Restricting CAR T Cell Trafficking Expands Targetable Antigen Space.

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin α4 (A4ko), an adhesion molecule essential for migration across the blood-brain barrier. A4ko LINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells.

Blinatumomab Therapy Is Associated with Favorable Outcomes after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with B Cell Acute Lymphoblastic Leukemia.

Blinatumomab, a bispecific T cell engager that binds CD19 in leukemic cells and CD3 in cytotoxic T cells and leads to leukemic blast lysis, is often used in pediatric patients with relapsed/refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) prior to allogeneic hematopoietic cell transplantation (allo-HCT). Concerns about the potential risk of blinatumomab-related immune-mediated toxicities after allo-HCT have not been adequately addressed. These include graft-versus-host disease (GVHD), delayed engraftment, and graft failure or rejection. Pediatric-specific data reporting post-HCT outcomes of patients treated with blinatumomab are scarce and limited to small cohorts. We sought to investigate the clinical outcomes of pediatric patients with R/R B-ALL who received blinatumomab therapy pre-HCT, focusing on overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM), as well as the incidence of immune-mediated post-HCT complications including GVHD, delayed neutrophil or platelet engraftment, graft failure, and graft rejection. We also investigated blinatumomab's effects on B cell reconstitution based on achievement of i.v. immunoglobulin (IVIG) independence post-HCT. This single-center, retrospective study included patients with B-ALL receiving blinatumomab therapy before undergoing allo-HCT, with transplantation performed between 2016 and 2021 at our institution. Patients receiving blinatumomab for relapse after allo-HCT were excluded. Patients receiving chemotherapy alone before allo-HCT during the same period composed the control group. Seventy-two patients were included, 31 of whom received blinatumomab before allo-HCT. Survival estimates were obtained using the Kaplan-Meier method, and the log-rank test was used to analyze differences between groups. Categorical variables were compared between groups using the chi-square test or Fisher exact test, and continuous variables were compared using the Wilcoxon rank-sum test. Cumulative incidences were estimated using the competing risks method, and Gray's test was used to analyze differences between groups. A Cox proportional hazards regression model was used for univariate and multivariable analyses for OS. Landmark analysis was performed at the set time points of 30 days and 100 days post-allo-HCT. Most patients in the study cohort had high-risk relapsed B-ALL. Blinatumomab therapy induced minimal residual disease (MRD)-negative remissions in all patients, whereas 5 patients (12.2%) receiving chemotherapy alone had persistent MRD pre-allo-HCT. Time from the start of therapy to the date of allo-HCT was shorter for patients who received blinatumomab compared with those who received chemotherapy (P < .0001). Blinatumomab therapy was associated with greater LFS compared to chemotherapy alone (P = .049), but when limited to 1 year, LFS was not significantly different from control (P = .066). There appeared to be higher OS, lower CIR, and lower NRM in patients receiving blinatumomab compared to the control group; however, the differences were not significant. None of the variables assessed in multivariable analysis was associated with differences in OS. When compared to the controls, blinatumomab therapy did not result in a higher incidence of acute or chronic GVHD, delayed neutrophil or platelet engraftment, or graft failure or rejection. The time to IVIG infusion independence post-allo-HCT was similar in the 2 groups. This study supports the use of blinatumomab salvage therapy for R/R B-ALL before allo-HCT given its efficacy in inducing MRD-negative remissions and optimizing LFS, as well as its lack of association with an increased incidence of post-allo-HCT adverse immune-mediated toxicities. Larger, prospective studies are needed to confirm these findings and to investigate blinatumomab's effects in long-term post-allo-HCT events.

Targeting the tumor microenvironment of Ewing sarcoma.

Ewing sarcoma is an aggressive tumor type with an age peak in adolescence. Despite the use of dose-intensified chemotherapy as well as radiation and surgery for local control, patients with upfront metastatic disease or relapsed disease have a dismal prognosis, highlighting the need for additional therapeutic options. Different types of immunotherapies have been investigated with only very limited clinical success, which may be due to the presence of immunosuppressive factors in the tumor microenvironment. Here we provide an overview on different factors contributing to Ewing sarcoma immune escape. We demonstrate ways to target these factors in order to make current and future immunotherapies more effective and achieve deeper and more durable responses in patients with Ewing sarcoma.

Lay abstract Ewing sarcoma is an aggressive type of cancer of the bones or soft tissues that mainly affects teenagers. Patients are often treated with intensive treatments which may include chemotherapy in combination with radiation and/or surgery. For patients who present with cancer that has already spread to other sites or that returns after treatment, the cancer can be very hard to cure. This leads to the need for different therapies. Therapies that use the help of the immune system to combat the cancer, called immunotherapies, have had limited success, which is thought to be due to factors in the environment of the tumor that weaken the immune system and so dampen any potential use of it to destroy the cancer cells. We provide an overview of these factors in the tumor environment that allow the cancer cells to escape the immune system; we also discuss potential options to target these factors and, in this way, allow the immunotherapies to destroy the cancer cells more effectively.

Multiple Intraspinal Gangliogliomas in a Child With Neurofibromatosis Type 1: Case Report and Literature Review.

Neurofibromatosis type 1 (NF1)-associated primary intramedullary spinal cord ganglioglioma has only rarely been reported. Because of frequent nonresectability, they pose significant management challenges despite clinical indolence. This report describes a 4-year-old girl with NF1 who was found to have multiple discrete, infiltrative intramedullary cord masses, and biopsy demonstrated World Health Organization grade I ganglioglioma. Panel-based next-generation sequencing showed her previously identified germline NF1 mutation and a second somatic NF1 mutation. This represents the first report of multiple primary intramedullary gangliogliomas in a child with NF1 and demonstrates how biopsy with panel-based next-generation sequencing provides potential targets for MAPK/MEK/BRAF pathway inhibitor therapy.

Role of immunotherapy in Ewing sarcoma.

Ewing sarcoma (ES) is thought to arise from mesenchymal stem cells and is the second most common bone sarcoma in pediatric patients and young adults. Given the dismal overall outcomes and very intensive therapies used, there is an urgent need to explore and develop alternative treatment modalities including immunotherapies. In this article, we provide an overview of ES biology, features of ES tumor microenvironment (TME) and review various tumor-associated antigens that can be targeted with immune-based approaches including cancer vaccines, monoclonal antibodies, T cell receptor-transduced T cells, and chimeric antigen receptor T cells. We highlight key reasons for the limited efficacy of various immunotherapeutic approaches for the treatment of ES to date. These factors include absence of human leukocyte antigen class I molecules from the tumor tissue, lack of an ideal surface antigen, and immunosuppressive TME due to the presence of myeloid-derived suppressor cells, F2 fibrocytes, and M2-like macrophages. Lastly, we offer insights into strategies for novel therapeutics development in ES. These strategies include the development of gene-modified T cell receptor T cells against cancer-testis antigen such as XAGE-1, surface target discovery through detailed profiling of ES surface proteome, and combinatorial approaches. In summary, we provide state-of-the-art science in ES tumor immunology and immunotherapy, with rationale and recommendations for future therapeutics development.