LS1 PRACTICAL APPLICATION AND UNDERLYING BIOLOGY OF TUMOR TREATING FIELDS

Glioblastoma (GBM) is the most common and most aggressive form of brain cancer in adults. For decades, the mainstay of therapeutic intervention was based on surgical resection (when safely feasible), followed by radiotherapy (RT). In 2005, data from the landmark EORTC-NCIC trial changed the standard of care treatment for GBM. This phase III trial demonstrated a survival advantage for concomitant and adjuvant temozolomide (TMZ) chemotherapy when added to the standard course of radiation. In the group of patients assigned to radiation plus TMZ, median survival improved from 12.1 months (radiotherapy alone) to 14.6 months, but all the patient finally relapsed on TMZ. In 2015, Tumor Treating Fields (TTF, Optune) became the first FDA-approved device for the treatment of for newly diagnosed GBM. This approval was based on the EF-14 clinical trial results, in which nearly half of the patients treated with Optune in combination with maintenance temozolomide (TMZ) were alive at 2 years compared with 31% of people on TMZ alone. Optune utilize the natural electrical properties of dividing cancer cells to disrupt mitosis and provide continuous antimitotic action against progression of GBM. TTF-treated tumor cells can exit the process of mitosis aberrantly and release cellular stress signals, such as the endoplasmic reticulum chaperonin calreticulin (CRT) and high mobility group box 1 protein (HMGB1). CRT is important to induce antitumor immune responses because CRT inhibition decreases immunogenicity. HMGB1, an endogenous chromatin-associated protein released from dying tumor cells, also plays a critical role in the activation of HMGB1-mediated toll-like receptor 2 (TLR2) immune signaling. The presence of those signals may facilitate immune activation, and immunogenic induced cell death, and eventually result in tumor destruction. In this presentation, Daniela Bota, MD, PhD, will review the clinical results of Optune in the treatment of GBM, and will discuss the novel biological mechanisms underlying the effects of Optune in controlling tumor growth and promoting the immune responses in GBM.