Immunotherapy for Pediatric Cancer

AbstractImprovements in adult cancer survivorship can be achieved from behavioral changes and adopting screening programs. Yet, these approaches cannot be readily applied to lower the morbidity and mortality from childhood cancers. Rather, pediatric oncologists must rely on procedures and therapies to treat, rather than prevent malignancies. The systematic application of chemotherapy, radiation therapy, and surgery has led to remarkable advances in survival but these improvements have come at a cost. Children routinely receive chemotherapy agents that were designed decades ago, and these drugs have predictable side effects that result in the loss of potential for long-term survivors. The advent of targeted applications of immune-based therapies offers children with cancer a new class of oncolytic therapies that may be used to treat disease refractory to conventional approaches and lessen the toxicity of current treatment regimens without compromising remission. This review explores how 3 components of the immune system—T cells, natural killer (NK) cells, and antibodies—can be used for therapy of pediatric malignancies

Quality Improvement Initiative to Improve Time and Adherence to Revaccination after Hematopoietic Cell Transplantation: Implementation of a Revaccination Clinic within the Transplantation Program

Background: Revaccination after hematopoietic cell transplantation (HCT) is critical to prevent morbidity and mortality from vaccine preventable illnesses. While earlier re-vaccination after HCT is desirable, they may be ineffective if deployed before partial reconstitution of adaptive immunity. Increasingly, personalized approaches to re-vaccination after HCT have replaced time-based protocols in order to minimize unvaccinated time and enhance vaccine effectiveness. Furthermore, for revaccination to be maximally beneficial, compliance with, and timely delivery of the complete revaccination schedule is imperative, but rare, and there is little data on strategies to optimize vaccine delivery. Objectives: The global aim of our quality improvement initiative was to enhance timely, correct, and effective revaccination after pediatric HCT. The SMART aim of our project was to decrease median unvaccinated time by four months, by decreasing time to vaccine eligibility, time from eligibility to vaccine start and time to completion of vaccine series. Quality improvement interventions: A multidisciplinary group performed a cross-sectional quantitative and qualitative evaluation of revaccination practices at our institution, we identified factors associated with delayed, incorrect, or incomplete revaccination. Several plan-do-study-act interventions were implemented to address these drivers including revising immune readiness criteria, increased auditing of primary care administered immunizations and importantly, establishing a dedicated revaccination clinic within the HCT clinic at our center. Results: Time to vaccine eligibility decreased from 12.6 months to 10 months (20% decrease) and time to complete vaccine series decreased from 19.3 months to 15.7 months (19% decrease). The proportion of patients who started re-vaccination within 13 months from HCT increased from 55% to consistently greater than 90%. Conclusions: With a quality improvement initiative, we addressed the many causes of delayed or incomplete revaccination post-HCT and through a team-based approach successfully decreased time to vaccine start and vaccine completion at our center. We believe this initiative can similarly be implemented within HCT centers at peer institutions, in both pediatrics and adults, to improve revaccination after transplantation

Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy

Cytokine release syndrome (CRS) is a systemic inflammatory response associated with chimeric antigen receptor T-cell (CAR-T) therapies. In severe cases, CRS can be associated with coagulopathy and hypofibrinogenemia. We present our global multicenter experience with CRS-associated coagulopathy after tisagenlecleucel therapy in 137 patients with relapsed or refractory B-cell acute lymphoblastic leukemia from the ELIANA and ENSIGN trials. These trials included clinical guidelines for fibrinogen replacement during CRS-associated coagulopathy. Hypofibrinogenemia requiring replacement was observed only in patients with severe CRS. A higher percentage of patients who required replacement were <10 years old, compared with those who did not require replacement. Twenty-three patients received replacement for hypofibrinogenemia (<1.5 g/L); 9 of them developed marked hypofibrinogenemia (<1 g/L). Very low fibrinogen levels (<1 g/L) were documented in patients before maximal CRS (n = 1), during maximal CRS (n = 7), and at CRS improvement (n = 1). Although hypofibrinogenemia was the most clinically significant coagulopathy, some patients also developed prolonged prothrombin time and activated partial thromboplastin time and increased international normalized ratio, further increasing the risk of bleeding. Hypofibrinogenemia was effectively managed using fibrinogen concentrate or cryoprecipitate replacement; severe (grade 4) bleeding events were rare (n = 2). CRS-associated coagulopathy with hypofibrinogenemia is manageable according to empiric guidelines of fibrinogen replacement for CAR-T trials. Fibrinogen concentrate should be used when cryoprecipitate is not reliably available. Monitoring fibrinogen levels in patients with moderate or severe CRS is essential for avoiding potentially fatal bleeding events

TNF-Receptor Inhibitor Therapy for the Treatment of Children with Idiopathic Pneumonia Syndrome. A Joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521)

AbstractIdiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS

T cell immunoengineering with advanced biomaterials

Recent advances in biomaterials design offer the potential to actively control immune cell activation and behaviour. Many human diseases, such as infections, cancer, and autoimmune disorders, are partly mediated by inappropriate or insufficient activation of the immune system. T cells play a central role in the host immune response to these diseases, and so constitute a promising cell type for manipulation. In vivo, T cells are stimulated by antigen presenting cells (APC), therefore to design immunoengineering biomaterials that control T cell behaviour, artificial interfaces that mimic the natural APC-T cell interaction are required. This review draws together research in the design and fabrication of such biomaterial interfaces, and highlights efforts to elucidate key parameters in T cell activation, such as substrate mechanical properties and spatial organization of receptors, illustrating how they can be manipulated by bioengineering approaches to alter T cell function

Clinical utilization of Chimeric Antigen Receptors T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL) – an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT)

On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor - T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved