Volume 3 Issue 11, November 2022

Immunovirotherapy is a promising therapeutic strategy for glioblastoma (GBM), a deadly tumor for which effective treatments remain a clinical need. A new study describes an oncolytic herpes simplex virus (oHSV) armed with a bispecific anti-EGFR–CCL5 fusion protein that activates innate and adaptive antitumor immune responses that are highly efficacious in preclinical GBM models.

Pancreatic ductal carcinoma exists within a heterogenous and complex microenvironment that imposes austere conditions with limited nutrient availability. Clonally separable neoplastic cell populations are now shown to segregate into two distinct metabolic configurations, facilitating symbiotic intratumoral crosstalk to support survival and growth.

Persistent senescent cancer cells have tumor-promoting potential, making their selective elimination a prime therapeutic objective. The death receptor inhibitor cFLIP has now been shown to counter the susceptibility of senescent cells to DR5-mediated extrinsic apoptosis, which can be therapeutically exploited.

Combinations of immune-checkpoint blockade and radiotherapy to modulate antitumor immunity have mainly focused on manipulating T cells. A study now shows that combining radiotherapy with activation of macrophages yields potent, abscopal effects in mouse tumor models that may be ready for translation into early clinical trials.

Bernards and colleagues identify cFLIP as a common dependency of cancer cells by conferring protection from senolytic-induced cell death. They nominate combination of DR5 activation and cFLIP suppression for enhanced killing of senescent cancer cells.

Karam and colleagues report a phase I/Ib trial in patients with HNSCC treated with neoadjuvant SBRT and anti-PD-L1, and perform high-dimensional analyses of immune correlates of response in the tissue microenvironment and peripheral blood.

Yu and colleagues develop a OV-Cmab-CCL5 oncolytic virus that targets EGFR⁺ glioblastoma cells and releases CCL5 into the tumor microenvironment, which promotes anti-tumor immune responses and prolonged survival in preclinical GBM models.

Yofe et al. demonstrate that FcγR engagement early after anti-CTLA-4 blockade induces a rapid remodeling of innate immunity and activation of type I interferon signaling, which are crucial for successful anti-CTLA-4 therapy.

Nishiga and colleagues show therapeutic efficacy for a combination of radiotherapy and CD47 blockade, which also elicits an abscopal effect mediated by macrophages migrating into non-irradiated tumor sites and phagocytosing cancer cells.

Barriga et al. develop MACHETE, a genome engineering strategy enabling the flexible modeling of megabase-sized deletions and show that the concomitant loss of the interferon cluster with CDKN2A/B deletions on 9p21.3 enhances immune evasion.

Halbrook et al. report two metabolic subgroups of pancreatic ductal adenocarcinoma cells defined by differential integrated stress response and asparagine production that permit symbiosis and phenformin resistance.