Cognitive complaints by hematopoietic cell transplantation recipients and change in neuropsychological performance over time.

PURPOSE: Hematopoietic stem cell transplant (HSCT) recipients are at risk for cognitive decline. Cross-sectional studies show patients' complaints of cognitive decline do not correlate well with concurrently measured objective neuropsychological performance, but rather with emotional variables and health-related quality of life. This longitudinal study investigated whether patient self-report of cognitive status would be concordant with objectively measured neuropsychological performance after accounting for change from their own pre-transplant objective baseline. METHODS: Pre-HSCT and at 30 and 100 days post-HSCT, 46 patients underwent computerized neuropsychological testing (CogState) and completed surveys assessing patient-reported cognitive complaints, emotional symptoms (depression, anxiety), sleep quality, daytime sleepiness, and physical and functional well-being. Correlations were calculated between cognitive complaints and neuropsychological performance (at each time-point and across time-points), as well as all other patient-reported variables. RESULTS: Patient-reported cognitive complaints were largely independent of concurrently assessed objective neuropsychological performance. Uniquely, our longitudinal data demonstrated significant medium to large effect size associations between subjective cognitive complaints post-HSCT with objectively measured change from pre-HSCT in attention, visual learning, and working memory (p < .05-.01). Subjective cognitive complaints post-HSCT were also associated with depression, anxiety, daytime sleepiness and physical well-being (p < .05-.001). CONCLUSIONS: Patients appear better able to assess their cognitive functioning relative to their own baseline and changes across time rather than relative to community norms. Thus, patient complaints of cognitive compromise justify further in-depth neuropsychological, emotional, and functional assessment. Future research into relationships between cognitive complaints and neuropsychological performance should account for changes in performance over time.

Prevention and Treatment of Acute Graft-versus-Host Disease in Children, Adolescents, and Young Adults.

Acute graft-versus-host disease (GVHD) continues to be a major cause of morbidity and mortality after allogeneic hematopoietic cell transplant (HCT) in pediatric patients (ie, children and adolescent and young adults) and limits broader application of the therapy. Pediatric HCT patients have faced major obstacles to access clinical trials that test new agents for GVHD prevention and treatment. According to a recent search, only 6 clinical trials of interventions for prevention or treatment of acute GVHD were conducted specifically in pediatric patients in the United States over the past decade, with 8 internationally. In this review, we summarize the studies that were performed and specifically enrolled and reported on pediatric patients after allogeneic HCT and provide a listing of studies currently under way.

Assessment of Individual versus Composite Endpoints of Acute Graft-versus-Host Disease in Determining Long-Term Survival after Allogeneic Transplantation.

The overall composite of graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS), defined as survival free of grade III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD) requiring systemic immunosuppressive therapy (IST), or relapse, has emerged as a useful composite in clinical trials and to capture clinically meaningful events that impact quantity and quality of survival after allogeneic hematopoietic cell transplantation (HCT). We reviewed 565 consecutive patients aged ≥18 years undergoing HCT for hematologic malignancy to analyze how baseline incidence, specifics of clinical definitions, and proposed reductions in any one individual event may dynamically alter the overall performance of the composite To determine the relative impact of each GRFS event (excluding death), we accounted for competing risks using Fine and Gray methods, and correlated each event with overall survival (OS) using Kaplan-Meier methods. The consequences of modulating individual or composite endpoints on OS, such as hypothesized reductions of events of an HCT interventional trial, were examined using Monte Carlo simulations. The median age of the cohort was 54 years (range, 18 to 73 years). The majority of patients received HLA-matched unrelated donor HCT (53%), consisting of peripheral blood stem cell grafts (90%) after myeloablative conditioning (68%). Relapse conferred the greatest risk for death (hazard ratio [HR], 7.89; 95% confidence interval [CI], 5.83 to 10.69), followed by grade III-IV aGVHD (HR, 6.16; 95% CI, 4.42 to 8.56) and cGVHD requiring IST (HR, 1.69; 95% CI, 1.16 to 2.46). The overall GRFS composite correlated with an HR of 4.81 (95% CI, 3.61 to 6.41), which was lower compared with either relapse or grade III-IV aGVHD. Statistical simulations found that modulating the combined risk of both relapse and grade III-IV aGVHD predicted the greatest change in 5-year OS. These simulations suggest that GRFS as currently defined may be less optimal for correlating with OS, and further refinement of composite endpoints is needed. Nonetheless, composite endpoints may be particularly helpful in mitigating potential difficulties in interpretation when competing risks are present, most commonly seen in HCT studies.

Cognitive Function and Quality of Life in Vorinostat-Treated Patients after Matched Unrelated Donor Myeloablative Conditioning Hematopoietic Cell Transplantation.

Myeloablative conditioning allogeneic hematopoietic cell transplantation (HCT) puts patients at greater risk for significant cognitive and quality of life decline compared with recipients of reduced-intensity conditioning or autologous HCT. Vorinostat, a histone deacetylase inhibitor, has been shown to have neuroprotective and neurorestorative effects in preclinical models of neurologic diseases. Thus, within the context of a myeloablative conditioning phase II clinical trial of vorinostat combined with tacrolimus and methotrexate for graft-versus-host disease prophylaxis, we conducted an ancillary study to evaluate feasibility of assessing associations between vorinostat and neurocognitive function and quality of life (ClinicalTrials.gov NCT02409134). Nine patients (mean age, 53 years; range, 36 to 66) underwent computerized neuropsychological testing (Cogstate) and completed surveys of mood (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), and quality of life (Functional Assessment of Cancer Therapy-General). Control cohorts from a separate concurrent longitudinal study (19 autologous and 18 allogeneic HCT patients, who matched the vorinostat patients on relevant medical and demographic variables) completed the same test battery. All allogeneic patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched unrelated donors. The total neurocognitive performance score of vorinostat patients did not change significantly across the study duration (ie, baseline, day 30, day 100, and day 160). Depression, anxiety, and quality of life also did not differ significantly across time. In univariate analyses (analysis of variance), vorinostat-treated patients showed no difference in neurocognitive function or quality of life compared with autologous and allogeneic control subjects. However, when medical variables were accounted for in a linear mixed effects regression model, the total neurocognitive performance of vorinostat-treated patients was comparable with autologous control subjects. Notably, autologous control subjects performed significantly better than allogeneic control subjects (estimate, .64; standard error, .23; P ≤ .01). Moreover, a smaller percentage of vorinostat-treated patients were classified as mildly, moderately, or severely impaired across neurocognitive domains as well as time points compared with both control cohorts. Thus, vorinostat may have neurorestorative or neuroprotective effects in the HCT setting. Accordingly, we recognize the need for a future, full-scale randomized controlled trial to further examine this hypothesis.

Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT.

The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) after reduced-intensity conditioning, related donor hematopoietic cell transplantation (HCT). However, its safety and efficacy in preventing acute GVHD in settings of heightened clinical risk that use myeloablative conditioning, unrelated donor (URD), and methotrexate are not known. We conducted a prospective, phase 2 study in this higher-risk setting. We enrolled 37 patients to provide 80% power to detect a significant difference in grade 2 to 4 acute GVHD of 50% compared with a reduction in target to 28%. Eligibility included adults with a hematological malignancy to receive myeloablative HCT from an available 8/8-HLA matched URD. Patients received GVHD prophylaxis with tacrolimus and methotrexate. Vorinostat (100 mg twice daily) was started on day -10 and continued through day +100 post-HCT. Median age was 56 years (range, 18-69 years), and 95% had acute myelogenous leukemia or high-risk myelodysplastic syndrome. Vorinostat was safe and tolerable. The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 22%, and for grade 3 to 4 it was 8%. The cumulative incidence of chronic GVHD was 29%; relapse, nonrelapse mortality, GVHD-free relapse-free survival, and overall survival at 1 year were 19%, 16%, 47%, and 76%, respectively. Correlative analyses showed enhanced histone (H3) acetylation in peripheral blood mononuclear cells and reduced interleukin 6 (P = .028) and GVHD biomarkers (Reg3, P = .041; ST2, P = .002) at day 30 post-HCT in vorinostat-treated subjects compared with similarly treated patients who did not receive vorinostat. Vorinostat for GVHD prevention is an effective strategy that should be confirmed in a randomized phase 3 study. This trial was registered at www.clinicaltrials.gov as #NCT01790568.

Nutritional status and weakness following pediatric hematopoietic cell transplantation.

Survivorship after pediatric HCT has increased over the past decade. Focus on long-term care and well-being remains critical due to risk of poor dietary habits and exaggerated sedentary behavior, which can lead to muscle weakness, increased risk for obesity, and cardiometabolic disorders. Nutrition and physical activity are key factors in survivorship; however, data are limited. Comprehensive nutritional assessments, including nutrition-focused physical examination, grip strength, and food/activity surveys, were completed in 36 pediatric HCT survivors (aged 2-25 years). Patients were divided into undernutrition, normal-nutrition, and overnutrition categories. Fifty percent of participants were classified as normal nutrition, 22% undernutrition, and 28% overnutrition. Few patients met the U.S. Dietary Guidelines recommended intake for vegetables, fiber, saturated fat, and So FAS. Patients in the undernutrition group demonstrated significantly lower grip strength than those in the normal- and overnutrition groups. When grip strength was normalized to body mass, patients in the overnutrition group had the highest prevalence of weakness. Using NHANES reference data, maximum grip strength and NGS cutoffs were identified that could significantly distinguish the nutrition groups. Comprehensive nutritional assessments and grip strength measurements are feasible, non-invasive, easy to perform, and inform both under- and overnutrition in pediatric HCT survivors.

FLT3 mutational status is an independent risk factor for adverse outcomes after allogeneic transplantation in AML.

Allogeneic hematopoietic cell transplantation (HCT) has been increasingly used in the setting of FMS-like tyrosine kinase-3 (FLT3)-mutated AML. However, its role in conferring durable relapse-free intervals remains in question. Herein we sought to investigate FLT3 mutational status on transplant outcomes. We conducted a retrospective cohort study of 262 consecutive AML patients who underwent first-time allogeneic HCT (2008-2014), of whom 171 had undergone FLT3-ITD (internal tandem duplication) mutational testing. FLT3-mutated AML was associated with nearly twice the relapse risk (RR) compared with those without FLT3 mutation 3 years post-HCT (63% vs 37%, P<0.001) and with a shorter median time to relapse (100 vs 121 days). FLT3 mutational status remained significantly associated with this outcome after controlling for patient, disease and transplant-related risk factors (P<0.05). Multivariate analysis showed a significant association of FLT3 mutation with increased 3-year RR (hazard ratio (HR) 3.63, 95% confidence interval (CI): 2.13, 6.19, P<0.001) and inferior disease-free survival (HR 2.05, 95% CI: 1.29, 3.27, P<0.01) and overall survival (HR 1.92, 95% CI: 1.14, 3.24, P<0.05). These data demonstrate high risk of early relapse after allogeneic HCT for FLT3-mutated AML that translates into adverse disease-free and overall survival outcomes. Additional targeted and coordinated interventions are needed to maintain durable remission after allogeneic HCT in this high-risk population.

Approaches for the prevention of graft-versus-host disease following hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is an important therapeutic option for malignant and non-malignant diseases, but the more widespread application of the therapy remains limited by the occurrence of graft versus host disease (GVHD). GVHD results from immune-mediated injury by donor immune cells against tissues in the HCT recipient, and can be characterized as acute or chronic depending on the time of onset and site of organ involvement. The majority of efforts have focused on GVHD prevention. Calcineurin inhibitors are the most widely used agents and are included in almost all regimens. Despite current prophylaxis strategies, 40-70% of patients remain at risk for developing GVHD. Herein, we review standard and emerging therapies used in GVHD management.

Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans.

We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease prophylaxis after allogeneic hematopoietic cell transplant. Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMCs) from treated patients, confirming target HDAC inhibition. HDAC inhibition reduced proinflammatory cytokine levels in plasma and from PBMCs and decreased ex vivo responses of PBMCs to proinflammatory TLR-4 stimuli, but did not alter the number or response of conventional T cells to nonspecific stimuli. However, the numbers of regulatory T cells (Tregs) were increased, which revealed greater demethylation of the Foxp3 T regulatory-specific demethylation region. Vorinostat-treated patients showed increased expression of CD45RA and CD31 on Tregs, and these Tregs demonstrated greater suppression on a per cell basis. Consistent with preclinical findings, HDAC inhibition also increased signal transducer and activator of transcription 3 acetylation and induced indoleamine-2,3-dioxygenase. Our data demonstrate that HDAC inhibition reduces inflammatory responses of PBMC but enhances Tregs after allo-HCT.

Engraftment syndrome after allogeneic hematopoietic cell transplantation predicts poor outcomes.

Engraftment syndrome (ES), characterized by fever, rash, pulmonary edema, weight gain, liver and renal dysfunction, and/or encephalopathy, occurs at the time of neutrophil recovery after hematopoietic cell transplantation (HCT). In this study, we evaluated the incidence, clinical features, risk factors, and outcomes of ES in children and adults undergoing first-time allogeneic HCT. Among 927 patients, 119 (13%) developed ES at a median of 10 days (interquartile range 9 to 12) after HCT. ES patients experienced significantly higher cumulative incidence of grade 2 to 4 acute GVHD at day 100 (75% versus 34%, P < .001) and higher nonrelapse mortality at 2 years (38% versus 19%, P < .001) compared with non-ES patients, resulting in lower overall survival at 2 years (38% versus 54%, P < .001). There was no significant difference in relapse at 2 years (26% versus 31%, P = .772). Suppression of tumorigenicity 2, interleukin 2 receptor alpha, and tumor necrosis factor receptor 1 plasma biomarker levels were significantly elevated in ES patients. Our results illustrate the clinical significance and prognostic impact of ES on allogeneic HCT outcomes. Despite early recognition of the syndrome and prompt institution of corticosteroid therapy, outcomes in ES patients were uniformly poor. This study suggests the need for a prospective approach of collecting clinical features combined with correlative laboratory analyses to better characterize ES.

Etanercept plus topical corticosteroids as initial therapy for grade one acute graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Clinical diagnosis of grade 1 acute graft-versus-host disease (GVHD) marks the beginning of a potentially progressive and fatal course of GVHD after hematopoietic stem cell transplantation (HSCT). However, interventional studies to treat early GVHD are lacking. We conducted a single-arm prospective phase II trial to test the hypothesis that treatment of newly diagnosed grade 1 acute GVHD with etanercept and topical corticosteroids would reduce progression to grade 2 to 4 within 28 days. Study patients (n = 34) had a median age of 51 years (range, 10 to 67 years) and had undergone unrelated (n = 22) or related (n = 12) donor HSCT. Study patients were treated with etanercept (.4 mg/kg, maximum 25 mg/dose) twice weekly for 4 to 8 weeks. Ten of 34 patients (29%) progressed to grade 2 to 4 acute GVHD within 28 days. The cumulative incidence of grade 2 to 4 and grade 3 to 4 acute GVHD at 1 year was 41% and 3%, respectively. Nonrelapse mortality was 19% and overall survival was 63% at 2 years. Among a contemporaneous control cohort of patients who were diagnosed with grade 1 acute GVHD and treated with topical corticosteroids but not etanercept during the study period, 12 of 28 patients (43%) progressed to grade 2 to 4 GVHD within 28 days, with a 1-year incidence of grade 2 to 4 GVHD and grade 3 to 4 GVHD of 61% (41% versus 61%, P = .08) and 18% (3% versus 18%, P = .05), respectively. Patients treated with etanercept also experienced less increase in GVHD plasma biomarkers suppression of tumorigenicity 2 (P = .06) and regenerating islet-derived 3-alpha (P = .01) 28 days after grade 1 acute GVHD diagnosis compared with contemporaneous control patients. This study was terminated early because of poor accrual. Future prospective studies are needed to identify patients with grade 1 acute GVHD at risk of swift progression to more severe GVHD and to establish consensus for the treatment of grade 1 acute GVHD. This trial is registered with ClinicalTrials.gov, number NCT00726375.

Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease.

Cells generate adenosine triphosphate (ATP) by glycolysis and by oxidative phosphorylation (OXPHOS). Despite the importance of having sufficient ATP available for the energy-dependent processes involved in immune activation, little is known about the metabolic adaptations that occur in vivo to meet the increased demand for ATP in activated and proliferating lymphocytes. We found that bone marrow (BM) cells proliferating after BM transplantation (BMT) increased aerobic glycolysis but not OXPHOS, whereas T cells proliferating in response to alloantigens during graft-versus-host disease (GVHD) increased both aerobic glycolysis and OXPHOS. Metabolomic analysis of alloreactive T cells showed an accumulation of acylcarnitines consistent with changes in fatty acid oxidation. Alloreactive T cells also exhibited a hyperpolarized mitochondrial membrane potential (ΔΨm), increased superoxide production, and decreased amounts of antioxidants, whereas proliferating BM cells did not. Bz-423, a small-molecule inhibitor of the mitochondrial F(1)F(0) adenosine triphosphate synthase (F(1)F(0)-ATPase), selectively increased superoxide and induced the apoptosis of alloreactive T cells, which arrested established GVHD in several BMT models without affecting hematopoietic engraftment or lymphocyte reconstitution. These findings challenge the current paradigm that activated T cells meet their increased demands for ATP through aerobic glycolysis, and identify the possibility that bioenergetic and redox characteristics can be selectively exploited as a therapeutic strategy for immune disorders.

Cutting edge: Negative regulation of dendritic cells through acetylation of the nonhistone protein STAT-3.

Histone deacetylase (HDAC) inhibition modulates dendritic cell (DC) functions and regulates experimental graft-vs-host disease and other immune-mediated diseases. The mechanisms by which HDAC inhibition modulates immune responses remain largely unknown. STAT-3 is a transcription factor shown to negatively regulate DC functions. In this study we report that HDAC inhibition acetylates and activates STAT-3, which regulates DCs by promoting the transcription of IDO. These findings demonstrate a novel functional role for posttranslational modification of STAT-3 through acetylation and provide mechanistic insights into HDAC inhibition-mediated immunoregulation by induction of IDO.

Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice.

Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allostimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors reduced experimental graft-versus-host disease (GVHD) in a murine allogeneic BM transplantation model. Exposure of DCs to HDAC inhibitors increased expression of indoleamine 2,3-dioxygenase (IDO), a suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with DCs from IDO-deficient animals caused substantial reversal of HDAC inhibition-induced in vitro suppression of DC-stimulated responses. Direct injection of HDAC inhibitors early after allogeneic BM transplantation to chimeric animals whose BM-derived cells lacked IDO failed to protect from GVHD, demonstrating an in vivo functional role for IDO. Together, these data show that HDAC inhibitors regulate multiple DC functions through the induction of IDO and suggest that they may represent a novel class of agents to treat immune-mediated diseases.

Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells.

Extracorporeal photopheresis (ECP), a technique that exposes isolated white blood cells to photoactivatable 8-methoxypsoralen and ultraviolet A radiation, is used clinically to treat cutaneous T-cell lymphoma and immune-mediated diseases such as graft-versus-host disease (GVHD). ECP is thought to control these diseases in part through direct induction of lymphocyte apoptosis, but its effects on the immune system beyond apoptosis remain poorly characterized. We have developed a novel method for incorporating ECP treatment into well-established and clinically relevant murine models of GVHD to examine its effects during an ongoing immune response. We demonstrate that the transfer of cells treated with ECP reverses established GVHD by increasing donor regulatory T cells and indirectly reducing the number of donor effector lymphocytes that themselves had never been exposed to psoralen and ultraviolet A radiation.

Differential susceptibility of C57BL/6NCr and B6.Cg-Ptprca mice to commensal bacteria after whole body irradiation in translational bone marrow transplant studies.

BACKGROUND: The mouse is an important and widely utilized animal model for bone marrow transplant (BMT) translational studies. Here, we document the course of an unexpected increase in mortality of congenic mice that underwent BMT. METHODS: Thirty five BMTs were analyzed for survival differences utilizing the Log Rank test. Affected animals were evaluated by physical examination, necropsy, histopathology, serology for antibodies to infectious disease, and bacterial cultures. RESULTS: Severe bacteremia was identified as the main cause of death. Gastrointestinal (GI) damage was observed in histopathology. The bacteremia was most likely caused by the translocation of bacteria from the GI tract and immunosuppression caused by the myeloablative irradiation. Variability in groups of animals affected was caused by increased levels of gamma and X-ray radiation and the differing sensitivity of the two nearly genetically identical mouse strains used in the studies. CONCLUSION: Our retrospective analysis of thirty five murine BMTs performed in three different laboratories, identified C57BL/6NCr (Ly5.1) as being more radiation sensitive than B6.Cg-Ptprca/NCr (Ly5.2). This is the first report documenting a measurable difference in radiation sensitivity and its effects between an inbred strain of mice and its congenic counterpart eventually succumbing to sepsis after BMT.

Adjuvant IL-15 does not enhance the efficacy of tumor cell lysate-pulsed dendritic cell vaccines for active immunotherapy of T cell lymphoma.

There has been a recent interest in using IL-15 to enhance antitumor activity in several models because of its ability to stimulate CD8+ T cell expansion, inhibit apoptosis and promote memory T cell survival and maintenance. Previously, we reported that C6VL tumor lysate-pulsed dendritic cell vaccines significantly enhanced the survival of tumor-bearing mice by stimulating a potent tumor-specific CD8+ T cell response. In this study, we determined whether IL-15 used as immunologic adjuvant would augment vaccine-primed CD8+ T cell immunity against C6VL and further improve the survival of tumor-bearing mice. We report that IL-15 given after C6VL lysate-pulsed dendritic cell vaccines stimulated local and systemic expansion of NK, NKT and CD8+ CD44hi T cells. IL-15 did not, however, augment innate or cellular responses against the tumor. T cells from mice infused with IL-15 following vaccination did not secrete increased levels of tumor-specific TNF-alpha or IFN-gamma or have enhanced C6VL-specific CTL activity compared to T cells from recipients of the vaccine alone. Lastly, IL-15 did not enhance the survival of tumor-bearing vaccinated mice. Thus, while activated- and memory-phenotype CD8+ T cells were dramatically expanded by IL-15 infusion, vaccine-primed CD8+ T cell specific for C6VL were not significantly expanded. This is the first account of using IL-15 as an adjuvant in a therapeutic model of active immunotherapy where there was not a preexisting pool of tumor-specific CD8+ T cells. Our results contrast the recent studies where IL-15 was successfully used to augment tumor-reactivity of adoptively transferred transgenic CD8+ T cells. This suggests that the adjuvant potential of IL-15 may be greatest in settings where it can augment the number and activity of preexisting tumor-specific CD8+ T cells.

Tumor cell lysate-pulsed dendritic cells are more effective than TCR Id protein vaccines for active immunotherapy of T cell lymphoma.

TCR Id protein conjugated to keyhole limpet hemocyanin (KLH) (TCR Id:KLH) and injected with a chemical adjuvant (QS-21) induces a protective, Id-specific immune response against the murine T cell lymphoma, C6VL. However, Id-based immunotherapy of C6VL has not demonstrated therapeutic efficacy in tumor-bearing mice. We report here that C6VL lysate-pulsed dendritic cells (C6VL-DC) vaccines display enhanced efficacy in both the prevention and the therapy of T cell lymphoma compared with TCR Id:KLH with QS-21 vaccines. C6VL-DC vaccines stimulated potent tumor-specific immunity that protected mice against lethal challenge with C6VL and significantly enhanced the survival of tumor-bearing mice. Tumor-specific proliferation and secretion of IFN-gamma indicative of a Th1-type immune response were observed upon ex vivo stimulation of vaccine-primed lymph node cells. Adoptive transfer of immune T cell-enriched lymphocytes was sufficient to protect naive recipients from lethal tumor challenge. Furthermore, CD8(+) T cells were absolutely required for tumor protection. Although C6VL-DC and control vaccines stimulated low levels of tumor-specific Ab production in mice, Ab levels did not correlate with the protective ability of the vaccine. Thus, tumor cell lysate-pulsed DC vaccines appear to be an effective approach to generate potent T cell-mediated immune responses against T cell malignancies without requiring identification of tumor-specific Ags or patient-specific Id protein expression.