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Immune effector cell (IEC) therapies have revolutionized our approach to relapsed B-cell malignancies, and interest in the investigational use of IECs is rapidly expanding into other diseases. Current challenges in the analysis of IEC therapies include small sample sizes, limited access to clinical trials and a paucity of predictive biomarkers of efficacy and toxicity associated with IEC therapies. Retrospective and prospective multi-center cell therapy trials can assist in overcoming these barriers through harmonization of clinical endpoints and correlative assays for immune monitoring, allowing additional cross-trial analysis to identify biomarkers of failure and success. The Consortium for Pediatric Cellular Immunotherapy (CPCI) offers a unique platform to address the aforementioned challenges by delivering cutting-edge cell and gene therapies for children through multi-center clinical trials. Here the authors discuss some of the important pre-analytic variables, such as biospecimen collection and initial processing procedures, that affect biomarker assays commonly used in IEC trials across participating CPCI sites. The authors review the recent literature and provide data to support recommendations for alignment and standardization of practices that can affect flow cytometry assays measuring immune effector function as well as interpretation of cytokine/chemokine data. The authors also identify critical gaps that often make parallel comparisons between trials difficult or impossible. [ABSTRACT FROM AUTHOR]

Background: Despite advances in immunotherapeutic strategies for neuroblastoma (NBL), relapse remains a significant cause of mortality for high risk patients. The discovery of novel tumor associated antigens to improve efficacy and minimize the toxicities of immunotherapy is therefore warranted. Receptor Tyrosine Kinase-like Orphan Receptor-1 and 2 (ROR1 and ROR2) have been found to be expressed in several malignancies with limited expression in healthy tissues. Objectives: Given their role in tumor migration and proliferation and the fact that they were originally cloned from a NBL cell line, we hypothesized that ROR1 and ROR2 could serve as potential targets for anti-ROR1 and anti-ROR2 based immunotherapies in NBL. Methods: We characterized the mRNA and protein expression of ROR1 and ROR2 in NBL cell lines and tissue microarrays of patient samples. To explore the potential of ROR1 targeting, we performed in vitro cytotoxicity assays against NBL using NK92 cells as effector cells. Results: Both ROR1 and ROR2 are expressed across all stages of NBL. In patients with non-MYC amplified tumors, expression of ROR1/ROR2 correlated with survival and prognosis. Moreover, in a proof-of-concept experiment, pretreatment of NBL cell line with anti-ROR1 antibody showed additive cytotoxicity with NK92 cells. Conclusions: ROR1 and ROR2 could serve as novel targets for immunotherapy in NBL. The additive effect of anti-ROR1 antibodies with NK cells needs to be explored further to evaluate the possibility of combining anti-ROR1 antibodies with immune effectors such as NK92 cells as a potential off-the shelf immunotherapy for NBL and other ROR1 expressing malignancies. [ABSTRACT FROM AUTHOR]

The article provides a comprehensive review on the standard of care in children who are suffering sickle cell disease, along with information on the pathophysiology, classification, common laboratory evaluations and clinical manifestations of the disease.

Background: Despite high cure rates for pediatric B-lineage acute lymphoblastic leukemia (B-ALL), short-term and longterm toxicities and chemoresistance are shortcomings of standard chemotherapy. Immunotherapy and chemoimmunotherapy based on monoclonal antibodies (mAbs) that target cell surface antigens with restricted expression in pediatric B-ALL may offer the potential to reduce toxicities and prevent or overcome chemoresistance. The receptor tyrosine kinase ROR1 has emerged as a candidate for mAb targeting in select B-cell malignancies. Methodology and Principal Findings: Using flow cytometry, Western blotting, immunohistochemistry, and confocal immunofluorescence microscopy, we analyzed the cell surface expression of ROR1 across major pediatric ALL subtypes represented by 14 cell lines and 56 primary blasts at diagnosis or relapse as well as in normal adult and pediatric tissues. Cell surface ROR1 expression was found in 45% of pediatric ALL patients, all of which were B-ALL, and was not limited to any particular genotype. All cell lines and primary blasts with E2A-PBX1 translocation and a portion of patients with other high risk genotypes, such as MLL rearrangement, expressed cell surface ROR1. Importantly, cell surface ROR1 expression was found in many of the pediatric B-ALL patients with multiply relapsed and refractory disease and normal karyotype or low risk cytogenetics, such as hyperdiploidy. Notably, cell surface ROR1 was virtually absent in normal adult and pediatric tissues. Conclusions and Significance: Collectively, this study suggests that ROR1 merits preclinical and clinical investigations as a novel target for mAb-based therapies in pediatric B-ALL. We propose cell surface expression of ROR1 detected by flow cytometry as primary inclusion criterion for pediatric B-ALL patients in future clinical trials of ROR1-targeted therapies. [ABSTRACT FROM AUTHOR]

T-cell lymphomas represent a subpopulation of non-Hodgkin lymphomas with poor outcomes when treated with conventional chemotherapy. A variety of novel agents have been introduced as new treatment strategies either as first-line treatment or in conjunction with chemotherapy. Immunotherapy has been demonstrated to be a promising area for new therapeutics, including monoclonal antibodies and adoptive cellular therapeutics. T-cell therapeutics have been shown to have significant success in the treatment of B-cell malignancies and are rapidly expanding as potential treatment options for other cancers including T-cell lymphomas. Although treating T-cell lymphomas with T-cell therapeutics has unique challenges, multiple targets are currently being studied both preclinically and in clinical trials. [ABSTRACT FROM AUTHOR]

Recipients of anti-CD19 targeted therapies such as chimeric antigen receptor (CAR)-T cell are considered at high risk for complicated Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection due to prolonged B cell aplasia and immunosuppression. These patients represent a unique cohort and so far, immune responses to SARS-CoV-2 have not been well characterized in this setting. We report a pediatric patient with B-cell acute lymphoblastic leukemia (B-ALL) who had asymptomatic SARS-CoV-2 infection while receiving blinatumomab, followed by lymphodepletion (LD) and tisagenlecleucel, a CD19 targeting CAR-T therapy. The patient had a complete response to tisagenlecleucel, did not develop cytokine release syndrome, or worsening of SARS-CoV-2 during therapy. The patient had evidence of ongoing persistence of IgG antibody responses to spike and nucleocapsid after LD followed by tisagenlecleucel despite the B-cell aplasia. Further we were able to detect SARS-CoV-2 specific T-cells recognizing multiple viral structural proteins for several months following CAR-T. The T-cell response was polyfunctional and predominantly CD4 restricted. This data has important implications for the understanding of SARS-CoV-2 immunity in patients with impaired immune systems and the potential application of SARS-CoV-2-specific T-cell therapeutics to treat patients with blood cancers who receive B cell depleting therapy. [ABSTRACT FROM AUTHOR]

CAR-T cells were not detectable in the blood sample for Patient 1, but for Patients 2 and 3, they were present at 30 days post-infusion, after treatment which included anakinra as well as corticosteroids. Chimeric antigen receptor-T (CAR-T) therapy has demonstrated impressive efficacy in B-cell malignancies, but its therapeutic index has been impaired by unique immune-mediated toxicities not seen with traditional cytotoxic chemotherapy.[1],[2] These toxicities include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hemophagocytic lymphohistiocytosis (HLH)-like syndrome.[2] Although IL-6 blockade with tocilizumab has become standard treatment for CRS, patients refractory to tocilizumab or those with ICANS often require corticosteroids. She was treated with bridging chemotherapy including cyclophosphamide, etoposide, vincristine, and dexamethasone, and then lymphodepleting therapy with fludarabine (30 mg/m SP 2 sp , 4 doses) and cyclophosphamide (500 mg/m SP 2 sp , 2 doses) prior to the CAR-T cell infusion. HT