Novel strategy to induce potent and long-term anti-tumour activity of chimeric antigen receptor (CAR) T cells in the setting of paediatric solid tumours by the activation of the host innate immune system.

• Applicant: Dr. Ignazio Caruana, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology ; Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470198222

Over the past decades great improvements have been made in the field of paediatric oncology. Nevertheless, children suffering from recurrent or resistant tumours still maintain an unfavourable clinical outcome. For this group of patients there is the urgent clinical need to identify new intervention strategies that are more efficient and less toxic. It has been clearly shown that tumours are susceptible to immunotherapy. One of the latest and most promising strategies is the Chimeric Antigen Receptor (CAR) T cell therapy. CAR-T cells are genetically modified T lymphocytes that acquire the capacity to recognise specific cell surface antigens expressed by tumour cells promoting the elimination of malignant cells. Unlike conventional drugs, these gene-modified T cells have the ability to persist in our body for many years and re-activate upon re-encounter of a tumour cell. Despite success in B-cell malignancies with the approval of this strategy as an official medication, CAR therapy still faces several challenges in solid tumours. It has been shown that the limited efficacy of CAR-T cells in solid tumours is mainly due to their low persistence, multiple immune escape mechanisms developed by the malignant cells and the immunosuppressive tumour microenvironment (TME). In this study we are exploring a new strategy capable to improve the anti-tumour response in patients with refractory or relapsed solid tumours ameliorating CAR T cell functionality both in terms of persistence and anti-tumour activity, essential features for an effective long-term tumour control. Therefore, using neuroblastoma as preferential model, we will optimize the third generation GD2.CAR developed and validated by the principal investigator in an on-going phase II clinical trial in Bambino Gesù Childen’s Hopsital - Rome (Italy). Based on the preliminary results obtained from this in human study, we will investigate the possibility to improve CAR T cell persistence and activity inside of the hostile TME forcing CAR T cells to express a molecule called Trike (trispecific killer enganger). This protein is a chimeric molecule capable to recruit, activate and redirect natural killer (NK) and/or γ/δ T cells versus a second antigen expressed by the tumour cells increasing the possibility to target tumour cells not expressing the antigen recognised by CAR T cells. Furthermore, this strategy will also allow the amelioration of the TME by targeting immune-elements with inhibitory capacity such as myeloid derived suppressor cells and tumour-associated macrophages creating a joint effort of CAR-T and NK/γ/δ T cells to eradicate the tumour. The local secretion of this molecule at the tumour site together with the presence of a suicide mechanism capable to block and quickly eliminate the gene-modified T cells is able to guaranty safety and reduce possible systemic toxicity.

• DFG Programme: Research Grants
• International Connection: Italy
• Cooperation Partner: Professorin Dr. Paola Paci, Ph.D.