Sanctuary Site Research Articles

Retinal vasculitis and ocular vitreous metastasis following complete response to PD-1 inhibition in a patient with metastatic cutaneous melanoma

We report on a 36-year-old woman treated with the anti PD-1 antibody Pembrolizumab for metastatic cutaneous melanoma in the first line setting. She achieved a complete response and then relapsed with metastases to the vitreous cavity with an associated angiographically determined retinal vasculitis. Vitreous metastasis without choroidal involvement is unusual and may be due to individual cell extravasation, vitreous hemorrhage containing malignant cells, or direct spread through the optic nerve. This finding highlights the need for immune sanctuary sites to be monitored in the presence of PD-1 inhibition and we hypothesize that the use of PD-1 inhibitor potentiated the patient’s angiographically determined retinal vasculitis.

Sustainable catchment restoration for reintroduction of captive bred freshwater pearl mussels Margaritifera margaritifera

The Ballinderry River, Co. Tyrone (SAC), is one of only six rivers in Northern Ireland that still supports a population of the globally endangered freshwater pearl mussel, Margaritifera margaritifera . Fewer than 1000 individuals still exist in the river; without intervention it is predicted the Ballinderry pearl mussel will be extinct by 2098. This paper aims to identify key catchment pressures on remaining mussel stocks and prioritise tributaries within the catchment for remediation work to ensure effective targeting of limited resources. A combination of redox assessment, river surveys and SCIMAP modelling was used to rank tributaries, taking into consideration their size and proximity to the main mussel population at the “sanctuary site”. Diffuse and point sources of sediment were identified within the prioritised catchment. The Tulnacross tributary was selected as the highest priority tributary and has been used in a pilot remediation study. A number of different hard and soft engineering techniques have been used for remediation as well as replacing cattle drinkers with pasture pumps and fencing alongside the river. Initial observations suggest river substrate is cleaner. This study is an example of how to tackle problems within a large-scale catchment with limited resources with participation of local stakeholders and riparian landowners.

Bone marrow as a reservoir for disseminated tumor cells: a special source for liquid biopsy in cancer patients.

Besides circulating tumor cells, disseminated tumor cells (DTCs) in bone marrow (BM) might be used as a 'liquid biopsy' to obtain information helpful to steer therapies in individual patients. Moreover, the molecular characterization of DTCs may provide important insight into the biology of cancer metastasis. BM is a frequent site of metastasis in breast, prostate and lung cancer, and it might represent a sanctuary site for DTCs derived from various additional types of epithelial tumors. Highly sensitive and specific immunocytological and molecular methods enable the detection of DTCs in BM of cancer patients at the single-cell level years before the occurrence of metastases. This information might be useful to assess individual prognosis and stratify patients at risk to systemic adjuvant anti-cancer therapies. Although most data on the prognostic value of DTCs are available for breast cancer, several single institution studies including patients with colon, lung, prostate, esophageal, gastric, pancreatic, ovarian and head and neck carcinomas have also documented an association between the presence of DTCs at primary surgery and subsequent metastatic relapse. Most DTCs are in a dormant (that is, non-proliferative) stage, frequently express HER2 and display a cancer stem cell and immune escape phenotype. Here, we summarize the current knowledge about specific biological properties of DTCs in BM, and discuss the clinical relevance of DTC detection in cancer patients with regard to an improved individualized therapeutic management. This will stimulate further technical developments that may make BM sampling more acceptable for the clinical management of patients with solid tumors.

Radiotherapy for brain metastases: are we getting better?

Brain metastases are the most common malignant adult CNS tumor. The blood brain barrier (BBB) prevents many drugs from achieving therapeutic concentrations in the central nervous system (CNS), leaving the brain as a potential sanctuary site of disease and underscoring the importance of radiotherapy. Neurons, glial cells and vascular endothelium are prone to radiation-induced damage. Efforts have been made to reduce radiation-induced toxicity and increase efficacy (Stereotactic radio-surgery - SRS, advanced radiation-techniques that allow decreasing the dose to the hippocampi, while intensifying the radiation dose to large brain metastases or administering neuroprotective or radiation sensitizing agents during whole brain radiotherapy -WBRT in order to increase the therapeutic ratio). Surgery, radiotherapy and new pharmacological agents may become advantages for specific patient subgroups or in specific disease stages. Choosing how to treat brain metastases, must take into consideration patients and disease parameters (the primary tumor, age and performance status, systemic and brain tumor burden), and the potential risks and benefits of a treatment tool emphasising QOL considerations. Which modality to apply and when, is often a matter of local practice and treatment availability since level I evidence is lacking. The technology behind WBRT, FSR and SRS has substantially advanced over the previous decade, however only formal clinical trials will allow a definite answer to the question - are we getting better?

Mouse models of primary central nervous system lymphomas: tools for basing funding and therapeutic strategies

Primary central nervous system lymphomas (PCNSL) include ocular and cerebral lymphomas and are rare aggressive malignancies with poor prognoses. Compared with other lymphomas, they are a challenge for clinicians and scientists, for diagnosis and therapeutic progress and their prognosis remains unsatisfactory, because of the lack of molecular and biological knowledge. Indeed, several limitations of human sample present a major obstacle to the identification of the particular microenvironment of the sanctuary sites where these tumor cells grow. In addition, the generally poor overall condition and performance status of patients with PCNSL limit their participation in prospective trials. Therefore, animal models of PCNSL are essential for tumor microenvironment characterization and for antitumor response studying. In this review, we have compiled the B-and T-cell PCNSL mouse models that are used to improve our understanding of the lymphoma microenvironment, tropism and migration and to investigate novel therapeutic strategies.

β-Catenin/TCF-4 signaling regulates susceptibility of macrophages and resistance of monocytes to HIV-1 productive infection.

Cells of the monocyte/macrophage lineage are an important target for HIV-1 infection. They are often at anatomical sites linked to HIV-1 transmission and are an important vehicle for disseminating HIV-1 throughout the body, including the central nervous system. Monocytes do not support extensive productive HIV-1 replication, but they become more susceptible to HIV-1infection as they differentiate into macrophages. The mechanisms guiding susceptibility of HIV-1 replication in monocytes versus macrophages are not entirely clear. We determined whether endogenous activity of β-catenin signaling impacts differential susceptibility of monocytes and monocyte-derived macrophages (MDMs) to productive HIV-1 replication. We show that monocytes have an approximately 4-fold higher activity of β-catenin signaling than MDMs. Inducing β-catenin in MDMs suppressed HIV-1 replication by 5-fold while inhibiting endogenous β-catenin signaling in monocytes by transfecting with a dominant negative mutant for the downstream effector of β- catenin (TCF-4) promoted productive HIV-1 replication by 6-fold. These findings indicate that β-catenin/TCF-4 is an important pathway for restricted HIV-1 replication in monocytes and plays a significant role in potentiating HIV-1 replication as monocytes differentiate into macrophages. Targeting this pathway may provide a novel strategy to purge the latent reservoir from monocytes/macrophages, especially in sanctuary sites for HIV-1 such as the central nervous system.

Protease inhibitor monotherapy is not associated with increased viral replication in lymph nodes.

There are concerns about residual viremia in sanctuary sites among patients on protease inhibitor monotherapy, so we aimed to study viro-immunological parameters in tonsil's lymphoid tissue of patients on highly active antiretroviral therapy (HAART) and on protease inhibitor monotherapy. Despite fully suppressed serum HIV viral load, we found viral replication in both groups; in addition, more patients had detectable proviral DNA among those on HAART, compared to those on protease inhibitor monotherapy (P = 0.08), supporting the absence of a deleterious effect of protease inhibitor monotherapy.

HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development.

Effective targeting of the human epidermal growth factor receptor 2 (HER2) has changed the natural history of HER2 overexpressing (HER2+) metastatic breast cancer. The initial success of trastuzumab improving time to progression and survival rates led to the clinical development of pertuzumab, ado-trastuzumab emtansine and lapatinib. These biologic therapies represent significant additions to the breast medical oncology armamentarium. However, drug resistance ultimately develops and most tumours progress within 1 year. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in tumours, including inhibition of PI3K/TOR, HSP90, IGF-IR and angiogenesis. Mounting experimental data support the clinical testing of immune checkpoint modulators and vaccines. The central nervous system remains a sanctuary site for HER2+ breast cancer and further studies are needed for the prevention and treatment of brain metastases in this population. Despite efforts to identify predictors of preferential benefit from HER2-targeted therapies (e.g., truncated HER2, PTEN loss and SRC activation), HER2 protein overexpression and/or gene amplification remains the most important predictive factor of response to HER2-targeted therapies. In this article, we review the optimal sequence of HER2-targeted therapies and describe ongoing efforts to improve the outcome of HER2+ advanced breast cancer through rational drug development.

Intrathecal Chemotherapy

The central nervous system is a unique sanctuary site for malignant disease. To ensure optimal disease control, intrathecal (IT) chemotherapy is commonly given in conjunction with standard chemotherapy protocols, thus providing the opportunity for medication errors. A systematic review of the current literature on medication errors associated with the administration of IT chemotherapy was conducted. English-language literature published from January 1960 through June 2013 was accessed. Case reports, clinical studies, and review articles pertaining to IT medication errors were included in the review. References of all relevant articles were searched for additional citations. Twenty-two cases of accidental IT overdoses have been reported with methotrexate and 1 with cytarabine. There have been numerous cases of antineoplastic agents intended for administration by the parenteral route being inadvertently given intrathecally. Vincristine has been implicated 31 times (25 deaths), as well as vindesine, asparaginase, bortezomib, daunorubicin, and dactinomycin. This has led to profound toxicity and, commonly, death. Unfortunately, many cases go unrecognized or unreported. The best method for eliminating the risk of IT medication errors is to develop effective methods of prevention and incorporate them into oncology and hematology practice internationally. Strategies include abolishing the syringe as a method of vinca alkaloid administration and substituting small-volume intravenous bags, and developing novel methods for intraspinal drug administration. The nursing profession is in a unique position to influence change and lead the way in establishing preventative strategies into current practice.

Syphilitic Gummas Mistaken for Liver Metastases

occurs years after the initial infection, and is characterized by a chronic inflammatory response to the organism in sanctuary sites. Gummatous syphilis is a type of tertiary syphilis caused by a delayed hypersensitivity reaction to the Treponema pallidum organism. 3 A gumma is a granuloma, histologically characterized by a central area of necrosis surrounded by mononuclear, epithelioid, and giant cells, and ranging in size from microscopic to several centimeters. 3 Spirochetes only rarely are identified in pathologic specimens, and diagnosis instead relies on serologic testing as well as therapeutic response. The incidence of hepatic involvement ranges from 0.9% to 16% in autopsy studies. 4 Gummas may be visible on CT imaging as low-attenuation lesions with slight peripheral enhancement and rare calcifications, which is an appearance that may be confused with metastatic cancer or an abscess. 5 Treatment for gummatous syphilis without neurosyphilis consists of intramuscular penicillin G for 3 weeks; if neurosyphilis is present, as in our patient, administration of intravenous penicillin may be necessary. 6

Microenvironmental Clues for Glioma Immunotherapy

Gliomas have been viewed for decades as inaccessible for a meaningful antitumor immune response as they grow in a sanctuary site protected from infiltrating immune cells. Moreover, the glioma microenvironment constitutes a hostile environment for an efficient antitumor immune response as glioma-derived factors such as transforming growth factor β and catabolites of the essential amino acid tryptophan paralyze T-cell function. There is growing evidence from preclinical and clinical studies that a meaningful antitumor immunity exists in glioma patients and that it can be activated by vaccination strategies. As a consequence, the concept of glioma immunotherapy appears to be experiencing a renaissance with the first phase 3 randomized immunotherapy trials entering the clinical arena. On the basis of encouraging results from other tumor entities using immunostimulatory approaches by blocking endogenous T-cell suppressive pathways mediated by cytotoxic T-lymphocyte antigen 4 or programmed cell death protein 1/programmed cell death protein 1 ligand 1 with humanized antibodies, there is now a realistic and promising option to combine active immunotherapy with agents blocking the immunosuppressive microenvironment in patients with gliomas to allow a peripheral antitumor immune response induced by vaccination to become effective. Here we review the current clinical and preclinical evidence of antimicroenvironment immunotherapeutic strategies in gliomas.

Rilpivirine exposure in plasma and sanctuary site compartments after switching from nevirapine-containing combined antiretroviral therapy

Pharmacokinetic parameters following modifications to antiretroviral therapy and sanctuary site exposure are often unknown for recently licensed antiretrovirals. We assessed plasma, CSF and seminal plasma (SP) exposure of rilpivirine after switching from nevirapine. HIV-infected male subjects receiving tenofovir/emtricitabine/nevirapine (245/200/400 mg) once daily switched to tenofovir/emtricitabine/rilpivirine (245/200/25 mg) once daily for 60 days when CSF and semen samples were collected. Mean and individual plasma concentrations of nevirapine and rilpivirine were compared with the proposed plasma target concentration for nevirapine (3000 ng/mL) and the protein binding-adjusted EC90 for rilpivirine (12.1 ng/mL). Mean rilpivirine CSF and SP concentrations were calculated and individual values compared with the EC50 and EC90 for wild-type virus (0.27 and 0.66 ng/mL, respectively). Of 13 subjects completing study procedures including CSF examination, 8 provided seminal samples. By day 3, the mean plasma rilpivirine trough concentration was 29.7 ng/mL (95% CI: 23.8-37). No patient presented rilpivirine plasma concentrations under the proposed threshold. The mean rilpivirine concentration in CSF was 0.8 ng/mL (95% CI: 0.7-1.0), representing a CSF : plasma ratio of 1.4%, with concentrations above the EC90 in 85% (11/13) of patients. In SP, the mean rilpivirine concentration was 4.9 ng/mL (95% CI: 3.3-7.2), representing an SP : plasma ratio of 9.5%, with all concentrations above the EC90. Switching from nevirapine- to rilpivirine-containing antiretroviral therapy was safe and well tolerated, with plasma rilpivirine concentrations above the protein binding-adjusted EC90 in all subjects. Rilpivirine concentrations were always above the EC50 in the CSF and the EC90 in SP.

Huge Metastatic Multicystic Ovarian Cancer with Liver Involvement: A Case Report

Introduction: Ovarian cancers are gynaecological malignancies described as the most lethal because they often present at the advanced stages. Metastasis to the liver parenchyma occurs in stage IVB disease. The diaphram is a tumour sanctuary site as most deposits are missed during cytoreductive surgeries and chemotherapy. Materials and method: This is a case presentation of a 39 year old lady with recurrent huge multicystic ovarian cancer with liver and diaphragmatic involvement. Abdominal ultrasound scan and a CT-scan were done amongst other investigations. This patient was co-managed by the Hepato-Pancreato-Biliary surgeons, Cardiothoracic Surgeons and the Gynaecologic oncologist. She had cytoreductive surgery and adjuvant chemotherapy. Conclusion: Diaphragmatic involvement from ovarian tumour is rare and represents an advanced disease. The superiority of CT-scan over abdominal ultrasound scan in this case is incontrovertible. A multidisciplinary approach is an important cornerstone in it’s management.

Successful outcome of postsplenectomy chemotherapy in an acute myeloid leukemia patient with massive bilharzial splenomegaly

Bilharzial hepatic fibrosis is usually accompanied by marked enlargement of the spleen. Schistosoma hematobium and Schistosoma mansoni infestation is endemic in Africa and southern part of Saudi Arabia. Patients with acute myeloid leukemia (AML) present with clinical features resulting from bone marrow failure, symptoms resulting from organ infiltration with leukemic cells (including splenomegaly), or both. Co-occurrence of bilharzial splenomegaly and AML is intuitively possible. Spontaneous splenic rupture has been reported to be catastrophic in both conditions and rarely splenic rupture may be the first manifestation of AML. Splenectomy is a considerable option in symptomatic splenomegaly in schistosomiasis. An enlarged spleen may also serve as a sanctuary site for residual leukemic cells after chemotherapy. Splenectomy has been reported in pediatric AML after chemotherapy and selected adult patients with myelodysplastic syndrome and myeloproliferative neoplasm (MPN). However, to the best of our knowledge, this is the first report of successful outcome of splenectomy prior to induction chemotherapy in an AML patient who presented with huge symptomatic splenomegaly due to past history of schistosomiasis, had also shown refractoriness to platelet transfusion due to hypersplenism and vaginal bleeding. Splenectomy in such a scenario was a difficult decision but was feasible with adequate expertise, vigilance and blood products availability. The patient is alive in complete remission with good performance status more than 2½ years after therapy.

Spatial modeling of HIV cryptic viremia and 2-LTR formation during raltegravir intensification

Combination Antiretroviral Therapy (cART) can suppress plasma HIV below the limit of detection in normal assays. Recently reported results suggest that viral replication may continue in some patients, despite undetectable levels in the blood. It has been suggested that the appearance of the circularized episomal HIV DNA artifact 2-LTR following treatment intensification with the integrase inhibitor raltegravir is a marker of ongoing viral replication. Other work has suggested that lymphoid organs may be a site of reduced antiviral penetration and increased viral production. In this study we model the hypothesis that this ongoing replication occurs in lymphoid follicle sanctuary sites and investigate the patterns of 2-LTR formation expected after raltegravir application. Experimental data is used to estimate the reaction and diffusion parameters in the model, and Monte-Carlo simulations are used to explore model behavior subject to variation in these rates. The results suggest that conditions for the formation of an observed transient peak in 2-LTR formation following raltegravir intensification include a sanctuary site diameter larger than 0.2mm, a viral basic reproductive ratio within the site larger than 1, and a total volume of active sanctuary sites above 20mL. Significant levels of uncontrolled replication can occur in the sanctuary sites without measurable changes in the plasma viral load. By contrast, subcritical replication (where the basic reproductive ratio of the virus is less than 1 in all sites) always results in monotonic increases of measured 2-LTR following raltegravir intensification, occurring at levels below the limit of detection.

Abstract OT1-1-13: A phase II study with lead-in safety cohort of cabazitaxel plus lapatinib as therapy for patients with HER2-positive metastatic breast cancer (MBC) and intracranial metastases

Abstract Background: HER2-targeted therapy has improved the progress of patients (pts) with HER2-positive breast cancer; however, CNS metastases remain a significant source of morbidity and mortality. It is hypothesized that the inability of drugs like trastuzumab to cross the intact blood-brain barrier (BBB) may render the CNS as a sanctuary site for metastases. Lapatinib is an oral small molecule tyrosine kinase EGFR1/HER2 inhibitor that crosses the BBB and has activity against CNS metastases. Cabazitaxel is a new taxoid that is active in docetaxel- or paclitaxel-resistant breast cancer, and differs from other taxanes in its ability to cross the BBB. The promising systemic activity shown by cabazitaxel in taxane-resistant MBC coupled with the CNS penetrance of both cabazitaxel and lapatinib make this an attractive combination to evaluate in HER2-positive MBC pts with CNS metastases. Study Objectives: The primary objectives of the study are to determine the safety and CNS objective response rate (ORR = CR+PR) in HER2-positive MBC pts with CNS metastases when treated with cabazitaxel and lapatinib. The secondary objectives include evaluation of the clinical benefit rate (CBR), 3- and 6-month PFS rate for CNS metastases, and response rate and CBR for extra-cranial metastases. Key eligibility: Pts >18 yrs with HER2-positive (IHC 3+ or FISH/SISH-positive) MBC and unequivocal evidence of brain metastases are eligible. Additional eligibility criteria include: at least one measurable brain lesion >1.0cm in longest dimension on MRI; pts with brain lesions previously treated with WBRT and/or SRS must have at least one intra-cranial lesion >1.0cm not treated with SRS and must have evidence of intra-cranial progressive disease. Pts must have received at least 1 prior HER2-directed therapy in the adjuvant or metastatic setting; pts without prior chemotherapy for MBC are eligible if they progressed during or within 6 months of adjuvant therapy. Otherwise, there is no specific minimum or maximum number of previous chemotherapy regimens for MBC. ECOG performance status 0-2, adequate renal, bone marrow, and hepatic function are required; prior treatment with cabazitaxel or lapatinib (for MBC) not permitted. Trial design: This is an open-label, non-randomized, phase II study with a lead-in safety cohort. During the lead-in phase, 6-15 pts will be treated in cohorts of 3 with increasing doses of cabazitaxel and lapatinib to determine the tolerability and optimal dose. Once the safety and dose is confirmed, subsequent pts will be treated at the optimal dose of the 2 agents. Each treatment cycle is 3 weeks and restaging will occur systemically and intra-cranially every 2 cycles for the first 8 cycles and every 3 cycles thereafter until progressive disease or unacceptable toxicity. Statistical methods: We hypothesize that the addition of cabazitaxel will increase the CNS ORR from 6% (expected with single agent lapatinib) to ≥20% in this pt population. Treatment of 27 evaluable pts with the identified phase II doses will detect this difference with a power of 80% and alpha = 10% (one-sided test). Accounting for a 10% inevaluable rate and lead-in pts, a total of 45 pts will be enrolled on the study. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-13.

Breaking and entering into the CNS: clues from solid tumor and nonmalignant models with relevance to hematopoietic malignancies

Various malignancies invade the CNS sanctuary site, accounting for the vast majority of CNS neoplastic foci and contributing to significant morbidity as well as mortality. The blood-brain barrier (BBB) exhibits considerable impermeability to chemotherapeutic agents, severely limiting therapeutic options available for patients developing metastatic CNS involvement, accounting for poor outcomes. The mechanisms by which malignant cells breach the highly exclusive BBB and subsequently survive in this unique anatomical site remain poorly understood, with most of the current knowledge stemming from nonmalignant and solid malignancy models. While solid and hematologic malignancies may face different challenges once within the CNS (e.g., solid tumor parenchymal metastasis compared to masses/nodules/leptomeningeal disease in hematologic malignancies), commonality exists in the process of migrating across the BBB from the circulation. Specifically considering this last point, this review aims to survey the current mechanistic knowledge regarding malignant migration across the BBB, necessarily emphasizing the better studied solid tumor and nonmalignant models with the intention of highlighting both the current knowledge gap and additional work required to effectively consider how hematopoietic malignancies breach the CNS.

The Central Nervous System as a Sanctuary Site in ALK-Positive Non–Small-Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small-cell lung cancer that is highly responsive to treatment with the ALK inhibitor crizotinib. Recently, it has been recognized that the brain is a frequent site of relapse among ALK-positive patients treated with crizotinib. In this report, we expand on these observations and present a series of ALK-positive patients with two distinct forms of metastatic, central nervous system involvement: intramedullary spinal cord metastasis and leptomeningeal carcinomatosis.

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

Despite major therapeutic advances in the management of patients with breast cancer, central nervous system (CNS) metastases remain an intractable problem, particularly in patients with metastatic HER2-positive and triple-negative breast cancer. As systemic therapies to treat extracranial disease improve, some patients are surviving longer, and the frequency of CNS involvement seems to be increasing. Furthermore, in the early-stage setting, the CNS remains a potential sanctuary site for relapse. This review highlights advances in the development of biologically relevant preclinical models, including the development of brain-tropic cell lines for testing of agents to prevent and treat brain metastases, and summarizes our current understanding of the biology of CNS relapse. From a clinical perspective, a variety of therapeutic approaches are discussed, including methods to improve drug delivery, novel cytotoxic agents, and targeted therapies. Challenges in current trial design and endpoints are reviewed. Finally, we discuss promising new directions, including novel trial designs, correlative imaging techniques, and enhanced translational opportunities.

The Regulation Of Central Nervous System Acute Lymphoblastic Leukemia By Natural Killer Cells

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy accounting for 80% of leukemias. The involvement of the central nervous system (CNS) by ALL is a major clinical problem and occurs in about 50% of the children without adequate treatment. The introduction of CNS-directed therapy consisting of intrathecal and high dose systemic chemotherapy and, occasionally, cranial irradiation, reduced relapse rate to less than 5% and has become a prerequisite for treating children with ALL. However, substantial neurotoxicity associated with this therapy is a major concern. Moreover the CNS is involved in up to a third from all relapses. To date very little is known about the pathogenesis of CNS leukemia.Our research was promoted by the previous observation that high mRNA expression of interleukin 15 (IL15) in leukemic blasts is associated with increased risk for CNS involvement (Cario et al JCO 2007;25:4813-20). As IL15 is a strong stimulant of Natural Killer (NK) cells, we hypothesized that the increased expression of IL15 may activate NK cells which, in turn, will control residual ALL cells in the peripheral blood but not in the relatively protected central nervous system. To investigate this hypothesis, we utilized two mouse models, a S49-derived T lymphoblastic leukemia syngeneic model and a novel human xenograft ALL model in immune-deficient mice.We found that constitutive expression of IL15 in mouse T lymphoblastic leukemia cells transplanted in neonatal Balb/c mice markedly slowed the development of systemic disease and caused CNS leukemia characterized by pronounced clinical CNS symptoms and subarachnoid infiltration of leukemia cells. This phenotype was accompanied by increase in activated natural killer (NK) cells (from 0.16% to 18.6% P<0.01). Similarly, we demonstrated that transplantation of the human B-cell precursor ALL line 018Z cause isolated CNS leukemia in NOD/SCID mice but induced aggressive systemic and CNS leukemia in NK-deficient NOD scid Il2rg null (NSG) mice. We further found that 018Z cells express and secrete endogenous IL15 and activated NK cells in-vivo in NOD/SCID mice. Remarkably, transplantation of 018Z cells in NOD/SCID mice after antibody mediated depletion of NK cells, resulted in a combined peripheral and CNS leukemia as observed in NSG mice. Mechanistic studies showed that 018Z leukemic blasts are efficiently killed by primary human NK cells and highly express ligands for the NKG2D and the NKp44 activating receptors. Blocking of the NKG2D receptor significantly reduced killing by NK cells.Taken together we show here, for the first time, a crucial role for NK cells in the control of CNS leukemia. We suggest that the association between IL15 expression in ALL blasts and isolated CNS relapse might be explained by activation of NK cells leading to increased surveillance of residual leukemia in the bone marrow but not in the CNS which serve as a sanctuary site for tumor growth. Disclosures:No relevant conflicts of interest to declare.