Complete surgical removal of HGGs is often not possible due to the location of the tumor or the highly migratory nature of HGG. Promising new strategies, like CAR-T cell immunotherapy, for example, have shown limited efficacy in the treatment of brain tumors to date. With CAR-T therapy, one harnesses the strength of the immune system by “teaching” the patient’s immune cells to recognize unique tumor antigens (for example some mutated proteins). The strength of CAR-T cells is that they are able to recognize and hone into the site of a tumor and deliver a cytotoxic response to shrink tumors. However, this strategy only works for tumors that display unique and new antigens, for example, because of mutations present in the tumor. Unfortunately, many NF1-associated HGGs have a low mutation count and do not have these unique new antigens, making it more difficult for CAR-T therapy to work. However, the paradigm of CAR-T, where we “teach” cells to hone into a tumor and deliver a cytotoxic response, has revolutionized the way we treat cancer and the way we think about therapeutic development. Any therapy where cells are able to migrate to the tumor and deliver a cytotoxic response is a potential viable therapy. We have developed exactly such a highly specific and sophisticated cell based drug delivery system. The cells used in our system are in essence developing neurons. Unlike their fully matured counterparts, developing neurons are very mobile and can rapidly migrate at least an inch in the brain. Moreover, their migration is not dependent on the expression of antigens, and we can thus use these cells to target brain tumors with low mutation burden. During their migration, developing neurons are guided by specific factors and, intriguingly, many brain tumors secrete these same factors. Excitingly, our data shows that, in mice, implanted developing neurons indeed migrate a tumor present in the brain. In this proposal, we want to evaluate whether these neurons can actually deliver cytotoxic agents that shrink tumors. We will use BiTE technology, which allows our developing neurons to force local immune cells to kill the tumor cells. Importantly, this BiTE technology again does not need unique tumor antigens to work and therefore can be used to kill brain tumors with low mutation levels. All that is required is for these BiTEs to be secreted close to the tumor. The prospect of being able to treat NF1-associated HGG using developing neurons is exciting. Importantly, if successful, these developing neurons would not only be effective against HGGs, but against any brain tumor that secretes the factors that induce their migration, including some NF1-associated Low-Grade Glioma. If we are able to shrink these HGGs, we still have a long way ahead to clinically implement our findings. During this implementation process, which is not part of the scope of this proposal, we expect to encounter similar issues as CAR-T therapy did during its clinical development. Fortunately, the CAR-T technology was developed at UPenn/CHOP, which means we can leverage the expertise of our UPenn/CHOP community in the years ahead.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110381
Entities
People
- Thomas De Raedt
Organizations
- United States Army