CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment.

PURPOSE: Glioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of cancer stem cells (CSCs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here, we identify CD70 as a potential therapeutic target for recurrent GBM CSCs. EXPERIMENTAL DESIGN: In the current study, we identified the relevance and functional influence of CD70 on primary and recurrent GBM cells, and further define its function using established stem cell assays. We use CD70 knockdown studies, subsequent RNAseq pathway analysis, and in vivo xenotransplantation to validate CD70's role in GBM. Next, we developed and tested an anti-CD70 chimeric antigen receptor (CAR)-T therapy, which we validated in vitro and in vivo using our established preclinical model of human GBM. Lastly, we explored the importance of CD70 in the tumor immune microenvironment (TIME) by assessing the presence of its receptor, CD27, in immune infiltrates derived from freshly resected GBM tumor samples. RESULTS: CD70 expression is elevated in recurrent GBM and CD70 knockdown reduces tumorigenicity in vitro and in vivo. CD70 CAR-T therapy significantly improves prognosis in vivo. We also found CD27 to be present on the cell surface of multiple relevant GBM TIME cell populations, notably putative M1 macrophages and CD4 T cells. CONCLUSION: CD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable polytherapeutic avenue to co-target both GBM and its TIME.

Solving Bilevel Optimization Problems Using Kriging Approximations.

Bilevel optimization involves two levels of optimization, where one optimization problem is nested within the other. The structure of the problem often requires solving a large number of inner optimization problems that make these kinds of optimization problems expensive to solve. The reaction set mapping and the lower level optimal value function mapping are often used to reduce bilevel optimization problems to a single level; however, the mappings are not known a priori, and the need is to be estimated. Though there exist a few studies that rely on the estimation of these mappings, they are often applied to problems where one of these mappings has a known form, that is, piecewise linear, convex, etc. In this article, we utilize both these mappings together to solve general bilevel optimization problems without any assumptions on the structure of these mappings. Kriging approximations are created during the generations of an evolutionary algorithm, where the population members serve as the samples for creating the approximations. One of the important features of the proposed algorithm is the creation of an auxiliary optimization problem using the Kriging-based metamodel of the lower level optimal value function that solves an approximate relaxation of the bilevel optimization problem. The auxiliary problem when used for local search is able to accelerate the evolutionary algorithm toward the bilevel optimal solution. We perform experiments on two sets of test problems and a problem from the domain of control theory. Our experiments suggest that the approach is quite promising and can lead to substantial savings when solving bilevel optimization problems. The approach is able to outperform state-of-the-art methods that are available for solving bilevel problems, in particular, the savings in function evaluations for the lower level problem are substantial with the proposed approach.