Despite more intensive therapy, high-risk neuroblastoma continues to be a challenging disease to treat. Postconsolidation immunotherapy has been studied for many years and has proven to be effective ...in clinical trials. Immunotherapy has become the standard of care for patients with high-risk disease, and many institutions across the country are providing this therapy. The care of these patients is complex and often associated with many side effects. The purpose of this article is to review the most common side effects seen in clinical practice and examine their management. Furthermore, this article will discuss the need for a consistent and educated multidisciplinary front-line team to care for these patients, with advanced practitioners playing a lead role to provide the care and attention needed for this patient population.
BACKGROUND: This article presents an overview of pediatric relapsed and refractory acute lymphoblastic leukemia (ALL) and chimeric antigen receptor (CAR) T-cell therapy in pediatric patients. ...OBJECTIVES: Acute and chronic post–CAR T-cell effects and considerations are discussed, along with survivorship considerations. METHODS: A case study illustrates the identification and management of physiologic and psychosocial sequelae. FINDINGS: B-cell aplasia, hypogammaglobulinemia, infections, and cumulative effects of CAR T-cell therapy and other treatments are a concern in the pediatric population. Unique to pediatric and young adult survivors of childbearing potential are implications for post-treatment fertility. Financial toxicities and psychosocial needs require a familycentered approach to interventions that address the impact of CAR T-cell therapy not only on the patient, but also on caregivers and siblings.
Abstract
CAR T cell therapy in relapsed B-ALL can result in complete response (CR) rates of 80-90%, but relapse-free survival declines to 60% within the first 12-months due to both CD19-positive and ...negative relapses. CD19-positive relapses that occur during this time are largely due to early CAR T cell loss. We hypothesize that inhibiting the PD-1:PD-L1 (programmed cell death 1) checkpoint axis may decrease T cell exhaustion, thereby improving CAR T cell function and persistence. We report our single institution experience of the use of PD-1 inhibitors in patients with relapsed or refractory B lymphoblastic malignancies treated with CD19-directed CAR T cell therapy.
Methods: Patients treated with CD19-directed CAR T cell therapy (murine CTL019 or humanized CTL119) at the Children's Hospital of Philadelphia who demonstrated repeated early CAR T cell loss or partial/no response to CAR T cell therapy received a PD-1 inhibitor starting no sooner than 14 days after CAR T cell infusion and after resolution of cytokine release syndrome (CRS) symptoms, with the possibility of repeated doses up to every 3 weeks.
Results: Fourteen patients, ages 4-17 years, with heavily pretreated, relapsed B-ALL (n=13) or B lymphoblastic lymphoma (n=1), were treated with CD19-directed CAR T cell therapy (CTL019, n=4; or CTL119, n=10) in combination with pembrolizumab (n=13) or nivolumab (n=1). Three of 6 patients treated with CD19 CAR T cells in combination with a PD-1 inhibitor for early B cell recovery re-established B cell aplasia (a reflection of CAR T cell function) for 5-15 months, 2 of whom have persistent B cell aplasia with ongoing pembrolizumab therapy. Four patients started pembrolizumab for bulky extramedullary disease unresponsive to or relapsed after CAR T cells, with 2 partial and 2 complete responses seen. In one patient, significant CAR T cell proliferation was measured within days of starting pembrolizumab and in temporal correlation to radiographic disease response. In 4 patients who failed to achieve disease remission with initial CAR T cell infusion, no CRs were achieved with the addition of pembrolizumab, although partial responses were seen, and one patient progressed with CD19-dim/negative disease.
CRS symptoms and fever typical of CAR T cell proliferative responses were observed in 3/14 patients within 2 days of starting pembrolizumab. Other early and delayed adverse effects associated with PD-1 inhibition were tolerable or reversible upon discontinuation, and including 1 case each of acute pancreatitis, hypothyroidism, arthralgias, urticaria, as well as 4 patients with grade 3-4 cytopenias. No grade 5 toxicities or graft-versus-host disease flares occurred. Two patients discontinued pembrolizumab for delayed adverse effects after multiple doses; both patients relapsed/progressed with CD19+ disease a few weeks after discontinuation.
Discussion: T cell exhaustion or activation induced CAR T death (AICD) has been suspected to contribute to poor persistence of CAR T cells. We hypothesized that the PD-1 checkpoint pathway may be involved in CAR T cell exhaustion in some cases, which may be overcome by checkpoint inhibition. Here, promising responses were specifically seen in those with early B-cell recovery and bulky extramedullary disease. In contrast, PD-1 inhibition had partial, but no durable, effect in the four B-ALL patients with poor initial marrow response to CAR T cell therapy alone, suggesting a different mechanism such as AICD may be responsible for poor initial responses. No unexpected or fatal toxicities were seen. This cohort shows initial evidence that checkpoint inhibitors can be used effectively and safely with CAR T cell therapy in children with relapsed B-ALL, and that this strategy may augment CAR T cell effect and persistence.
Teachey:Amgen: Consultancy; La Roche: Consultancy. Callahan:Novartis Pharmaceuticals Corporation: Consultancy. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board. Lacey:Novartis Pharmaceuticals Corporation: Patents & Royalties; Tmunity: Research Funding; Parker Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. June:Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Background: Chimeric antigen receptor (CAR) T-cell therapy is a cellular immunotherapy that redirects the killing activity of T cells to fight tumor cells. CD19 CAR T-cell therapies have demonstrated ...high rates of complete response in clinical trials in patients with relapsed or refractory B-cell malignancies and have been associated with on-target side effects. Objectives: This article describes educational opportunities for patients and families during the CAR T-cell therapy procedure, highlighting specific points where education by nurses is critical for safety and protocol adherence. Methods: Current literature on CAR T-cell therapy was reviewed and supported by the authors' professional experiences. Findings: CAR T-cell therapy is a novel treatment, and repetition of information and building the knowledge base of patients and families is important. The role of nurses in educating patients about the side effects of CAR T-cell therapy is critical for the safety and psychological well-being of patients.
Robe à la Polonaise Callahan, Colleen
Clothing and Fashion : American Fashion from Head to Toe: Pre-colonial Times through the American Revolution,
2016
Reference
Hairstyles, 1715-1785 Callahan, Colleen
Clothing and Fashion : American Fashion from Head to Toe: Pre-colonial Times through the American Revolution,
2016
Reference
Children’s Dress and Fashion, 1715-1785 Callahan, Colleen
Clothing and Fashion : American Fashion from Head to Toe: Pre-colonial Times through the American Revolution,
2016
Reference
Background
Chimeric antigen receptor (CAR)-modified T cells targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). We ...previously demonstrated durable remissions with the CD19-targeted CAR T cell product CTL019; however, a subset of patients has limited persistence, which can increase the risk of relapse. Most CAR single chain variable fragment (scFv) domains, including that of CTL019, are of murine origin; therefore, anti-mouse reactivity is one potential cause of immune-mediated rejection that may be overcome by fully human or humanized CAR designs. We developed a humanized anti-CD19 scFv domain and now report on treatment with humanized CD19-directed CAR T cells (CTL119).
Design
A pilot/phase 1 study of CTL119 enrolled children and young adults with relapsed/refractory B-ALL or lymphoblastic lymphoma (B-LL) with or without prior exposure to a CAR T cell product in retreatment and CAR-naive cohorts, respectively. Patients in the retreatment cohort were eligible if they met 1 of 3 criteria: 1) CD19+ relapse 2) no response or 3) early B cell recovery indicating poor persistence of CAR T cells. Patient-derived T cells were transduced ex vivo with a lentiviral vector encoding the CAR composed of CD3z, 4-1BB, and humanized anti-CD19 scFv domains and activated/expanded with anti-CD3/CD28 beads. Patients received lymphodepletion with cyclophosphamide and fludarabine 1 week prior to infusion with CTL119.
Results
Thirty-eight children and young adults (2-24 yr) with B-ALL (n=37) and B-LL (n=1) were infused with CTL119 in 2 cohorts: CAR-naive (n=22) and retreatment (n=16). Indications included primary refractory disease (n=4), first relapse (n=9), second or greater relapse (n=25), relapse after prior allogeneic stem cell transplant (SCT, n=22), CNS disease (n=7), and other extramedullary disease (n=6). Sixteen patients with prior exposure to murine-derived CD19-specific CAR-modified T cells (CTL019, n=10; other, n=6) were retreated for B cell recovery (n=5), CD19+ relapse (n=10), or no response to prior CAR T cells (n=1). Two retreatment patients previously received 2 different CAR T cell products.
At assessment 1 month after infusion, 22/22 (100%) CAR-naive patients were in complete remission. Multiparameter flow cytometry for minimal residual disease (MRD) was negative at a detection level of 0.01% in all responding patients. Four patients relapsed 3-9 months after infusion, 2 CD19+, 2 CD19-. Median follow-up was 14 mo. RFS in responding patients was 86% (95% CI: 63, 95) at 6 months and 82% (95% CI: 58, 93) at 12 months, with 3/22 (14%) proceeding to SCT in remission.
In the retreatment cohort, 9/16 (56%) patients achieved a complete response (CR), defined as morphologic remission with B cell aplasia. Refractory disease showed reduced CD19 expression in 3 non-responding patients. MRD was negative in 7/9 responding patients and positive in 2 patients, who progressed to CD19+ relapse at 1.6 and 3 mo. Median follow-up was 13 months. Relapse-free survival (RFS) in responding patients was 67% (95% CI: 28, 88) at 6 months and 56% (95% CI: 20, 80) at 12 months.
B cell aplasia, a functional marker of CD19-targeted CAR T cell persistence, continued for 6 months or more in 15/26 patients with adequate follow-up: 13/17 CAR-naive, 2/9 retreatment. Cytokine release syndrome (CRS) was observed in 34/38 patients and mild in most patients (grade 1, n=6; grade 2, n=23). Four patients experienced grade 3 CRS requiring supplemental oxygen and/or low-dose vasopressor support and 1 experienced grade 4 CRS requiring high-dose vasopressor and ventilatory support. Neurologic toxicity included encephalopathy (n=5) and seizure (n=5) and was fully reversible.
Conclusion
In the first study of humanized anti-CD19 CAR T cells, CTL119 induced CR in 100% of patients with no prior CAR T cell exposure, with a 12-mo RFS of 82%. In the retreatment setting, 56% of patients with poor or transient response to prior murine CD19-directed CAR T cells achieved CR. CTL119 can induce durable remissions without further therapy in children and young adults with relapsed/refractory B-ALL.
Maude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Brogdon:Novartis: Employment. Young:Novartis: Research Funding. Levine:Tmunity Therapeutics: Equity Ownership, Research Funding; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding; Brammer Bio: Consultancy; GE Healthcare: Consultancy. Frey:Novartis: Research Funding. Porter:Genentech/Roche: Employment, Other: Family member employment, stock ownship - family member; Incyte: Honoraria; Immunovative Therapies: Other: Member DSMB; Servier: Honoraria, Other: Travel reimbursement; Novartis: Honoraria, Patents & Royalties, Research Funding. Lacey:Novartis: Research Funding; Genentech: Honoraria. Melenhorst:Novartis: Research Funding. June:Novartis: Patents & Royalties, Research Funding; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Grupp:Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant.
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