Publications by authors named "Kenneth DeSantes"

25 Publications

  • Page 1 of 1

Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers.

J Clin Immunol 2021 Jan 2;41(1):38-50. Epub 2020 Oct 2.

Division of Allergy and Immunology, Children's Hospital of Philadelphia, Wood 3301, 3401 Civic Center Blvd, Philadelphia, PA, 19104, USA.

Purpose: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention.

Methods: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management.

Results: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented.

Conclusion: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS.

Trial Registration: NCT01186913.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00865-9DOI Listing
January 2021

Correction: Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

J Clin Immunol 2020 Nov;40(8):1211-1213

Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

The original version of this article unfortunately contained the missing author, Caridad Martinez. The authors would like to correct the list. We apologize for any inconvenience that this may have caused. The correct author list is shown above.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00852-0DOI Listing
November 2020

Analysis of ex vivo expanded and activated clinical-grade human NK cells after cryopreservation.

Cytotherapy 2020 08 11;22(8):450-457. Epub 2020 Jun 11.

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin, USA. Electronic address:

Background Aims: Several methods to expand and activate (EA) NK cells ex vivo have been developed for the treatment of relapsed or refractory cancers. Infusion of fresh NK cells is generally preferred to the infusion of cryopreserved/thawed (C/T) NK cells because of concern that cryopreservation diminishes NK cell activity. However, there has been little head-to-head comparison of the functionality of fresh versus C/T NK cell products.

Methods: We evaluated activity of fresh and C/T EA NK cells generated by interleukin (IL)-15, IL-2 and CD137L expansion.

Results: Analysis of C/T NK cell products demonstrated decreased recovery of viable CD56 cells, but the proportion of NK cells in the C/T EA NK cell product did not decrease compared with the fresh EA NK cell product. Fresh and C/T EA NK cells demonstrated increased granzyme B compared with NK cells pre-expansion, but only fresh EA NK cells showed increased NKG2D. Compared with fresh EA NK cells, cytotoxic ability of C/T EA NK cells was reduced, but C/T EA NK cells remained potently cytotoxic against tumor cells via both antibody-independent and antibody-dependent mechanisms within 4 h post-thaw. Fresh EA NK cells generated high levels of gamma interferon (IFN-γ), which was abrogated by JAK1/JAK2 inhibition with ruxolitinib, but C/T EA NK cells showed lower IFN-γ unaffected by JAK1/JAK2 inhibition.

Discussion: Usage of C/T EA NK cells may be an option to provide serial "boost" NK cell infusions from a single apheresis to maximize NK cell persistence and potentially improve NK-induced responses to refractory cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcyt.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387178PMC
August 2020

Isobaric Labeling Strategy Utilizing 4-Plex ,-Dimethyl Leucine (DiLeu) Tags Reveals Proteomic Changes Induced by Chemotherapy in Cerebrospinal Fluid of Children with B-Cell Acute Lymphoblastic Leukemia.

J Proteome Res 2020 07 27;19(7):2606-2616. Epub 2020 May 27.

School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin 53705, United States.

The use of mass spectrometry for protein identification and quantification in cerebrospinal fluid (CSF) is at the forefront of research efforts to identify and explore biomarkers for the early diagnosis and prognosis of neurologic disorders. Here we implemented a 4-plex ,-dimethyl leucine (DiLeu) isobaric labeling strategy in a longitudinal study aiming to investigate protein dynamics in children with B-cell acute lymphoblastic leukemia (B-cell ALL) undergoing chemotherapy. The temporal profile of CSF proteome during chemotherapy treatment at weeks 5, 10-14, and 24-28 highlighted many differentially expressed proteins, such as neural cell adhesion molecule, neuronal growth regulator 1, and secretogranin-3, all of which play important roles in neurodegenerative diseases. A total of 63 proteins were significantly altered across all of the time points investigated. The most over-represented biological processes from gene ontology analysis included platelet degranulation, complement activation, cell adhesion, fibrinolysis, neuron projection, regeneration, and regulation of neuron death. We expect that results from this and future studies will provide a means to monitor neurotoxicity and develop strategies to prevent central nervous system injury in response to chemotherapy in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jproteome.0c00291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334086PMC
July 2020

Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report.

Blood 2020 06;135(23):2094-2105

Pediatric Allergy, Immunology, and Blood and Marrow Transplant Division, University of California, San Francisco Benioff Children's Hospital, San Francisco, CA.

Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019002939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273831PMC
June 2020

Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 01;18(1):81-112

National Comprehensive Cancer Network.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Advancements in technology that enhance our understanding of the biology of the disease, risk-adapted therapy, and enhanced supportive care have contributed to improved survival rates. However, additional clinical management is needed to improve outcomes for patients classified as high risk at presentation (eg, T-ALL, infant ALL) and who experience relapse. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric ALL provide recommendations on the workup, diagnostic evaluation, and treatment of the disease, including guidance on supportive care, hematopoietic stem cell transplantation, and pharmacogenomics. This portion of the NCCN Guidelines focuses on the frontline and relapsed/refractory management of pediatric ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2020.0001DOI Listing
January 2020

Reduction in oral mucositis severity using a topical vasoconstrictor: A case report of three bone marrow transplant patients.

Integr Cancer Sci Ther 2018 Dec 29;5(6). Epub 2018 Nov 29.

Wisconsin Institutes of Medical Research, University of Wisconsin-Madison, USA.

Background: Grade 3 oral mucositis (OM) is historically observed in >90% of bone marrow transplant patients who received the cyclophosphamide + total body irradiation (CY+TBI) conditioning regimen. It was previously shown that orotopically applied adrenergic vasoconstrictor prevented up to 100% of radiation-induced oral mucositis in two preclinical animal models.

Methods: drenergic vasoconstrictor (i.e., phenylephrine in an aqueous-alcohol NG11-1 formulation) was orotopically applied to three patients (ages 24-29) who received the CY+TBI conditioning regimen; they were compared to five matched controls who received no orotopical vasoconstrictor. All patients received the CY+TBI conditioning regimen for acute lymphoblastic leukemia within the University of Wisconsin Adult Bone Marrow Transplant Program. Over the seven-day Cy+TBI conditioning regimen, 20 min before each treatment, either radiation or chemotherapy, vasoconstrictor was applied topically to the oral cavity, and patients then received either 1.5 Gy whole-body radiation or IV cyclophosphamide.

Results: OM severity was scored over a three-week period using: i) physican assessments, ii) daily photos of the oral cavity, iii) oral pain and oral function score sheets, and iv) recorded narcotic consumption. Both "Grade 3 OM" duration and "any OM" duration in vasoconstrictor-treated patients were substantially lower than for the five control patients. Though nasogastric tube or total parenteral nutrition were used in 3 out of 5 control patients, there was no use of these supportive care measures in the three vasoconstrictor-treated patients.

Conclusion: Orotopically applied NG11-1 vasoconstrictor formulation substantially reduced the incidence and severity of "Grade 3" and "any" oral mucositis when compared to matched control patients, all of whom received the same CY+TBI conditioning regimen. The liquid orotopical formulation was easily tolerated by patients both in its ease of use and lack of side effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15761/ICST.1000293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907163PMC
December 2018

Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

J Clin Immunol 2019 10 2;39(7):653-667. Epub 2019 Aug 2.

Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Introduction: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking.

Methods: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016.

Results: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT.

Conclusions: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-019-00659-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754755PMC
October 2019

Role of the extent of prophylactic regional lymph node radiotherapy on survival in high-risk neuroblastoma: A report from the COG A3973 study.

Pediatr Blood Cancer 2019 07 9;66(7):e27736. Epub 2019 Apr 9.

Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.

Purpose: Neuroblastoma is the most common extracranial solid pediatric malignancy, with poor outcomes in high-risk disease. Standard treatment approaches employ an increasing array of aggressive multimodal therapies, of which local control with surgery and radiotherapy remains a backbone; however, the benefit of broad regional nodal irradiation remains controversial. We analyzed centrally reviewed radiation therapy data from patients enrolled on COG A3973 to evaluate the impact of primary site irradiation and the extent of regional nodal coverage stratified by extent of surgical resection.

Methods: Three hundred thirty high-risk neuroblastoma patients with centrally reviewed radiotherapy plans were analyzed. Outcome was evaluated by the extent of nodal irradiation. For the 171 patients who also underwent surgery (centrally reviewed), outcome was likewise analyzed according to the extent of resection. Overall survival (OS), event-free survival (EFS), and cumulative incidence of local progression (CILP) were examined by Kaplan-Meier, log-rank test (EFS, OS), and Grey test (CILP).

Results: The five-year CILP, EFS, and OS for all 330 patients receiving radiotherapy on A3973 were 8.5% ± 1.5%, 47.2% ± 3.0%, and 59.7% ± 3.0%, respectively. There were no significant differences in outcomes based on the extent of lymph node irradiation regardless of the degree of surgical resection (< 90% or ≥90%).

Conclusion: Although local control remains a significant component of treatment of high-risk neuroblastoma, our results suggest there is no benefit of extensive lymph node irradiation, irrespective of the extent of surgical resection preceding stem cell transplant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281832PMC
July 2019

A Retrospective Analysis of Antithrombin III Replacement Therapy for the Treatment of Hepatic Sinusoidal Obstruction Syndrome in Children Following Hematopoietic Stem Cell Transplantation.

J Pediatr Hematol Oncol 2020 03;42(2):145-148

Departments of Pediatrics.

Hepatic sinusoidal obstruction syndrome (SOS) remains a serious complication of hematopoietic stem cell transplantation (HSCT). In this single institution retrospective case series, 18 children developed SOS after HSCT. Patients were treated with antithrombin III (ATIII), defibrotide, or ATIII followed by defibrotide. Twelve of 13 patients who were treated with ATIII therapy alone had complete resolution of SOS, including 4 of 5 children with severe SOS. In this limited cohort, ATIII was safe and successfully prevented progression of hepatic SOS following HSCT in the majority of children at our center.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000001422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646100PMC
March 2020

SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery.

Blood 2018 10 28;132(17):1737-1749. Epub 2018 Aug 28.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with , , or defects and was significantly better compared with patients with or mutations. Patients with or mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4 and CD4CD45RA cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4 cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-03-840702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202916PMC
October 2018

Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study.

Blood 2017 12 11;130(25):2718-2727. Epub 2017 Oct 11.

Division of Pediatric Allergy, Immunology and Bone Marrow Transplant, University of California, San Francisco, San Francisco, CA.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection ( = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/μL, CD8 < 50 cells/μL, CD45RA < 10%, or a restricted Vβ T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2017-05-781849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746165PMC
December 2017

Donor selection for ex vivo-expanded natural killer cells as adoptive cancer immunotherapy.

Future Oncol 2017 05 11;13(12):1043-1047. Epub 2017 May 11.

Department of Human Oncology, University of Wisconsin, Madison, WI, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2017-0039DOI Listing
May 2017

Neck Rhabdoid Tumors: Clinical Features and Consideration of Autologous Stem Cell Transplant.

J Pediatr Hematol Oncol 2018 01;40(1):e50-e54

Departments of Pediatric Hematology, Oncology & Bone Marrow Transplant.

Extrarenal malignant rhabdoid tumors (MRT) have a poor prognosis despite aggressive therapy. Adding high-dose chemotherapy with autologous stem cell rescue (HDC-ASCR) as consolidative therapy for MRT is controversial. We describe 2 patients, age 13 years and 19 months, with unresectable neck MRT. After chemotherapy and radiotherapy, both underwent HDC-ASCR and remain in remission over 4 years later. We reviewed all published cases of neck MRT, and found poorer outcomes and more variable age of presentation and time to progression than MRT at other sites. Neck MRT may represent a higher-risk subset of MRT, and addition of HDC-ASCR merits consideration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000000829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624815PMC
January 2018

Curative potential of allogeneic hematopoietic stem cell transplant in type 1 diabetes.

Pediatr Diabetes 2017 Dec 30;18(8):832-834. Epub 2016 Aug 30.

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

The mainstay of treatment for type 1 diabetes (T1D) is exogenous insulin. Here, we report a case in which exogenous insulin requirements were eliminated after an allogeneic hematopoietic stem cell transplant for aplastic anemia in a pediatric patient recently diagnosed with T1D, and explore the validity of this approach compared with current treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pedi.12430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955001PMC
December 2017

NK cell-based immunotherapies in Pediatric Oncology.

J Pediatr Hematol Oncol 2015 Mar;37(2):79-93

Department of Pediatrics, Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, The University of Wisconsin, Madison, WI.

The past decade has seen several anticancer immunotherapeutic strategies transition from "promising preclinical models" to treatments with proven clinical activity or benefit. In 2013, the journal Science selected the field of Cancer Immunotherapy as the overall number-1 breakthrough for the year in all of scientific research. In the setting of cancer immunotherapy for adult malignancies, many of these immunotherapy strategies have relied on the cancer patient's endogenous antitumor T-cell response. Although much promising research in pediatric oncology is similarly focused on T-cell reactivity, several pediatric malignancies themselves, or the chemo-radiotherapy used to achieve initial responses, can be associated with profound immune suppression, particularly of the T-cell system. A separate component of the immune system, also able to mediate antitumor effects and less suppressed by conventional cancer treatment, is the NK-cell system. In recent years, several distinct immunotherapeutic approaches that rely on the activity of NK cells have moved from preclinical development into clinical testing, and some have shown clear antitumor benefit. This review provides an overview of NK cell-based immunotherapy efforts that are directed toward childhood malignancies, with an emphasis on protocols that are already in clinical testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000000303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429888PMC
March 2015

Immunotherapy in pediatric malignancies: current status and future perspectives.

Future Oncol 2014 ;10(9):1659-78

Department of Pediatrics & Carbone Cancer Center, University of Wisconsin School of Medicine & Public Health, 1111 Highland Avenue, WIMR 4137, Madison, WI 53705, USA.

Novel immune-based therapies are becoming available as additions to, and in some cases as alternatives to, the traditional treatment modalities such as chemotherapy, surgery and radiation that have improved outcomes for childhood cancer for decades. In this article, we will discuss what immunotherapies are being tested in the clinic, barriers to widespread application, and the future of immuno-oncology for childhood cancer. While in many cases, these therapies have shown dramatic responses in the setting of refractory or relapsed cancer, much remains to be learned about how to integrate these therapies into existing upfront regimens. The progress and challenges of developing immunotherapies for childhood cancer in a timely and cost-effective fashion will be discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon.14.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793725PMC
April 2015

KIR receptor-ligand incompatibility predicts killing of osteosarcoma cell lines by allogeneic NK cells.

Pediatr Blood Cancer 2010 Dec;55(7):1300-5

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

Background: The effectiveness of killer immunoglobulin-like receptor (KIR) incompatible, alloreactive natural killer (NK) cells has been primarily documented in hematological malignancies following stem-cell transplant. This effect has not been thoroughly evaluated for pediatric solid tumors. In this study, we evaluated KIR receptor-ligand incompatibility of NK cells against osteosarcoma cell lines.

Procedure: Following the KIR receptor-ligand mismatch model, MHC I cell surface expression and KIR ligand mRNA content of 3 osteosarcoma cell lines was determined by flow cytometry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. NK cells were isolated from healthy volunteer donor peripheral blood mononuclear cells (PBMCs) and KIR surface expression determined by flow cytometry. An Annexin-V based flow cytometric killing assay was used to determine % of dying osteosarcoma target cells by donor NK effector cells.

Results: One of seven healthy volunteer donors tested lacked phenotypic expression of one KIR. However, variable expression of KIR ligands was observed in 3 osteosarcoma cell lines. The highest rates of dying cells were seen in osteosarcoma cells with the lowest KIR ligand expression. Following down-regulation of KIR ligand expression, an increased susceptibility to NK cell-mediated killing was observed in a previously NK-resistant osteosarcoma cell line.

Conclusions: Variable MHC I and KIR ligand expression was observed in osteosarcoma cell lines and this resulted in variable susceptibility to NK cell-mediated killing predicted by the degree of KIR receptor-ligand incompatibility. Collectively, these data provide rationale for the study of KIR incompatible stem-cell transplant for osteosarcoma, although further studies with fresh osteosarcoma samples are necessary.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.22665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081247PMC
December 2010

Genotypes of NK cell KIR receptors, their ligands, and Fcγ receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy.

Cancer Res 2010 Dec 8;70(23):9554-61. Epub 2010 Oct 8.

Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, USA.

Response to immunocytokine (IC) therapy is dependent on natural killer cells in murine neuroblastoma (NBL) models. Furthermore, killer immunoglobulin-like receptor (KIR)/KIR-ligand mismatch is associated with improved outcome to autologous stem cell transplant for NBL. Additionally, clinical antitumor response to monoclonal antibodies has been associated with specific polymorphic-FcγR alleles. Relapsed/refractory NBL patients received the hu14.18-IL2 IC (humanized anti-GD2 monoclonal antibody linked to human IL2) in a Children's Oncology Group phase II trial. In this report, these patients were genotyped for KIR, HLA, and FcR alleles to determine whether KIR receptor-ligand mismatch or specific FcγR alleles were associated with antitumor response. DNA samples were available for 38 of 39 patients enrolled: 24 were found to have autologous KIR/KIR-ligand mismatch; 14 were matched. Of the 24 mismatched patients, 7 experienced either complete response or improvement of their disease after IC therapy. There was no response or comparable improvement of disease in patients who were matched. Thus KIR/KIR-ligand mismatch was associated with response/improvement to IC (P = 0.03). There was a trend toward patients with the FcγR2A 131-H/H genotype showing a higher response rate than other FcγR2A genotypes (P = 0.06). These analyses indicate that response or improvement of relapsed/refractory NBL patients after IC treatment is associated with autologous KIR/KIR-ligand mismatch, consistent with a role for natural killer cells in this clinical response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-10-2211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999644PMC
December 2010

Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children's Oncology Group (COG) phase II study.

J Clin Oncol 2010 Nov 4;28(33):4969-75. Epub 2010 Oct 4.

Dana-Farber Cancer Institute and Children's Hospital Boston, Boston, MA, USA.

Purpose: The hu14.18-IL2 fusion protein consists of interleukin-2 molecularly linked to a humanized monoclonal antibody that recognizes the GD2 disialoganglioside expressed on neuroblastoma cells. This phase II study assessed the antitumor activity of hu14.18-IL2 in two strata of patients with recurrent or refractory neuroblastoma.

Patients And Methods: Hu14.18-IL2 was given intravenously (12 mg/m(2)/daily) for 3 days every 4 weeks for patients with disease measurable by standard radiographic criteria (stratum 1) and for patients with disease evaluable only by [(123)I]metaiodobenzylguanidine (MIBG) scintigraphy and/or bone marrow (BM) histology (stratum 2). Response was established by independent radiology review as well as BM histology and immunocytology, and durability was assessed by repeat evaluation after more than 3 weeks.

Results: Thirty-nine patients were enrolled (36 evaluable). No responses were seen in stratum 1 (n = 13). Of 23 evaluable patients in stratum 2, five patients (21.7%) responded; all had a complete response (CR) of 9, 13, 20, 30, and 35+ months duration. Grade 3 and 4 nonhematologic toxicities included capillary leak, hypoxia, pain, rash, allergic reaction, elevated transaminases, and hyperbilirubinemia. Two patients required dopamine for hypotension, and one patient required ventilatory support for hypoxia. Most toxicities were reversible within a few days of completing a treatment course and were expected based on phase I results.

Conclusion: Patients with disease evaluable only by MIBG and/or BM histology had a 21.7% CR rate to hu14.8-IL2, whereas patients with bulky disease did not respond. Hu14.18-IL2 warrants further testing in children with nonbulky high-risk neuroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2009.27.8861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020698PMC
November 2010

Unrelated donor bone marrow transplantation for children with acute myeloid leukemia beyond first remission or refractory to chemotherapy.

J Clin Oncol 2008 Sep;26(26):4326-32

Children's Hospital of Philadelphia, Philadelphia, USA.

Purpose: Identify prognostic factors that influence outcome after unrelated donor bone marrow transplantation in children with acute myeloid leukemia (AML).

Patients And Methods: Included are 268 patients (age
Results: In this analysis, the only risk factor that predicted leukemia recurrence and overall and leukemia-free survival was disease status at transplantation. The 5-year probabilities of leukemia-free survival were 45%, 20%, and 12% for patients who underwent transplantation at second complete remission, relapse, and primary induction failure, respectively. As expected, risk of acute but not chronic graft-versus-host disease (GVHD) was lower with T-cell-depleted bone marrow grafts; T-cell-depleted grafts were not associated with higher risks of leukemia recurrence. We observed similar risks of leukemia relapse in patients with and without acute and chronic GVHD.

Conclusion: Children who underwent transplantation in remission had a superior outcome compared with children who underwent transplantation during relapse or persistent disease. Nevertheless, 20% of children who underwent transplantation in relapse are long-term survivors, suggesting that unrelated donor bone marrow transplantation is an effective therapy in a significant proportion of children with recurrent or primary refractory AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2008.16.4442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653120PMC
September 2008

Successful treatment of an infant with constitutional chromosomal abnormality and hemangiopericytoma with chemotherapy alone.

J Pediatr Hematol Oncol 2007 Jun;29(6):409-11

Pediatric Hematology/Oncology, Cleveland Clinic Children's Hospital, Cleveland, OH 44195, and Department of Surgery, University of Wisconsin Cytogenetic Services-WSLH, University of Wisconsin Madison, WI, USA.

Hemangiopericytoma is a rare vascular tumor, of which 5% to 10% occur in the pediatric population. Although usually benign in infants, local recurrence, metastasis, and deaths have been reported. Clonal chromosomal rearrangements have been described, most involving the long arm of chromosome 12. We report a case of a 6-month-old boy with an hemangiopericytoma of the left forearm initially incorrectly diagnosed as hemangioma. He was treated successfully with chemotherapy alone using vincristine, doxorubicin, actinomycin-D, and cyclophosphamide. Although cytogenetic analysis was not performed on his biopsy, it was later discovered that a prenatal karyotype had shown 46,XY,inv(12)(q15q24.1).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0b013e31806210daDOI Listing
June 2007

Pleasant memories: remembering immune protection while forgetting about graft-versus-host disease.

J Clin Invest 2003 Jul;112(1):25-7

Department of Pediatrics, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI19095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC162299PMC
July 2003