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Page 699 Sharma et al. Cancer Drug Resist 2023;6:688-708 https://dx.doi.org/10.20517/cdr.2023.82

The CAR-NK cells have also been explored to treat glioblastoma either by Her2 targeting monotherapy
[170]
or in combination therapy. For instance, the Off-the-Shelf EGFR-targeting CAR-NK cells have been tested
in combination with an oncolytic virus expressing the IL15/IL15Ralpha complex and the combinatorial
therapy demonstrates a strong anti-tumor immunity . A significant problem associated with CAR-NK cell
[171]
therapy is the shedding or down-regulation of the ligands in cancer cells that bind natural killer group 2D
(NKG2D) receptors on the natural killer (NK) cells. NKG2D is an activating receptor widely expressed in
NK cells as well as in some subsets of T cells . To overcome the limitation of NKG2DL heterogeneity in
[172]
the tumor, a recent study using a bispecific antibody with two ScFv fragments (linked with a IgG4-Fc) that
target Her2 (tumor) and NKG2D (NK cells), respectively, in combination with human NK-92 cells, showed
synergistic tumor cell killing effects in both in vitro and in vivo conditions . Although the syngeneic
[173]
tumor model they used represents a situation of a heterogenous expression of NKG2DLs in tumor cells, the
flank tumors they used did not address the difficulty in delivery of the combination therapy across the
BBB .
[173]
Another interesting phenomenon is the sex difference in response to immunotherapy in glioma. The sex
disparity in brain cancer has been reported by several groups [174-177] . A recent meta-analysis revealed that
female patients with glioblastoma treated with immunotherapy had a statistically significant survival
advantage in overall survival over their male counterparts . They also found that female patients exhibited
[178]
a more robust survival advantage with cancer vaccine treatment. Another study by Bayik et al. discovered
that two subsets of myeloid-derived suppressor cells (MDSCs) have a sex-specific tumor-promoting
phenotype in both mouse and human glioblastoma . All these data suggest that a more personalized
[179]
approach, which at least considers sex differences in glioblastoma treatment, will more accurately evaluate
the efficacy of immunotherapy.

New drug delivery technologies to overcome BBB limitation and activate glioblastoma TME
Various new technologies have demonstrated promising progress in overcoming BBB, and we summarized
a few new approaches with great potential to improve the glioblastoma treatment outcome [Figure 3].
Among those new approaches, the use of ultrasound to open BBB for glioblastoma treatment has been
applied in several areas, including immunotherapy delivery. Using low-intensity pulsed ultrasound to
temporarily disrupt BBB, Sabbagh et al. demonstrated a significantly improved BBB penetration of both
anti-PD1 antibody and EGFRvIII targeting CAR-T cells, as well as significantly improved survival in mouse
glioblastoma models . Another study by Sheybani et al. applied MRI-guided focused ultrasound with
[180]
systemic injection of microbubbles and studied the impact of this approach on temporary BBB disruption in
a mouse glioma model . This approach caused a transient local inflammatory phenotype in the mouse
[181]
glioblastoma, with an increased number of dendritic cells and the upregulated maturation marker.
However, they did not see a significant increase in CD8 T cells in the TME .
[181]
Another technology to modulate BBB function is photodynamic therapy (PDT). Conventionally, PDT relies
on a photosensitizer, such as 5-aminolevulinic acid (5-ALA) , that can accumulate in tumor tissue, plus a
[182]
laser that can stimulate the photosensitizer, followed by energy transfer to generate reactive oxygen species,
leading to damages to the cancer cells . It is noteworthy that PDT has shown promise in temporary
[183]
opening of BBB, possibly through modulating certain components of TJs . Interestingly, PDT can also
[184]
induce an acute inflammatory response in which both innate and adaptive immune systems are
activated . Recently, BBB opening was shown to affect the meningeal lymphatic system characterized by
[185]
an anti-tumor effect of talaporfin sodium (TS)-PDT as well as its synergy with the immune checkpoint
inhibitor . In vitro studies have demonstrated that targeted TS-PDT triggers various forms of cell death,
[186]
including apoptosis, necrosis, and autophagy-associated cell death. Furthermore, TS-PDT induces the acute
activation of lymphatic drainage in the brain and the clearance of unwanted molecules from the CNS [187,188] .