New immunotherapy shows promise against rare childhood cancer

A new CAR T-cell therapy developed by UCL researchers and designed to target cancerous tumors has shown promise in early children with neuroblastoma, a rare form of childhood cancer.

For this proof-of-principle study, researchers at UCL Great Ormond Street Institute for Child Health (GOS ICH) and UCL Cancer Institute modified the patient’s T cells (a type of immune cell), equipping them to recognize and kill neuroblastoma cancer cells.

Twelve children with relapsed or refractory neuroblastoma (in whom the disease does not respond to treatment) were treated as part of the UK cancer research-funded Phase I clinical trial.

The research, published in Scientific translational medicine, is one of the first studies to show that CAR T lymphocytes achieve rapid regression against solid cancer (non-blood cancer). Although the beneficial effects only lasted a short time, the study provides important evidence that this specific CAR T cell treatment could be used as a future treatment for children with solid tumors.

Neuroblastoma is a rare type of cancer that mainly affects infants and young children and develops from specialized nerve cells (neuroblasts) left behind by the baby’s development in the womb.

Up to 100 children are diagnosed with neuroblastoma each year in the UK. Current treatment for children with an aggressive type of neuroblastoma includes surgical removal, stem cell transplant chemotherapy, radiation therapy, and antibody therapy. Despite this intensive treatment, long-term survival is between 50 and 60%.

In CAR T cell therapy, a type of immunotherapy, T cells are designed to contain a molecule called chimeric antigen receptor (CAR) on their surface that can specifically recognize cancer cells.

For this study, patients’ T cells were modified with a CAR to target the surface protein GD2, which is very abundant on almost all neuroblastoma cells, but is found at very low levels in healthy cells.

Researchers found that when a sufficient dose * of modified CAR T cells was used, this treatment resulted in rapid shrinkage of the tumor in some of the patients treated. These effects were transient. Importantly, CAR T lymphocytes did not cause harmful side effects in healthy tissues expressing the GD2 molecule in all patients.

Lead author, Dr Karin Straathof, research group leader at UCL GOS ICH and pediatric oncologist consultant at Great Ormond Street Hospital NHS Trust, said: “It is encouraging to see the antitumor activity induced by these. modified T cells in some of the patients in this study.

“Although the observed antitumor activity was only transient, it provides important proof of principle that CAR T cells directed at the GD2 molecule could be used against solid tumors in children.

“New treatments are needed for high-risk neuroblastoma and with further research we hope to develop it further into a treatment that results in lasting responses and increases the number of patients who can be cured.”

Senior author Dr Martin Pule (UCL Cancer Institute) said: “The targeting of solid tumors by CAR T lymphocytes depends on their infiltration and expansion within the tumor microenvironment, and clinical responses of far inferior.

“Rapid regression in neuroblastoma cells is promising, particularly because this activity has been observed in the absence of the neurotoxicity that occurs with antibody-based approaches that target GD2.”

Dr Pule added: “Targeting neuroblastoma with CAR GD2 T cells appears to be a valid and safe strategy, but requires further modification to promote CAR T cell longevity.”

Dr Sue Brook, medical consultant at Cancer Research UK, said: ‘Children who have difficulty treating cancers such as neuroblastoma have limited treatment options available to them, especially when the cancer returns.

“The first results for the GD2 CAR-T treatment look promising, especially thanks to the initial safety data. However, more work is needed to extend the response time and we look forward to seeing the next steps in its development.” .

The research team is preparing for the next clinical trial in collaboration with Autolus, a clinical-stage biopharmaceutical company developing next-generation programmed T-cell therapies for the treatment of cancer. This study will evaluate AUTO6NG, which builds on this approach using the GD2 CAR itself along with additional programming modules designed to improve effectiveness and persistence.

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* Increasing doses of GD2-directed CAR T cells were used to establish the minimum effective dose. The first group of patients was given a low dose, the second group a higher dose and the third group still a higher dose. Each patient received only one dose. The researchers found that a minimum cell dose of 10e8 / m2 ** was required for CAR T cells to divide and activate once administered to the patient.

** The dose is expressed per square meter of surface area as this is a pediatric study and this is how doses in children are calculated (or alternatively per kilogram of body weight). The cell dose is 10e8 per square meter of body surface area or 100 million cells per square meter of body surface area.

To speak to the researchers or for a copy of the article, contact Henry Killworth, UCL Media Relations: T +44 (0) 7881 833274 or E: [email protected]

The research paper, Karin Straathof, Martin Pule, John Anderson, “Antitumor activity without off-tumor toxicity on the target of chimeric GD2 antigen receptor T cells in patients with neuroblastoma” will be published in Scientific translational medicine, Wednesday 25 November 2020 at 7pm (UK time) and 2pm (East Coast time).

The DOI for this article will be: 10.1126 / scitranslmed.abd6169

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