Combination Treatment Improves Antitumor Efficacy in Difficult-to-Treat Sarcomas

Aggressive cancers found more susceptible to combination treatment compared with monotherapy.

Alisertib used in combination with HSV1716 demonstrated a significant increase in antitumor efficacy for the treatment of neuroblastoma and malignant peripheral nerve sheath tumor (MPNST).

Alisertib is an aurora A kinase inhibitor, and HSV1716 is a virus derived from HSV-1 and attenuated by RL1 deletion, according to the investigators.

In early clinical trials, the agents showed some antitumor efficacy as monotherapy, but a new study published in Oncotarget found that a combined treatment appeared to increase efficacy in the treatment of MPNST and neuroblastoma.

“We chose to investigate this combination in MPNST and neuroblastoma because these are 2 difficult-to-treat sarcomas that have shown susceptibility to these agents individually,” said principal investigator Dr Timothy Cripe, MD, PhD. “MPNST is a rare pediatric cancer, but for patients with neurofibromatosis 1, a genetic cancer predisposition disorder, it is the leading cause of death. More importantly, MPNST is resistant to chemotherapy.”

Accord to Dr Cripe, it was likely that many mechanisms worked synergistically to increase this antitumor effect.

The results of the study showed that HSV1716 increased the sensitivity of uninfected cells to alisertib cytotoxicity, while alisertib increased peak virus production and slowed viral clearance from tumors. Furthermore, alisertib was found to inhibit 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,” Dr Cripe said. “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.”

Important next steps will be to confirm the sustained immunotherapeutic benefits of HSV1716 in the presence of alisertib and to conduct a clinical trial. This will provide a better understanding of how the agents work together, and how they may impact patient care, Dr Cripe concluded.

“Our results, in the context of early trials of both substances individual that have shown safety and efficacy, support the testing of this combination in children and young adults with neuroblastoma and MPNST,” Dr Cripe said. “As these agents continue to move through the development and approval processes, we look forward to studying them further.”