MSK Research Highlights, May 18, 2023

An MSK scientist pipettes in the lab

New research from Memorial Sloan Kettering Cancer Center (MSK) shows how high-risk neuroblastoma evolves to be so deadly; finds continued safety and efficacy for sotorasib in patients with KRAS G12C-mutated advanced non-small cell lung cancer; and demonstrates promise in eradicating tumors by delivering a viral-based immunotherapeutic to melanoma and breast cancer in mouse models.

Research shows how high-risk neuroblastoma evolves to be so deadly 

Neuroblastoma, a tumor arising from the adrenal gland during embryo development, accounts for 15% of all childhood cancer deaths. In two-thirds of cases, the tumor is called high-risk and is very difficult to cure. Children with high-risk neuroblastoma are often diagnosed with stage 4 disease, which includes widespread metastasis. Leveraging surgical samples from 283 high-risk patients, MSK researchers Gunes Gundem, PhD, Nai-Kong V. Cheung, MD, PhD, Elli Papaemmanouil, PhD, and colleagues performed a comprehensive analysis of genomic evolution of these tumors. They found that the disease arises early during development in utero and rapidly diversifies genetically. At the time of diagnosis, metastatic cancer cells had already established themselves at distant sites throughout the body, where they could stay dormant for periods of up to 10 years, only to cause relapses years later. Finally, they show that treatment-resistant disease can spread and repopulate sites that responded to therapy. While the researchers note that their data portray “a dismal picture of neuroblastoma pathogenesis,” they also state that their work has important implications for developing and choosing the right targeted therapies to improve the chances of cure of this disease. Read more in Nature Genetics.

Longest follow-up to date finds continued safety, efficacy for sotorasib in patients with KRAS G12C-mutated advanced NSCLC

Sotorasib (Lumakras®) was found to have continued safety and efficacy in the longest follow-up to date in patients with KRAS G12C-mutated advanced non-small cell lung cancer. Results from CodeBreaK 100, an international, multicenter clinical trial co-led by MSK medical oncologist Bob T. Li, MD, PhD, MPH, found the KRAS G12C inhibitor offered long-term benefit to many patients — with an overall survival rate of 51% after one year, and 33% after two years. Sotorasib performed significantly better than standard docetaxel-based chemotherapy regimens, which have an overall survival rate of 14% after two years. The trial enrolled people whose cancers had continued to grow with other treatments — and nearly a quarter of the 174 participants (23%) saw no progression of their disease for a year or more while on sotorasib. The trial was also important for another reason, Dr. Li notes: It was conducted in midst of the pandemic through international collaboration and innovative uses of telemedicine, remote monitoring and novel technologies. The study was sponsored and funded by Amgen. Read more in the Journal of Clinical Oncology.

OX40L-expressing recombinant modified vaccinia virus induces potent antitumor immunity by reprogramming Tregs

Immunotherapies that unleash the body’s immune system to fight cancer have revolutionized how solid tumors are treated. Patients without a strong pre-existing antitumor immune response, however, do not benefit from these therapies. A study led by co-first authors Ning Yang, PhD and Yi Wang, MS, and senior author Liang Deng, MD, PhD, demonstrated that delivering a viral-based immunotherapeutic, in the form of a recombinant modified vaccinia Ankara (rMVA), to melanoma and breast tumors in mouse models successfully depleted specialized regulatory T cells (Tregs) that suppress the body’s immune response. Researchers used single-cell RNA sequencing to show that rMVA depleted OX40hiCCR8hi Tregs and expanded Tregs expressing interferon-stimulated genes. This study provides a proof-of-concept that intratumoral depletion of Tregs via rMVA is an effective way to eradicate tumors, the authors note. Co-authors include Jedd D. Wolchok, MD, PhD, and Taha Merghoub, PhD (both now at Weill Cornell Medicine).  A phase 1 clinical trial for the human version of the virus, led by Lara Dunn, MD, has just opened at MSK. Read more in the Journal of Experimental Medicine.