Highlights of This Issue

AKT kinase, as a component of the PI3K/mTOR/AKT cascade, mediates chemotherapy resistance in ovarian cancer. Following preclinical evidence that AKT inhibition restores chemotherapy efficacy, Blagden and colleagues conducted a Phase IB combination study of the AKT inhibitor afuresertib given with carboplatin and paclitaxel chemotherapy in 29 patients with platinum-resistant ovarian cancer. A 32% response rate was observed, and the combination showed acceptable tolerability. These findings support a future randomized evaluation of this combination in treatment-resistant ovarian cancer.

CNS involvement worsens the prognosis of patients with T-cell acute lymphoblastic leukemia (T-ALL), because most anticancer drugs cannot pass the blood brain barrier. The histone demethylase LSD1 is considered to be a therapeutic target of T-ALL, in which LSD1 is overexpressed and acts as a founder abnormality. T-ALL cells, however, are resistant to tranylcypromine-based conventional LSD1 inhibitors. Saito and colleagues developed a novel LSD1 inhibitor, S2157, via N-alkylation of tranylcypromine and demonstrated its ability to eradicate CNS leukemia in a murine T-ALL model. The brain-permeable LSD1 inhibitor S2157 would be highly beneficial for T-ALL patients with CNS involvement.

JX-594 (Pexa-vec) is one of the most promising oncolytic virus platforms in clinical development as one of the few oncolytic viruses in phase III clinical trials. Chon and colleagues show that a murine version of JX-594 (JX) remodels the tumor microenvironment by facilitating the accumulation of T cells. As a result, poorly immunogenic tumors become sensitive to cancer immunotherapy. Of note, the triple-combination therapy of JX, αPD-1, and αCTLA-4 maximizes anticancer immunity and induces durable regression with improved overall survival. These findings demonstrate the potential of JX in combination with immune checkpoint inhibitors for improving anticancer immune responses.

Tumor-infiltrating NK cell (TI-NK) numbers were an independent predictor of pathological complete response, a surrogate marker of patient outcome, to anti-HER2 antibody-based treatment in primary HER2 positive breast cancer. The findings of Muntasell and colleagues add strong support for a role of antibody-dependent cellular cytotoxicity for the antitumor effects of anti-HER2 antibodies and, hence, for future research strategies to overcome resistance directed at the recruitment of NK cells in NK “cold” tumors. Furthermore, combination of HLA class I expression and TI-NK cell numbers improved the ability to predict long-term clinical outcomes, suggesting new ways to tailor anti-HER2 therapeutic strategies.