Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increases recruitment of CD8 + T and myeloid cells to the tumor microenvironment. CD8 + T cells are required for ZIKV-dependent tumor clearance, as survival benefits are lost with CD8 + T cell depletion. Moreover, while anti-PD1 antibody therapy alone moderately improves tumor survival, when co-administered with ZIKV, survival increases. ZIKV-mediated tumor clearance also results in durable protection against syngeneic tumor re-challenge, which also depends on CD8 + T cells. To address safety concerns, we generated an immune-sensitized ZIKV strain, which is effective alone or in combination with immunotherapy. Thus, oncolytic ZIKV treatment can be leveraged by immunotherapies, which may prompt combination treatment paradigms for adult GBM patients.

Purpose: Patients with glioblastoma (GBM) are treated with radiotherapy (RT) and temozolomide (TMZ). These treatments may cause prolonged systemic lymphopenia, which itself is associated with poor outcomes. NT-I7 is a long-acting IL7 that expands CD4 and CD8 T-cell numbers in humans and mice. We tested whether NT-I7 prevents systemic lymphopenia and improves survival in mouse models of GBM. Experimental Design: C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day × 5 days), TMZ (33 mg/kg/day × 5 days), and/or NT-I7 (10 mg/kg on the final day of RT). We followed the mice for survival while serially analyzing levels of circulating T lymphocytes. We assessed regulatory T cells (Treg) and cytotoxic T lymphocytes in the tumor microenvironment, cervical lymph nodes, spleen, and thymus, and hematopoietic stem and progenitor cells in the bone marrow. Results: GBM tumor–bearing mice treated with RT+NT-I7 increased T lymphocytes in the lymph nodes, thymus, and spleen, enhanced IFNγ production, and decreased Tregs in the tumor which was associated with a significant increase in survival. NT-I7 also enhanced central memory and effector memory CD8 T cells in lymphoid organs and tumor. Depleting CD8 T cells abrogated the effects of NT-I7. Furthermore, NT-I7 treatment decreased progenitor cells in the bone marrow. Conclusions: In orthotopic glioma-bearing mice, NT-I7 mitigates RT-related lymphopenia, increases cytotoxic CD8 T lymphocytes systemically and in the tumor, and improves survival. A phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).

Purpose-To identify and mathematically model molecular predictors of response to the enediyne chemotherapeutic agent, neocarzinostatin, in nervous system cancer cell lines.Methods-Human neuroblastoma, breast cancer, glioma, and medulloblastoma cell lines were maintained in culture. Content of caspase-3 and Bcl-2, respectively, was determined relative to actin content for each cell line by Western blotting and optical densitometry. For each cell line, sensitivity to neocarzinostatin was determined. Brain tumor cell lines were stably transfected with human Bcl-2 cDNA cloned into the pcDNA3 plasmid vector.Results-In human tumor cell lines of different tissue origins, sensitivity to neocarzinostatin is proportional to the product of the relative contents of Bcl-2 and caspase-3 (r 2 = 0.9; p < 0.01). Neuroblastoma and brain tumor cell lines are particularly sensitive to neocarzinostatin; the sensitivity of brain tumor lines to neocarzinostatin is enhanced by transfection with an expression construct for Bcl-2 and is proportional in transfected cells to the product of the relative contents of Bcl-2 and caspase-3 (r 2 = 0.7).Conclusion-These studies underscore the potential of molecular profiling in identifying effective chemotherapeutic paradigms for cancer in general and tumors of the nervous system in particular. KeywordsEnediyne; Caspase-3; Bcl-2; Brain Tumors; Targeted Therapy Overproduction of Bcl-2 and other antiapoptotic gene products is a common mechanism of chemotherapeutic resistance. [1][2][3][4][5][6][7] We have previously reported the paradoxical potentiation by Bcl-2 of apoptosis induction by the disulfide reduction-dependent enediyne, neocarzinostatin (NCS). [8][9][10][11] As overproduction of Bcl-2 in PC12 pheochromocytoma cells is associated with increased cellular reducing potential, [12] it was hypothesized that this condition resulted in enhanced activation of NCS and consequent potentiation of apoptosis.[8] However, Bcl-2 acts downstream of NCS activation and should block apoptosis even in the face of enhanced enediyne activation. Further mechanistic studies revealed that, in PC12 neural crest tumor cells, NCS treatment results in caspase-3-dependent cleavage of Bcl-2 to its proapoptotic counterpart, [13] and that this cleavage is critical for potentiation of apoptosis by Bcl-2. [9,13] This suggests that NCS could be an effective and relatively non-toxic chemotherapeutic agent for those tumors that overproduce Bcl-2 and express caspase-3. Potentiation of efficacy would be predicted to occur only in those cells for which both conditions obtained. If this is indeed the case, it would serve as proof-of-principle for the notion of identification of molecular markers for responsiveness of particular human cancers to particular chemotherapeutic strategies.To test this hypothesis and the generalizability of the prediction it suggests, we examined the correlations between the EC 50 of NCS for cell culture growth rate depression (i.e., the concentration of NCS at which cell culture growth rate is h...

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