peripheral nerve sheath tumor (MPNST) is a rare pediatric cancer. For patients with
neurofibromatosis 1, a genetic cancer predisposition disorder, MPNST is the
leading cause of death. More importantly, MPNST is resistant to
Two investigational agents, Aurora A kinase inhibitor (alisertib) and
HSV1716, a virus derived from HSV-1 and attenuated by the deletion of
RL1, have shown some antitumor efficacy in early clinical trials as
‘The synergistic effects of a kinase inhibitor and an oncolytic herpes virus show promise for difficult-to-treat neuroblastomas and malignant peripheral nerve sheath tumors.’
A new study published last week in Oncotarget
however, demonstrates that the combined usage of the agents results in
significantly increased antitumor efficacy in models of malignant
peripheral nerve sheath tumor (MPNST) and neuroblastoma.
"We chose to investigate this combination in MPNST and neuroblastoma
because these are two difficult-to-treat sarcomas that have shown
susceptibility to these agents individually," explains Timothy Cripe, division chief of Hematology/Oncology & BMT
at Nationwide Children's Hospital and senior author on the study.
According to Dr. Cripe, who is also a principal investigator in the Center for Childhood Cancer and Blood Diseases
in The Research Institute at Nationwide Children's, many mechanisms
likely worked synergistically to increase the antitumor effect in this
study. Particularly, HSV1716 increased the sensitivity of uninfected
cells to alisertib cytotoxicity.
Second, alisertib increased peak virus
production and slowed virus clearance from tumors. The team also found
that alisertib inhibited virus-induced accumulation of intratumoral
myeloid derived suppressor cells.
"Our study shows that alisertib helps the infection phase of HSV1716
because innate immunity is impacted," says Dr. Cripe, also professor of
Pediatrics at The Ohio State University College of Medicine. "It's
possible that it could inhibit the second phase, the downstream
immunotherapeutic effects of the virotherapy, but based on data from
other studies, we don't think that is the case."
Moving forward, Dr. Cripe says that confirming the sustained
immunotherapeutic benefits of HSV1716 in the presence of alisertib and
building a clinical trial are important next steps in understanding how
these agents work together and how they could impact care for patients.
"Our results, in the context of early trials of both substances
individually that have shown safety and efficacy, support the testing of
this combination in children and young adults with neuroblastoma and
MPNST," says Dr. Cripe. "As these agents continue to move through the
development and approval processes, we look forward to studying them