Kenneth B. DeSantes

Antitumor Activity of Hu14.18-IL2 in Patients With Relapsed/Refractory Neuroblastoma: A Children's Oncology Group (COG) Phase II Study

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.

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

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 Childrens 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.

Reduced intensity conditioning using intravenous busulfan, fludarabine and rabbit ATG for children with nonmalignant disorders and CML

The major problems with busulfan/cyclophosphamide (Bu/Cy)-containing conditioning regimens are acute toxicities and graft failure. To decrease acute toxicities, we have prospectively evaluated a reduced intensity conditioning (RIC) regimen using targeted dosing of i.v. busulfan, fludarabine, and rabbit ATG (Bu/Flu/rATG) in children with diagnoses that historically would have been conditioned with Bu/Cy regimens. Nineteen pediatric patients were enrolled in the study. The donors included HLA-matched and one antigen-mismatched unrelated volunteers (n=11), unrelated cord blood (n=1), and related donors (n=7). Four patients developed graft failure, which occurred between 1 and 8.5 months post transplant. All four of them underwent a second transplantation and 3/4 are alive without evidence of disease. The mean follow-up of living patients is 29.5±s.d. 11 months. Despite excellent 2-year post-transplant overall survival (89±s.d.7%) and event-free survival (74±s.d.10%), the study was closed prematurely due to high graft failure rate (21%). Receiving a transplant from a mismatched unrelated donor was identified as a risk factor for graft failure. The Bu/Flu/rATG RIC regimen was very well tolerated, resulted in excellent overall survival, and provided sustained engraftment in patients undergoing transplant from matched sibling and unrelated donors. However, it did not provide sustained engraftment in the majority of children with nonmalignancies undergoing mismatched unrelated donor transplants.

Unrelated Donor Bone Marrow Transplantation for Children With Acute Myeloid Leukemia Beyond First Remission or Refractory to Chemotherapy

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 <or= 18 years) with AML in second complete remission (n = 142), relapse (n = 90), or primary induction failure (n = 36) at transplantation. All patients received bone marrow grafts from an unrelated donor and a myeloablative conditioning regimen. Cox regression models were constructed to identify risk factors that influence outcome after transplantation. 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.

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

Graft-versus-host disease (GVHD) represents a major cause of morbidity and mortality following conventional allogeneic hematopoietic stem cell transplantation (HSCT). A study in mice (see related article on pages 101–108) demonstrates that the selective administration of donor memory CD4+ T cells results in immune reconstitution without GVHD, a result that, if translatable to humans, has important clinical implications for HSCT.

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

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 (P = .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.

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

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.

NK Cell-based Immunotherapies in Pediatric Oncology

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.

Immunotherapy in pediatric malignancies: current status and future perspectives

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.

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

Department of Human Oncology, University of Wisconsin, Madison, WI, USA Department of Pediatrics, University of Wisconsin, Madison, WI, USA *Author for correspondence: Tel.: +1 608 263 9069; Fax: +1 608 263 4226; pmsondel@humonc.wisc.edu