Monday, May 12, 2025
5/12/2025
Cell surface receptor targeted therapies for brain tumors - SUMMARY New therapeutic approaches are desperately needed for highly malignant brain tumors, glioblastomas (GBMs), where standard therapy has shown limited to no efficacy. In our previous studies, we have developed mouse tumor models of GBM resection and extensively demonstrated that engineered “off the shelf” mesenchymal stem cells (MSC) encapsulated in biocompatible synthetic extracellular matrix (sECM) have therapeutic benefits post-GBM surgery. Engineered T cell based therapies have demonstrated impressive clinical efficacy in hematological cancers, however their success has been limited in solid tumors like GBM, particularly due to evasive and inhibitive tumor micro-environment (TME) and chronic antigen triggering in the presence of suppressive signals in the TME. In order to address the issues related to excessive engineering and exhaustion of T cells, we took advantage of the homing and allorecognition avoidance properties of MSC and engineered them to release bi-specific T cell engager (BITEs) consisting of nanobodies (vHH domain of a heavy chain antibody) simultaneously targeting over-expressed EGFR and specifically expressed EGFRvIII variant in GBM and a CD3 specific scFv (MSC-ENb-BiTE). Our exciting preliminary data indicate that MSC-ENb-BiTE redirect wild type blood derived untransduced T cells to tumors and induce tumor regression in GBM mouse models. These results although promising, have raised fundamental questions for our engineered MSC and naïve T cell therapeutic strategy to target multiple antigens and simultaneously enhance the immunomodulatory function of T cells in mouse tumor models that mimic clinical settings of resected GBM tumors and present nodular and invasive phenotypes? In this proposal, we will develop a broad platform of MSC releasing BiTEs targeting EGFR/EGFRvIII and IL13Rα2 and twin (Tw)-BiTE that simultaneously targets EGFR/EGFRvIII and IL13Rα2 and extensively test their therapeutic efficacy post transplantation of sECM encapsulated MSC-BiTE/Tw-BiTE and intraventricular delivery of T cells in mouse GBM models of resection. Based on the hypothesis that interleukin (IL)-12 will improve the potency of T cell therapy and blocking PD-1 on recruited T cells will result in effective eradication of residual GBM cells, we will co-engineer MSC- Tw-BiTE to express IL-12 and immune-check point inhibitor and assess their efficacy with T cells in GBM models of resection derived from primary GBM lines representing distinct tumor nodular and invasive phenotypes. To ease clinical translation, we will assess the mechanism underlying efficacy of encapsulated engineered MSC and T cells in humanized mouse GBM models. The integration of the kill switch in engineered MSC will ensure safety of our approach and the incorporation of genetically engineered imaging markers into both MSC and GBMs will allow us to follow fate and efficacy in vivo and thus to fine tune the proposed approaches. We anticipate that our findings will have a major contribution towards developing novel cellular therapies for GBM and are likely to define a new treatment paradigm for patients with other cancers.
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