Close
Enter your
text here

New Trial Aims to Boost Kids’ Immune Systems to Fight Neuroblastoma

New Trial Aims to Boost Kids’ Immune Systems to Fight Neuroblastoma 1024 558 Lauren Dembeck

A new cellular therapy approach could improve outcomes and ease the treatment burden for patients and families.

Neuroblastoma is rare, with only 700 to 800 new cases diagnosed in the United States each year, but it is the most common extracranial solid tumor in children. Neuroblastoma typically occurs in children younger than 5 years, with a median age of diagnosis of just 17 months.

Neuroblastoma tumors arise from immature nerve cells (neuroblasts) of the sympathetic nervous system. They can occur anywhere along the sympathetic chain but most frequently develop in the adrenal glands.

Children with low- or intermediate-risk neuroblastoma have excellent outcomes, with up to 90% of children cured if the cancer is caught early. However, neuroblastoma claims more lives of children under the age of 5 than any other cancer. Despite recent advances in therapy, children with relapsed or refractory neuroblastoma have poor outcomes, with a survival rate of less than 20%.

“Children with high-risk disease undergo some of the most intensive therapy that we use across pediatric oncology,” explains pediatric oncologist Mark Ranalli, MD, medical director of the Embryonal Tumor Program at Nationwide Children’s Hospital. “Because of its intensity, the treatment is associated with numerous and significant acute and long-term side effects, often leaving families to seriously question whether they want their child to undergo such a rigorous treatment regimen.”

Neuroblastoma is a devastating diagnosis for families, but advances in immunotherapy and cellular therapy are offering new hope — especially for those whose children have few treatment options left. Dr. Ranalli and colleagues are attempting to establish a new treatment strategy that is at least as effective as the current standard of care but also gentler with less toxicity for children with relapsed or refractory high-risk neuroblastoma.

Promising New Treatment Strategy

Chemoimmunotherapy combining temozolomide, irinotecan and dinutuximab has demonstrated notable anti-tumor activity in children with relapsed or refractory neuroblastoma. Dinutuximab, a monoclonal antibody, enhances the effectiveness of the irinotecan–temozolomide regimen through antibody-dependent cellular cytotoxicity. It targets a protein that is highly expressed on neuroblastoma cells, binding specifically to the tumor and recruiting immune cells — such as natural killer (NK) cells — to attack and destroy the antibody-coated cancer cells.

In an active clinical trial, the researchers are using this treatment and, in an attempt to enhance the body’s immune response, infusing the patient with allogeneic NK cells. This novel approach, a form of adoptive or cellular immunotherapy, has shown efficacy against numerous cancers, including sarcoma, myeloma, carcinoma, lymphoma and leukemia.

“These allogeneic NK cells that are derived from healthy donors are then even more activated than autologous NK cells from the patient would be because they are being infused into an environment that is foreign to them, which enhances their anti-tumor activity,” explains Dr. Ranalli who is a site principal investigator for the Children’s Oncology Group.

Dr Ranalli’s research team is combining this treatment with the infusion of modified allogeneic NK cells in an effort to boost the body’s immune response against neuroblastoma. This innovative strategy — an example of adoptive or cellular immunotherapy — has demonstrated effectiveness against a variety of cancers, including sarcoma, myeloma, carcinoma, lymphoma and leukemia.

“These allogeneic NK cells, sourced from healthy donors, become even more activated than the patient’s own NK cells would be,” explains Dr. Ranalli. “Because they’re introduced into a foreign environment, their anti-tumor activity is heightened.”

Universal NK Cells

Dr. Ranalli is collaborating with Dean Lee, MD, PhD, director of the Cellular Therapy and Cancer Immunology Program and Margaret Lamb, MD, pediatric oncologist and associate investigator in the Center for Childhood Cancer Research at Nationwide Children’s. Dr Lee, in conjunction with colleagues, developed an innovate approach to grow large numbers of NK cells taken from specially selected “universal donors.” They can then freeze these cells and bring them to the bedside to administer to patients as needed.

“There is a lot of variability in the anti-tumor activity of NK cells from different donors. So, we spent about three years identifying and collecting large banks of cells from donors with ideal NK-cell characteristics,” says Dr. Lee. “Having a universal donor product that is immediately available and ready to infuse will make a huge difference in cost and availability of this approach.”

A newly opened phase I-II trial at Nationwide Children’s is testing the strategy using these novel therapeutic agents. By targeting the cancer with greater precision, the study aims to maintain or improve upon current treatment efficacy while reducing treatment related toxicity.

The Allogeneic STING (Sequential Temozolomide Irinotecan NK Cells and GD2mab) Trial

The phase I-II study is evaluating whether infusion of allogeneic universal donor NK cells will improve the efficacy of dinutuximab therapy in combination with irinotecan and temozolomide in children with relapsed or refractory neuroblastoma. The trial is open to pediatric and young adult patients up to 30 years of age who have experienced any relapsed disease, a first episode of progressive disease during initial multi-drug induction myelosuppressive therapy, or primary resistant/refractory disease after completing at least four cycles of induction multi-drug induction chemotherapy.

During each treatment cycle, participants first undergo treatment with temozolomide, irinotecan and dinutuximab followed by a single fixed dose infusion of universal donor NK cells. Patients can receive up to six cycles of therapy, and undergo disease assessments after cycles 2, 4 and 6. They will be followed for up to 5 years following the completion of treatment.

The phase 1 portion of the study will evaluate the safety and tolerability of a fixed dose of universal donor NK cells (1 x 108 cells/kg) in combination with chemoimmunotherapy, while the phase 2 portion will estimate the efficacy of the therapy.

Clinical Responses To Date

Thus far, the results suggest that adding universal donor NK cells to chemoimmunotherapy is safe for children with relapsed high-risk neuroblastoma. Of 24 infusions among four patients, the researchers have observed no significant NK cell-related toxicities. Additionally, they have observed clinical responses after six cycles therapy in these patients with multiply relapsed high-risk neuroblastoma.

Dr. Ranalli presented the preliminary findings last year at the 2024 American Society for Clinical Oncology Annual Meeting.

“Three of the children had measurable responses, and one experienced a stable response,” shares Dr. Ranalli. “Most of the toxicity they experienced was related to the chemotherapy component of their treatment.”

Relevance and Future Directions

The study may provide a much-needed, more tolerable alternative for children and families already worn down by arduous treatments. With continued success, this approach could redefine what hope looks like for children with high-risk neuroblastoma — offering not only longer lives but better ones.

The trial is currently ongoing only at Nationwide Children’s but will expand nationally through the New Approaches to Neuroblastoma (NANT) Consortium.

“Parents and providers who are interested can reach out to us, and we will work with their home centers to check their eligibility and enroll them if possible,” says Dr. Ranalli. “As our study continues, the goal remains clear: to give every child not just a fighting chance — but a future filled with more birthdays, milestones and moments with their loved ones.”

 

Image credit: Adobe Stock

About the author

Lauren Dembeck, PhD, is a freelance science and medical writer based in New York City. She completed her BS in biology and BA in foreign languages at West Virginia University. Dr. Dembeck studied the genetic basis of natural variation in complex traits for her doctorate in genetics at North Carolina State University. She then conducted postdoctoral research on the formation and regulation of neuronal circuits at the Okinawa Institute of Science and Technology in Japan.

You might also like