Selected Articles from This Issue

Outcomes for acute myeloid leukemia (AML) remain suboptimal. The curative approach is hematopoietic cell transplantation (HCT) for most patients, although subsequent relapse is common. IDH inhibitors have revealed tolerability and activity in relapsed/refractory patients and have been approved for use. Despite this, maintenance therapy with the IDH1 inhibitor ivosidenib has not been adequately studied. In this phase I study, Fathi and colleagues evaluated ivosidenib as maintenance following HCT for AML and found the agent to be well tolerated. At the recommended phase II dose of 500 mg daily, progression-free and overall survival compared favorably to historical data. The authors also assessed IDH1 allelic burden prior to transplant and prior to maintenance, and, due to the small number of patients in this phase II study, could not conclude a definitive predictive trend for outcomes. The results from this trial have substantial value in promoting a rationale to pursue more advanced-phase, larger clinical studies of maintenance ivosidenib.

Tumors express IDO1, an intracellular enzyme involved in the degradation of tryptophan to kynurenine, to evade immunosurveillance. Epacadostat inhibits IDO1 and shifts the tumor microenvironment from an immunosuppressive state toward an immune-stimulated state. Early-phase studies confirmed the safety of epacadostat as monotherapy and in combination with pembrolizumab. Epacadostat has not been examined in a sarcoma population. Pembrolizumab previously demonstrated activity in select sarcoma subtypes. A phase II trial of epacadostat plus pembrolizumab demonstrated promising activity in advanced melanoma. Before the subsequent negative phase III trial in melanoma reported, Kelly and colleagues performed an open-label, single-center, phase II study of epacadostat and pembrolizumab in patients with advanced sarcoma. The primary endpoint was best objective response rate at 24 weeks by RECIST v1.1. The combination therapy was safe and well tolerated but showed limited clinical activity; the study did not meet its primary endpoint. Correlative analyses suggest that on-target IDO1 inhibition was not achieved.

Jang and colleagues designed a phase II clinical trial testing the combination of guadecitabine (DNMTi) and atezolizumab (anti-PD-L1) with the goal to restimulate the immune-mediated anticancer effects of immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma patients who were resistant to prior ICI treatment. No RECIST criteria responses were observed, however, patients could be separated into those with either progressive or stable disease outcomes. Analysis of the tumors did not show substantial DNA hypomethylation in the tumor or the upregulation of viral mimicry after two cycles of combination treatment. The authors did observe that the therapy associated with markers of immune activation in circulating immune cells and abundance of tumor-infiltrating CD8 T cells within the tumor, which correlated with a longer survival outcome. These results suggest that further studies to target the reprogramming of T cells with alternate methodologies may be of benefit in this disease setting.

Immunotherapy is considered an innovation and has become a trend in the field of tumor treatment. However, for advanced colorectal cancer (CRC), only a small portion of patients (about 5%) benefit from this therapy. How to turn these “cold tumors” into “hot tumors” is of great significance. Priming the immune response might be a potential method for sensitizing the effect of immunotherapy. Ding and colleagues found a tumor suppressive molecular axis EP300/circRERE/miR-6837-3p/MAVS that could activate type I interferon pathway and anti-tumor immunity in CRC. Delivery of circRERE by adeno-associated virus (circRERE-AAV) elicits significant antitumor effects, and combination treatment with circRERE-AAV and anti-PD-1 antibody exhibits synergistic effects on tumor growth in preclinical models of CRC. These results demonstrate that circRERE-AAV might represent a new therapeutic avenue to prime immune responses and boost the effects of immunotherapy in the clinic.