Viral therapy research
Over the past 20 years, the Lang laboratory has played a significant role in the development and bench-to-bedside translation of Delta-24-RGD, a novel replication-competent, tumor selective oncolytic adenovirus. Our laboratory has demonstrated the efficacy of this virus in treating gliomas, in both preclinical glioma models and in human clinical trials. Specifically, we have shown that Delta-24-RGD is able to directly kill tumors by infecting and replicating in glioma cells, and ultimately lysing them. We have also recently provided evidence that Delta-24-RGD activates an immune response, which is an important finding because it indicates that Delta-24-RGD is an effective immunotherapy that could circumvent the known immune-evading properties of glioblastomas (GBMs). These preclinical studies led to a Phase I clinical trial where patients with recurrent GBM were treated with Delta-24-RGD, the results of which were published in 2018 (Lang FF et al. J Clin Oncol.). We are currently exploring mechanisms underlying the immune-mediated killing of tumor cells by Delta-24-RGD, developing strategies to combine Delta-24-RGD with immune checkpoint inhibitors and developing next-generation oncolytic viruses.
Current research includes understanding the immune effects of Delta-24-RGD through the use of several animal models including: an immune-competent, adenovirus-permissive hamster with hamster brain tumors to evaluate Delta-24-RGD tumor cell killing, and anti-tumor and anti-viral immune responses; immune-compromised mouse models with tumors derived from human brain tumor cells to evaluate Delta-24-RGD tumor cell killing in an immune-deficient setting; immune-competent mouse models with mouse brain tumors to evaluate the immune response to Delta-24-RGD in the context of low levels of viral replication.
Mesenchymal stem cell research
Delta-24-RGD is an effective anti-GBM therapy, but more efficient delivery mechanisms need to be developed to be able to target the tumor more effectively. The Lang lab was the first to show that bone marrow human mesenchymal stem cells (BM-hMSCs) migrate toward gliomas after intracranial delivery, and even more notably, localize to human gliomas after systemic intra-arterial delivery. We demonstrated that this homing capability can be exploited for therapeutic benefit in a mouse model of glioma, where intra-arterially delivered mesenchymal stem cells loaded with Delta-24-RGD (MSC-D24) selectively localized to orthotopic human glioma xenografts in mice, resulting in improved survival and eradication of tumors in subsets of mice (Yong RL et al, Cancer Research 2009). Based on these findings, we have initiated a clinical trial to evaluate MSC-D24 in patients, and a co-clinical trial to evaluate the same MSC-D24 preparations used in each patient in laboratory studies. We are currently working to increase the amount of D24 in the MSCs and developing improved MSC delivery systems.
Exosomes and microRNA
MicroRNA (miRs) are a promising new therapeutic approach for GBMs, because there is strong evidence to suggest that dysregulated miR expression can drive GBM formation. Our work has demonstrated that restoring specific miRs that are down-regulated in GBMs inhibits the growth of human glioma stem cells (GSCs) (Lang FM et al, Neuro Oncol. 2018). To effectively deliver miRs to patients we are developing exosomes loaded with miRs (Exo-miRs). When intravenously administered to mice, our Exo-miRs home to brain tumors, resulting in down-regulation of the miR target genes. This system may be a novel and potent therapeutic, because multiple miRs can be delivered simultaneously to a given tumor, which may address the known heterogeneity of GBMs.
Human Cerebral Organoids
We have developed human cerebral organoids (COs) from induced pluripotent stem cells as a pre-clinical model system to study brain tumors. These COs harbor neural stem cells (NSCs), differentiated progenies of NSCs and microglia. We use COs to study the interaction between well-characterized glioblastoma stem-like cells and normal brain cells, and our initial studies indicate that the CO model system can differentiate between types of GSCs in terms of their invasiveness and ability to attract microglia. (Singh S et al., Neuro-Oncology 2020). We also use COs to study the side effects of radiotherapy on normal human neural cells, and preliminary findings suggest that radiation has an effect on NSC proliferation (Bronk L et al., Neuro-Oncology 2020).
5P50 CA127001 (SPORE in Brain Cancer)
R01 CA214749 (MSC-derived exosomes and microRNA in glioma therapy)
R01 CA247970 (A Novel Adenoviral-Permissive, Immunocompetent Hamster Model to evaluate Oncolytic Adenoviral Therapy for Glioblastoma)