Encapsulated Cell Based Oncolytic Virus Therapy for Brain Tumors

Brigham And Women'S Hospital, Boston MA

Investigators

Abstract

ABSTRACT Glioblastoma (GBM) is the most lethal primary brain tumor with standard-of-care therapies providing only partial palliation. One of the cornerstones of clinical care for GBM patients is surgical tumor debulking and subsequent chemo- and radiotherapeutic treatment. Oncolytic herpes simplex virus (oHSV) that selectively replicate in tumor cells and illicit antitumor effect via oncolysis and production of neoantigens are among the recently approved promising therapies for cancer patients. Although phase I and Ib oHSV clinical trials in GBM patients have shown signs of anti-tumor activity, clinical response rates have been sub-optimal primarily due incomplete understanding of the immune evasion and oHSV delivery issues in the tumor resection cavity post-surgery. Considering the critical and very limited timeline from diagnosis to primary surgical intervention in GBM patients, allogeneic “off-the-shelf” engineered stem cells offer a promising therapeutic strategy to target residual GBM cells post-surgery. We have previously demonstrated that MSC armed with different oHSV variants (MSC-oHSV) home to tumors and synthetic extracellular matrix (sECM) encapsulated MSC-oHSV have a significantly better therapeutic efficacy than the purified oHSV in GBM. These results although promising, have raised fundamental questions on how to develop MSC based therapeutic approaches that specifically kill tumor cells and simultaneously activate immune effector functions against GBMs. To enhance the therapeutic efficacy of MSC-oHSV, we have created oHSV resistant CRISPR/Cas9 nectin-1 (utilized by oHSV as a mode of entry into the cell) knockout MSC (MSC-N1KO) thus allowing us to co-deliver immunomodulators in combination with MSC-oHSV. Utilizing MSC-N1KO engineered immunomodulator screening, we have identified interleukin (IL)-12, which is known to activate both innate and adaptive immunity, to enhance the therapeutic efficacy of MSC-oHSV. Based on these findings, MSC-N1KO will be engineered to express regulatable IL-12 and the therapeutic efficacy of co-delivered MSC-oHSV and MSC-N1KO- IL12 will be tested in immune-phenotyped nodular and semi-invasive syngeneic GBM models of resection that we have recently developed and characterized. Given that oHSV/IL12 mediated therapies upregulate programmed death ligand (PD-L)1, MSC-N1KO-IL12 will be further engineered to express next generation of anti-PD-1 antibodies (nanobodies; Nb) and the therapeutic efficacy and fate of encapsulated MSC-oHSV and MSC-N1KO-IL12/Nb-PD1 will be assessed in syngeneic GBM models of resection. We hypothesize that surgical resection-elicited recruitment of immune effector cells at the residual tumor site will synergize with MSC-delivered oHSV, IL-12 and Nb-PD-1, resulting in increased therapeutic benefit. To ease clinical translation, engineered human MSC will be developed and tested in invasive and nodular patient derived GBM resection models in humanized mice. The integration of the kill switch in MSC will ensure safety in our approach and the incorporation of 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 MSC based therapies for GBM and are likely to define a new treatment paradigm for patients with other cancers.