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Cancer immunotherapies are associated with remarkable therapeutic response rates but also with unique and severe toxicities, which potentially result in rapid deterioration in health. The number of clinical applications for novel immune effector-cell therapies, including chimeric antigen receptor (CAR)-expressing cells, and other immunotherapies, such as immune-checkpoint inhibitors, is increasing. In this Consensus Statement, members of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Cell Transplantation-Cancer Immunotherapy (HCT-CI) Subgroup, Paediatric Diseases Working Party (PDWP) of the European Society of Blood and Marrow Transplantation (EBMT), Supportive Care Committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) and MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program collaborated to provide updated comprehensive recommendations for the care of children, adolescents and young adults receiving cancer immunotherapies. With these recommendations, we address emerging toxicity mitigation strategies, we advocate for the characterization of baseline organ function according to age and discipline-specific criteria, we recommend early critical care assessment when indicated, with consideration of reversibility of underlying pathology (instead of organ failure scores) to guide critical care interventions, and we call for researchers, regulatory agencies and sponsors to support and facilitate early inclusion of young patients with cancer in well-designed clinical trials.

In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy., Chimeric antigen receptor (CAR) T cell therapies have impressive activity in the treatment of cancer but are associated with potentially fatal toxicities. In light of the approval of CAR T cell therapy for paediatric patients, a panel of experts from the Hematopoietic Stem Cell Transplantation (HSCT) Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network, the CAR T Cell Therapy-Associated Toxicity (CARTOX) Program at The University of Texas MD Anderson Cancer Center, and several other institutions have developed consensus guidelines for the use and management of these treatments in paediatric patients, which are presented herein.

TPS3645 Background: Pre-clinical studies of aerosol gemcitabine (GCB) in mice and dogs with osteosarcoma (OS) lung metastases demonstrated therapeutic efficacy. Aerosol GCB administered once weekly proved to be safe in adults with lung cancer. Direct delivery of GCB to the lungs via inhalation may offer higher drug concentration in the tumor with fewer side effects. We initiated a Phase I study to evaluate the feasibility and safety of aerosol GCB treatment in patients >12 years with solid tumors and lung metastases (2015-0720- NCT03093909). Methods: Eligibility criteria: 1) Diagnosis of solid tumor with lung metastases, 2) willing to comply with protocol therapy, 3) adequate organ function, 4) patient age > 12 and < 50 years, 5) good performance status, 6) resolution of all acute toxic effects of any prior anti-cancer therapy, and 7) no radiotherapy within 2 weeks. Patients who previously received systemic GCB are eligible. Objectives: To determine the maximum tolerated dose (MTD) and toxicities of aerosol GCB, to evaluate for drug spillover into the circulation, and to preliminarily assess the anti-tumor activity. Correlative studies include effect of aerosol GCB on immune cell infiltration in the lung, autophagy, apoptosis, heat shock protein 27, evidence of DNA strand breaks (gH2AX) and expression of human equilibrative nucleoside transporter-1.Aerosol GCB is administered via a breath-induced nebulizer twice a week in 28-day cycles. A maximum of 6 dose levels will be studied; the starting dose is 0.75 mg/kg twice weekly. If no progressive disease or unacceptable treatment-related toxicity, patients may continue for 12 cycles. The study uses the accelerated titration method for the first 2 dose levels then the 3+3 design for the remaining dose levels. After determining the MTD, we will evaluate the defined MTD in an expansion cohort of 14 patients with relapsed OS. Symptoms, pulse oximetry, and pulmonary function are assessed prior to each nebulized dose using remote spirometry that allows raw numbers and flow-volume curves to be uploaded and transmitted via bluetooth to an android tablet provided to patients. Data is transmitted to a web portal and captured in a HIPAA-compliant web-based database (REDCap) that is accessible to the research team. Results: To date, the study enrolled 4 patients and accrual is ongoing at dose level 3. Conclusions: This study will provide information on the feasibility and safety of aerosol GCB. If proven to be feasible and safe, it can potentially offer a novel approach to treat metastatic OS to the lungs while minimizing systemic toxicity. Clinical trial information: NCT03093909 .