Mobilization of innate and adaptive antitumor immune responses by the RNP-targeting antibody ATRC-101.

Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC-101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses.

Unruh and Cherenkov Radiation from a Negative Frequency Perspective.

A ground-state atom uniformly accelerated through the Minkowski vacuum can become excited by emitting an Unruh-Minkowski photon. We show that from the perspective of an accelerated atom, the sign of the frequency of the Unruh-Minkowski photons can be positive or negative depending on the acceleration direction. The accelerated atom becomes excited by emitting an Unruh-Minkowski photon which has negative frequency in the atom's frame, and decays by emitting a positive-frequency photon. This leads to interesting effects. For example, the photon emitted by accelerated ground-state atom cannot be absorbed by another ground-state atom accelerating in the same direction, but it can be absorbed by an excited atom or a ground-state atom accelerated in the opposite direction. We also show that similar effects take place for Cherenkov radiation. Namely, a Cherenkov photon emitted by an atom cannot be absorbed by another ground-state atom moving with the same velocity, but can be absorbed by an excited atom or a ground-state atom moving in the opposite direction.

Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia.

Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse transcriptase-polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10-3) received blinatumomab 15 µg/m2 per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; P = .002) and OS (38.9 vs 12.5 months; P = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. This study is registered at www.clinicaltrials.gov as #NCT01207388.

Harnessing T cells to fight cancer with BiTE® antibody constructs--past developments and future directions.

Bispecific T-cell engager (BiTE(®)) antibody constructs represent a novel immunotherapy that bridges cytotoxic T cells to tumor cells, thereby inducing target cell-dependent polyclonal T-cell activation and proliferation, and leading to apoptosis of bound tumor cells. Anti-CD19 BiTE(®) blinatumomab has demonstrated clinical activity in Philadelphia chromosome (Ph)-negative relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) eventually resulting in conditional approval by the U.S. Food and Drug Administration in 2014. This drug is currently further developed in pediatric and Ph(+) r/r, as well as in minimal residual disease-positive ALL, and might also offer clinical benefit for patients with non-Hodgkin's lymphoma, especially for those with aggressive forms like diffuse large B-cell lymphoma. Another BiTE(®) antibody construct in hemato-oncology designated AMG 330 targets CD33 on acute myeloid leukemia blast cells. After showing promising ex vivo activity, this drug candidate has recently entered phase 1 clinical development, and has further indicated potential for combination with checkpoint inhibitors. In solid tumor indications, three BiTE(®) antibody constructs have been tested in phase 1 studies so far: anti-EpCAM BiTE(®) AMG 110, anti-CEA BiTE(®) MEDI-565/AMG 211, and anti-PSMA BiTE(®) BAY2010112/AMG 212. Pertinent questions comprise how to maximize BiTE(®) penetration and T-cell infiltration of the tumor while simultaneously minimizing any adverse events, which is currently explored by a continuous intravenous infusion approach. Thus, BiTE(®) antibody constructs will hopefully provide new treatment options for patients in several indications with high unmet medical need.

Donor-Derived Cytokine-Induced Killer Cell Infusion as Consolidation after Nonmyeloablative Allogeneic Transplantation for Myeloid Neoplasms.

Non-myeloablative conditioning, such as with total lymphoid irradiation and antithymocyte globulin (TLI-ATG), has allowed allogeneic hematopoietic cell transplantation (allo-HCT) with curative potential for older patients and those with comorbid medical conditions with myeloid neoplasms. However, early achievement of full donor chimerism (FDC) and relapse remain challenging. Cytokine-induced killer (CIK) cells have been shown to have antitumor cytotoxicity. Infusion of donor-derived CIK cells has been studied for hematologic malignancies relapsed after allo-HCT but has not been evaluated as post-transplant consolidation. In this phase II study, we prospectively studied whether a one-time infusion of 1 × 108/kg CD3+ donor-derived CIK cells administered between day +21 and day +35 after TLI-ATG conditioning could improve achievement of FDC by day +90 and 2-year clinical outcomes in patients with myeloid neoplasms. CIK cells, containing predominantly CD3+CD8+NKG2D+ cells along with significantly expanded CD3+CD56+ cells, were infused in 31 of 44 patients. Study outcomes were compared to outcomes of a retrospective historical cohort of 100 patients. We found that this one-time CIK infusion did not increase the rate of FDC by day +90. On an intention-to-treat analysis, 2-year non-relapse mortality (6.8%; 95% confidence interval [CI], 0-14.5%), event-free survival (27.3%; 95% CI, 16.8-44.2%), and overall survival (50.6%; 95% CI, 37.5-68.2%) were similar to the values seen in the historical cohort. The cumulative incidence of grade II-IV acute graft-versus-host disease at 1-year was 25.1% (95% CI, 12-38.2%). On univariate analysis, the presence of monosomal or complex karyotype was adversely associated with relapse-free survival and overall survival. Given the favorable safety profile of CIK cell infusion, strategies such as repeat dosing or genetic modification merit exploration. This trial was registered at ClinicalTrials.gov (NCT01392989).

Excitation of an Atom by a Uniformly Accelerated Mirror through Virtual Transitions.

We find that uniformly accelerated motion of a mirror yields excitation of a static two-level atom with simultaneous emission of a real photon. This occurs because of virtual transitions with probability governed by the Planck factor involving the photon frequency ν and the Unruh temperature. The result is different from the Unruh radiation of an accelerated atom, which is governed by the frequency of the atom, ω, rather than frequency of the emitted photon. We also find that the excitation probability oscillates as a function of the atomic position because of interference between contributions from the waves incident on and reflected from the mirror.

Blinatumomab treatment of older adults with relapsed/refractory B-precursor acute lymphoblastic leukemia: Results from 2 phase 2 studies.

BACKGROUND: Older adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) are reported to have a poor prognosis and few therapeutic options. In the current study, the authors evaluated treatment with single-agent blinatumomab in adults aged ≥65 years with r/r ALL. METHODS: A total of 261 adults with r/r ALL who were examined across two phase 2 studies received blinatumomab in cycles of 4-week continuous infusion and 2-week treatment-free intervals. The primary endpoint in each study was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first 2 cycles. Data were pooled and analyzed according to patient age at screening (aged ≥65 years vs aged <65 years). RESULTS: Of 36 older adults, 56% (95% confidence interval [95% CI], 38%-72%) achieved CR/CRh during the first 2 cycles compared with 46% (225 patients) (95% CI, 40%-53%) of younger adults. Complete minimal residual disease responses were 60% in older and 70% in younger responders. Three older responders (15%) and 61 younger responders (59%) proceeded to allogeneic hematopoietic stem cell transplantation. Kaplan-Meier curves overlapped for relapse-free and overall survival for both age groups. Older adults were found to have a similar incidence of grade ≥3 adverse events (AEs) as younger adults (86% vs 80%) but more grade ≥3 neurologic events (28% vs 13%). Cytokine release syndrome occurred in 7 older (19%) (1 case of grade 3) and 23 younger (10%) (4 cases of grade ≥3) adults. There were no treatment-related fatal AEs reported. CONCLUSIONS: Older adults with r/r ALL who were treated with single-agent blinatumomab were found to have similar hematologic response rates and incidence of grade ≥3 AEs compared with younger adults but had more neurologic events, which were reversible and primarily resolved with treatment interruption. Cancer 2016;122:2178-85. © 2016 American Cancer Society.

Learning from the gobiid.

The purpose of specialization in medicine is to create physicians with divergent skills and approaches, each suited to a different domain. Yet when viewpoints inevitably conflict, the result is too often distrust and disparagement of our colleagues. Medical students are particularly well positioned to observe this phenomenon. We are sequentially absorbed into one specialty after another, rapidly absorbing the worldview of the physicians around us. We stand with one group after another, watching other teams involved with our patients do things that we find inexplicable and which we often judge as poorly thought out, not patient centered, or even stupid. The frustration born of this type of experience feeds into what have become deeply engrained specialty-based stereotypes. Whole groups of professionals are labeled as egocentric or ineffectual, rude, unskilled, or uncaring. Yet we all start as one group of medical school classmates who get along and admire each other greatly. How can we fail to see that, through specialized training paths, our approaches and perspectives are simply different, and that a seemingly unjustified action probably has a justification that we are now too differentiated to fully appreciate? I explore this issue, and briefly consider underlying factors and solutions.

Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer?

Older patients are increasingly undergoing allogeneic hematopoietic transplantation. A relevant question is whether outcomes can be improved with a younger allele-level 8/8 HLA-matched unrelated donor (MUD) rather than an older HLA-matched sibling (MSD). Accordingly, transplants in leukemia/lymphoma patients age ≥50 years were analyzed comparing outcomes for recipients of MSD ≥50 (n = 1415) versus MUD <50 years (n = 757). Risks of acute graft-versus-host disease (GVHD) grade 2 to 4 (hazard ratio [HR], 1.63; P < .001), 3 to 4 (HR, 1.85; P < .001), and chronic GVHD (HR, 1.48; P < .0001) were higher after MUD compared with MSD transplants. The effect of donor type on nonrelapse mortality (NRM), relapse, and overall mortality was associated with performance score. For patients with scores of 90 or 100, NRM (HR, 1.42; P = .001), relapse (HR, 1.45; P < .001), and overall mortality (HR, 1.28; P = .001) risks were higher after MUD transplants. For patients with scores below 90, NRM (HR, 0.96; P = .76), relapse (HR, 0.86; P = .25), and overall mortality (HR, 0.90; P = .29) were not significantly different after MUD and MSD transplants. These data favor an MSD over a MUD in patients age ≥50 years.

Equations of motion for rays in a Snell's law medium.

The equations of motion for a ray in a Snell's law medium with a varying index of refraction are derived. A stratified medium is considered. Explicit expressions are given for the velocity and acceleration components of the ray. These are derived directly from Snell's law. It is further shown that the propagation of a ray can be modeled in terms of Newtonian-like equations of motion and that momentum is conserved along the interface. It is shown that Snell's law follows from this conservation law. Properties of the motion are studied and an example is given.

A phase space approach to wave propagation with dispersion.

A phase space approximation method for linear dispersive wave propagation with arbitrary initial conditions is developed. The results expand on a previous approximation in terms of the Wigner distribution of a single mode. In contrast to this previously considered single-mode case, the approximation presented here is for the full wave and is obtained by a different approach. This solution requires one to obtain (i) the initial modal functions from the given initial wave, and (ii) the initial cross-Wigner distribution between different modal functions. The full wave is the sum of modal functions. The approximation is obtained for general linear wave equations by transforming the equations to phase space, and then solving in the new domain. It is shown that each modal function of the wave satisfies a Schrödinger-type equation where the equivalent "Hamiltonian" operator is the dispersion relation corresponding to the mode and where the wavenumber is replaced by the wavenumber operator. Application to the beam equation is considered to illustrate the approach.

Influence of Demography and Personality on Patient Choice of Treatment in Symptomatic Benign Prostate Hyperplasia.

UNLABELLED: Background: Benign prostate hyperplasia (BPH) is a common age-dependent urological condition that can adversely affect quality of life if the patient's treatment choice is inap- propriate. OBJECTIVES: To examine whether patients' demography and personality affect their decision regarding the type of treatment: namely, conservative or surgical. METHODS: A total of 105 BPH patients treated during the period 2005-2008 were retrospectively categorized into three groups according to treatment received: (i) medication only (n = 056), (ii) combined treatment (the initial medication treatment was switched to surgical treatment) (n = 32), and (iii) surgery only (n = 17). A prerequisite for inclusion in the study was use of BPH medication for at least half a year before the study (groups 1 and 2). These groups completed the International Prostate Symptom Score (IPSS) questionnaire at the start of BPH medical treatment (IPSS 1) and at the start of the trial (IPSS 2), and the staff calculated the difference (IPSS 1-IPSS 2 = Delta IPSS = DIPSS). All three groups provided demographic data (age, country of origin, education) and completed tri-dimensional personality questionnaires (TPQ) to measure three independent "temperament" personality dimensions to evaluate how different individuals feel or behave: novel seeking (NS), harm avoidance (HA), and reward dependence (RD). Data were analyzed using chi-square, t-test, one-way ANOVA and logistic regression. RESULTS: The choice of BPH treatment differed according to demographic variables and the RD dimension. CONCLUSIONS: Our study suggests that symptomatic BPH treatment is influenced less by the patient's personality and more by his life circumstances. Israeli-born patients were more conservative, Russian-born patients were ambivalent, and other foreign-born patients predominantly preferred surgical treatment. We assume that personality has a more decisive effect on patients with malignant disease and they accept the medical advice more easily.

Total lymphoid irradiation-antithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms.

Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but treatment toxicity has been a barrier to its more widespread use. The nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease (aGVHD), but it has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n = 32), therapy-related myeloid neoplasms (n = 15), MPN (n = 9), and chronic myelomonocytic leukemia (n = 5). The median age of all patients was 63 years (range, 50 to 73). The cumulative incidence of aGVHD grades II to IV was 14% (95% confidence interval [CI], 4% to 23%) and for grades III to IV, 4% (95% CI, 0 to 9%), and it did not differ between patients who received allografts from related or unrelated donors. The cumulative incidence of nonrelapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival and progression-free survival were 41% (95% CI, 29% to 53%) and 35% (95% CI, 23% to 48%), respectively. The safety and tolerability of TLI-ATG, as exemplified by its low NRM, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression.

Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence.

B cells are involved in the pathogenesis of chronic GVHD (cGVHD). We hypothesized that prophylactic anti-B-cell therapy delivered 2 months after transplantation would decrease allogeneic donor B-cell immunity and possibly the incidence of cGVHD. Therefore, in the present study, patients with high-risk chronic lymphocytic leukemia (n = 22) and mantle-cell lymphoma (n = 13) received a total lymphoid irradiation of 80 cGy for 10 days and antithymocyte globulin 1.5 mg/kg/d for 5 days. Rituximab (375 mg/m(2)) was infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute GVHD was 6%. The cumulative incidence of cGVHD was 20%. Nonrelapse mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development in male patients with female donors (P = .01). Overall survival and freedom from progression at 4 years for chronic lymphocytic leukemia patients were 73% and 47%, respectively; for mantle-cell lymphoma patients, they were 69% and 53%, respectively.

The transition from cranial surgery to neurosurgery in East London, 1760-1960.

The emergence of neurosurgery from the practice of cranial surgery between the eighteenth and the twentieth centuries in London, UK, is well documented, including the role of Sir Victor Horsley, the first neurosurgical appointee at the National Hospital Queen Square in 1886. The process of this transition elsewhere in London and the subsequent foundation of other neurosurgical units are less well described. In East London, the status of St. Bartholomew's Hospital (Barts) as the oldest London hospital still active on its original site and its comprehensive archives allow an unusually long history of surgical practice in the specialty to be studied. Using these archives and other primary and secondary sources, this article describes the transition of cranial surgery in East London from the general surgeons, limited to the treatment of brain and skull injury, to the specialized discipline of neurosurgery. We discuss the culmination of this process in the foundation of three neurosurgical units at London Hospital, Whitechapel, by Sir Hugh B. Cairns from 1927; at Barts Hospital, Smithfield, by John E. A. O'Connell from 1937; and at Oldchurch Hospital, Romford, by Leslie C. Oliver from 1945. Two modern neurosurgical units, in Whitechapel and Romford, have taken forward the work begun by this group.

Patient-Reported Outcome Measures After Endoscopic Cubital Tunnel Release With At Least 1-Year Postoperative Follow-up.

BACKGROUND: The primary objective of this study was to investigate midterm outcomes following endoscopic cubital tunnel release (ECuTR) with the Seg-Way system using patient-reported outcome measures (PROMs). A secondary aim was to evaluate symptom resolution as assessed through Dellon's stage, McGowan's grade, and Messina's criteria and recurrence following ECuTR. METHODS: Functional outcomes were assessed in 38 patients who underwent 43 surgeries. Details on baseline characteristics as well as preoperative and postoperative symptoms were collected. Patient-reported outcome measures were administered with at least 1-year follow-up in all patients. RESULTS: Mean age of patients was 50.2 ± 16.1 years, with 20 men (52.6%) and 18 women (47.4%). Postoperatively, pain completely resolved in 21 (72.4%), while sensory and motor deficits improved completely in 22 (56.4%) and 11 (64.7%) patients, respectively. Mean time interval between ECuTR and PROMs was 26.3 (13-63) months. Median Michigan Hand Outcomes Questionnaire score was 73.2 (48-91). Median Disabilities of the Arm, Shoulder and Hand (DASH) and Numerical Rating Scale (NRS) scores were 12.9 (7-35) and 2.5 (0-5), respectively. Most of the patients were satisfied postoperatively with a median satisfaction score of 4 (3-5). There was a significant difference in median DASH and NRS scores between patients with and without concomitant proximal nerve disease. CONCLUSION: Endoscopic cubital tunnel release is a safe and effective option for surgical management of primary cubital tunnel syndrome. The presence of other proximal nerve disease is associated with poorer outcomes, less symptom resolution, and higher recurrence rates. One-year postoperative PROMs show equivalence to those reported in other studies following open cubital tunnel release.

Neurostimulation for Spinal Lesions: Enhancing Recovery and Axonal Regeneration.

Spinal neurostimulation is a promising approach for treating spinal lesions and has implications in various neurological disorders. It promotes axonal regeneration and neuronal plasticity to reestablish disrupted signal transduction pathways following spinal injuries or degeneration. This paper reviews the current technology and its differing utilities in various types of neurostimulation, including invasive and noninvasive methods. The paper also explores the efficacy of spinal compression and decompression therapy, with a primary focus on degenerative spinal disorders. Moreover, the potential of spinal neurostimulation in therapies for motor disorders, such as Parkinson's disease and demyelinating disorders, is discussed. Finally, the paper examines the changing guidelines of use for spinal neurostimulation following surgical tumor resection. The review suggests that spinal neurostimulation is a promising therapy for axonal regeneration in spinal lesions. This paper concludes that future research should focus on the long-term effects and safety of these existing technologies, optimizing the use of spinal neurostimulation to enhance recovery and exploring its potential for other neurological disorders.

Correction: Aboriginal artefacts on the continental shelf reveal ancient drowned cultural landscapes in northwest Australia.

[This corrects the article DOI: 10.1371/journal.pone.0233912.].

The requirement for NKG2D in NK cell-mediated rejection of parental bone marrow grafts is determined by MHC class I expressed by the graft recipient.

Natural killer (NK) cells provide a unique barrier to semiallogeneic bone marrow (BM) transplantation. In the setting where the parents donate to the F1 offspring, rejection of parental bone marrow occurs. This "hybrid resistance" is completely NK cell dependent, as T cells in the F1 recipient tolerate parental grafts. Previously, we demonstrated that rejection of BALB/c parental BM by (BALB/c × C57BL/6) F1-recipient NK cells is dependent on the NKG2D-activating receptor, whereas rejection of parental C57BL/6 BM does not require NKG2D. BALB/c and B6 mice possess different NKG2D ligand genes and express these ligands differently on reconstituting BM cells. Herein, we show that the requirement for NKG2D in rejection depends on the major histocompatibility complex haplotype of donor cells and not the differences in the expression of NKG2D ligands. NKG2D stimulation of NK cell-mediated rejection was required to overcome inhibition induced by H-2D(d) when it engaged an inhibitory Ly49 receptor, whereas rejection of parental BM expressing the ligand, H-2K(b), did not require NKG2D. Thus, interactions between the inhibitory receptors on F1 NK cells and parental major histocompatibility complex class I ligands determine whether activation via NKG2D is required to achieve the threshold for rejection of parental BM grafts.

Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation.

Donor leukocyte infusions induce remissions in some patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT); however, graft-versus-host disease (GVHD) remains the major complication of this strategy. Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes that express the CD3(+)CD56(+) phenotype and show marked up-regulation of the natural killer cell receptor NKG2D (CD314). CIK cells are non-major histocompatibility complex-restricted and NKG2D-dependent in target recognition and cytotoxicity. We explored the feasibility of ex vivo expansion of allogeneic CIK cells in patients with relapsed hematologic malignancies after allogeneic HCT. Eighteen patients (median age, 53 years; range, 20-69 years) received CIK cell infusions at escalating doses of 1 × 10(7) CD3(+) cells/kg (n = 4), 5 × 10(7) CD3(+) cells/kg (n = 6), and 1 × 10(8) CD3(+) cells/kg (n = 8). The median expansion of CD3(+) cells was 12-fold (range, 4- to 91-fold). CD3(+)CD56(+) cells represented a median of 11% (range, 4%-44%) of the harvested cells, with a median 31-fold (range, 7- to 515-fold) expansion. Median CD3(+)CD314(+) cell expression was 53% (range, 32%-78%) of harvested cells. Significant cytotoxicity was demonstrated in vitro against a panel of human tumor cell lines. Acute GVHD grade I-II was seen in 2 patients, and 1 patient had limited chronic GVHD. After a median follow-up of 20 months (range, 1-69 months) from CIK infusion, the median overall survival was 28 months, and the median event-free survival was 4 months. All deaths were due to relapsed disease; however, 5 patients had longer remissions after infusion of CIK cells than from allogeneic HCT to relapse. Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD, supporting further investigation as an upfront modality to enhance graft-versus-tumor responses in high-risk patient populations.