Low-dose acetylsalicylic acid for cancer prevention considering risk factors: a retrospective cohort study.

PURPOSE: Aspirin (acetylsalicylic acid) has been reported to protect against certain cancers. However, patient-related risk factors may moderate protective effects, including excess weight, smoking, risky alcohol use, and diabetes. We explore the cancer-risk relationship between aspirin intake and those four factors. METHODS: Retrospective cohort study of cancers, aspirin intake, and four risk factors in persons aged ≥50 years. Participants received medication during 2007-2016, and cancers were diagnosed in 2012-2016. Adjusted hazard ratios (aHR) for 95% confidence intervals (95%CI) were calculated for aspirin intake and risk factors using Cox proportional hazard modeling. RESULTS: Of 118,548 participants, 15,793 consumed aspirin, and 4003 had cancer. Results indicated a significant protective effect of aspirin against colorectal (aHR: 0.7; 95%CI: 0.6-0.8), pancreatic (aHR: 0.5; 95%CI: 0.2-0.9), prostate (aHR: 0.6; 95%CI: 0.5-0.7) cancers and lymphomas (aHR: 0.5; 95%CI: 0.2-0.9), and also, although not significantly, against esophageal (aHR: 0.5; 95%CI: 0.2-1.8), stomach (aHR: 0.7; 95%CI: 0.4-1.3), liver (aHR: 0.7; 95%CI: 0.3-1.5), breast (aHR: 0.8; 95%CI: 0.6-1.0), and lung and bronchial (aHR: 0.9; 95%CI: 0.7-1.2) cancers. Aspirin intake was not significantly protective against leukemia (aHR: 1.0; 95%CI: 0.7-1.4) or bladder cancer (aHR: 1.0; 95%CI: 0.8-1.3). CONCLUSIONS: Our results suggest that aspirin intake is associated with a reduced incidence of colorectal, pancreatic, and prostate cancers and lymphomas.

Use of dipyridamole is associated with lower risk of lymphoid neoplasms: a propensity score-matched cohort study.

The anti-cancer potential of dipyridamole has been suggested from experiments, but evidence from population-based studies is still lacking. We aimed to explore if dipyridamole use was related to a lower risk of lymphoid neoplasms. We identified individuals with prescription of aspirin after diagnosis of ischaemic cerebrovascular disease since 2006 by linking several Swedish registers. In these aspirin users, those with dipyridamole prescription were further identified as the study group and patients without dipyridamole were randomly selected as reference group with 1:1 ratio using a propensity score-matching approach. After a median of 6·67 years of follow-up, a total of 46 patients with dipyridamole use developed lymphoid neoplasms with an incidence rate of 0·49 per 1 000 person-years, while the rate in the matched group was 0·74 per 1 000 person-years. As compared to non-users, dipyridamole users were associated with a significantly decreased risk of lymphoid neoplasms [hazard ratio (HR) = 0·65; 95% confidence interval (CI) = 0·43-0·98]. Specifically, the reduced risk was observed for non-Hodgkin lymphomas (HR = 0·64; 95% CI = 0·42-0·94), especially B-cell lymphomas (HR = 0·56; 95% CI = 0·35-0·88). Dipyridamole use was related to a lower risk of lymphoid neoplasms, indicating a clinical potential of dipyridamole to be an adjunct anti-tumour agent against lymphoid neoplasms.

Survival and Functional Immune Reconstitution After Haploidentical Stem Cell Transplantation in Atm-Deficient Mice.

Hematopoietic stem cell transplantation (HSCT) has been proposed as a promising therapeutic opportunity to improve immunity and prevent hematologic malignancies in Ataxia-telangiectasia (A-T). However, experience in the transplantation strategy for A-T patients is still scarce. The aim of this study was to investigate whether different approaches of HSCT are feasible in regard to graft versus host response and sufficient concerning functional immune reconstitution. Atm-deficient mice were treated with a clinically relevant non-myeloablative host-conditioning regimen and transplanted with CD90.2-depleted, green fluorescent protein (GFP)-expressing, and ataxia telangiectasia mutated (ATM)-competent bone marrow donor cells in a syngeneic, haploidentical or allogeneic setting. Like syngeneic HSCT, haploidentical HSCT, but not allogeneic HSCT extended the lifespan of Atm-deficient mice through the reduction of thymic tumors and normalized T-cell numbers. Donor-derived splenocytes isolated from transplanted Atm-deficient mice filled the gap of cell loss in the naïve T-cell population and raised CD4 cell functionality up to wild-type level. Interestingly, HSCT using heterozygous donor cells let to a significantly improved survival of Atm-deficient mice and increased CD4 cell numbers as well as CD4 cell functionality equivalent to HSCT using with wild-type donor cells. Our data provided evidence that haploidentical HSCT could be a feasible strategy for A-T, possibly even if the donor is heterozygous for ATM. However, this basic research cannot substitute any research in humans.

Transplantation of Unirradiated Bone Marrow Cells after Total-Body Irradiation Prevents the Development of Thymic Lymphoma in Mice through Niche Competition.

Mouse models of radiation-induced thymic lymphoma are commonly used to study the biological effects of total-body irradiation (TBI) on the formation of hematologic malignancies. It is well documented that radiation-induced thymic lymphoma can be inhibited by protecting the bone marrow (BM) from irradiation; however, the mechanisms underlying this phenomenon are poorly understood. Here, we aimed to address this question by performing transplantation of BM cells from genetically engineered mice that have defects in tumor immunosurveillance or occupying different thymic niches. We found that BM cells from mice that have impaired tumor immunosurveillance, by deleting tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ) or perforin-1 (PRF1), remained sufficient to suppress the formation of radiation-induced thymic lymphoma. On the other hand, BM cells from Rag2-/-; γc-/- mice and Rag2-/- mice, which have defects in occupying thymic niches beyond double negative (DN2) and DN3, respectively, failed to inhibit radiation-induced lymphomagenesis in the thymus. Taken together, based on our findings, we propose a model where unirradiated BM cells suppress radiation-induced lymphomagenesis in the thymus by competing with tumor-initiating cells for thymic niches beyond the DN3 stage.

Paediatric computed tomography and subsequent risk of leukaemia, intracranial malignancy and lymphoma: a nationwide population-based cohort study.

Red bone marrow and brain tissue are highly radiosensitive in children. We investigate the relationship between childhood computed tomography (CT) exposure and leukaemia, intracranial malignancy and lymphoma. All participants in the study were aged less than 16 years. A total of 1,479 patients in the leukaemia group, 976 patients in the intracranial malignancy group and 301 patients in the lymphoma group were extracted from the Catastrophic Illness Certificate Database in Taiwan as the disease group. In total, 126,677 subjects were extracted from the Longitudinal Health Insurance Database 2010 of the Taiwan National Health Insurance Research Database as the non-disease group. The odds ratios (ORs) and 95% confidence intervals (CIs) for childhood CT exposure and times of childhood CT were estimated. Childhood CT exposure was correlated to the intracranial malignancy group in both one-year (OR = 1.95, 95% CI 1.40-2.71, p < 0.001) and two-year (OR = 1.56, 95% CI 1.04-2.33, p = 0.031) exclusion periods. The time of childhood CT was also correlated to intracranial malignancy in both one-year (OR = 1.69, 95% CI 1.34-2.13, p < 0.001) and two-year (OR = 1.55, 95% CI 1.17-2.04, p = 0.002) exclusion periods. The results indicated that childhood CT exposure was correlated with an increased risk of future intracranial malignancy.

Healthy lifestyle and the risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition study.

Limited evidence exists on the role of modifiable lifestyle factors on the risk of lymphoma. In this work, the associations between adherence to healthy lifestyles and risks of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) were evaluated in a large-scale European prospective cohort. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 2,999 incident lymphoma cases (132 HL and 2,746 NHL) were diagnosed among 453,808 participants after 15 years (median) of follow-up. The healthy lifestyle index (HLI) score combined information on smoking, alcohol intake, diet, physical activity and BMI, with large values of HLI expressing adherence to healthy behavior. Cox proportional hazards models were used to estimate lymphoma hazard ratios (HR) and 95% confidence interval (CI). Sensitivity analyses were conducted by excluding, in turn, each lifestyle factor from the HLI score. The HLI was inversely associated with HL, with HR for a 1-standard deviation (SD) increment in the score equal to 0.78 (95% CI: 0.66, 0.94). Sensitivity analyses showed that the association was mainly driven by smoking and marginally by diet. NHL risk was not associated with the HLI, with HRs for a 1-SD increment equal to 0.99 (0.95, 1.03), with no evidence for heterogeneity in the association across NHL subtypes. In the EPIC study, adherence to healthy lifestyles was not associated with overall lymphoma or NHL risk, while an inverse association was observed for HL, although this was largely attributable to smoking. These findings suggest a limited role of lifestyle factors in the etiology of lymphoma subtypes.

Impact of fear of cancer recurrence on survival among lymphoma patients.

OBJECTIVE: This study aimed to evaluate fear of cancer recurrence (FCR) among lymphoma patients who completed treatment and its impact on survival and quality of life (QOL). METHODS: In this prospective cohort study, 467 lymphoma patients were included who completed treatment with curative intent between February 2012 and March 2017. FCR was measured using a question from the Korean version of the QOL in Cancer Survivors Questionnaire. QOL and general health and functioning were measured using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30. Participants were actively followed up for all-cause and disease-specific mortality. RESULTS: In total, 16.3% of the patients had severe FCR. The adjusted hazard ratio (HR) for all-cause mortality comparing participants with and without severe FCR was 2.52 (95% CI = 1.15-5.54), and the association was stronger in indolent non-Hodgkin lymphoma (NHL) (HR = 6.77; 95% CI = 1.04-43.92). Participants with severe FCR were also at higher risk of lymphoma-specific mortality (HR = 2.62; 95% CI = 1.13-6.05) than patients without severe FCR. Patients with severe FCR had significantly worse general health status (64.3 vs 71.0, P = .03) and physical (82.4 vs 76.7, P < .01), emotional (68.5 vs 84.8, P < .001), and social functioning (67.8 vs 84.2, P < .001) than patients without severe FCR. CONCLUSIONS: A substantial number of participants with lymphoma experience FCR after treatment completion, even in the case of indolent lymphomas. Given the negative impact of severe FCR on survival and general health and functional status, active monitoring and appropriate management of FCR should be considered in clinical settings.

Towards a mechanistic understanding of the synergistic response induced by bivalent Marek's disease vaccines to prevent lymphomas.

BACKGROUND: Marek's disease (MD) is a lymphoproliferative disease of chickens caused by Marek's disease virus (MDV), an oncogenic α-herpesvirus. Since 1970, MD has been controlled by widespread vaccination; however, more effective MD vaccines are needed to counter more virulent MDV strains. The bivalent vaccine combination of SB-1 and herpesvirus of turkey (HVT) strain FC126 has been widely used. Nonetheless, the mechanism(s) underlying this synergistic effect has not been investigated. METHODS: Three experiments were conducted where SB-1 or HVT were administered as monovalent or bivalent vaccines to newly hatched chickens, then challenged five days later with MDV. In Experiment 1, levels of MDV replication in PBMCs were measured over time, and tumor incidence and vaccinal protection determined. In Experiment 2, MDV and vaccine strains replication levels in lymphoid organs were measured at 1, 5, 10, and 14 days post-challenge (DPC). In Experiment 3, to verify that the bursa was necessary for HVT protection, a subset of chicks were bursectomized and these birds plus controls were similarly vaccinated and challenged, and the levels of vaccinal protection determined. RESULTS: The efficacy of bivalent SB-1 + HVT surpasses that of either SB-1 or HVT monovalent vaccines in controlling the level of pathogenic MDV in PBMCs until the end of the study, and this correlated with the ability to inhibit tumor formation. SB-1 replication in the spleen increased from 1 to 14 DPC, while HVT replicated only in the bursa at 1 DPC. The bursa was necessary for immune protection induced by HVT vaccine. CONCLUSION: Synergy of SB-1 and HVT vaccines is due to additive influences of the individual vaccines acting at different times and target organs. And the bursa is vital for HVT to replicate and induce immune protection.

Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses.

Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53R178E mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53-/- mice. Surprisingly, stabilization of p53R178E in Mdm2-/- mice nevertheless triggers extensive apoptosis, indicative of residual wild-type activities. Although this apoptotic activity suffices to trigger lethality of Trp53R178E ;Mdm2-/- embryos, it proves insufficient for suppression of spontaneous and oncogene-driven tumorigenesis. Trp53R178E mice develop tumors indistinguishably from Trp53-/- mice and tumors retain and even stabilize the p53R178E protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53R178E tumors exhibit remarkably better chemotherapy responses than Trp53-/- ones, resulting in enhanced eradication of p53-mutated tumor cells. Together, this provides genetic proof-of-principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of cancer therapy.

Structured DVD Education: Impact on Teaching Satisfaction and Anxiety Among Patients With Leukemia and Lymphoma and Their Family Members.

BACKGROUND: Many factors can interfere with a patient's ability to cope with a new cancer diagnosis. The method of education delivery may improve satisfaction with teaching and reduce anxiety. Structured DVD education combined with other teaching methods has shown positive results. However, few such studies have included family members. OBJECTIVES: The purpose of this study was to evaluate the impact of structured DVD education versus standard one-on-one education on satisfaction with teaching and on anxiety among patients newly diagnosed with leukemia and lymphoma and their families. METHODS: A post-test randomized controlled trial study design evaluated the effects of structured DVD education compared to standard one-on-one education. FINDINGS: Family members in the intervention group had higher satisfaction with teaching than those in the control group; this difference was found to be statistically significant.

Comparison of the Transcriptomes and Proteomes of Serum Exosomes from Marek's Disease Virus-Vaccinated and Protected and Lymphoma-Bearing Chickens.

Marek's disease virus (MDV) is the causative agent of Marek's disease (MD), a complex pathology of chickens characterized by paralysis, immunosuppression, and T-cell lymphomagenesis. MD is controlled in poultry production via vaccines administered in ovo or at hatch, and these confer protection against lymphoma formation, but not superinfection by MDV field strains. Despite vaccine-induced humoral and cell-mediated immune responses, mechanisms eliciting systemic protection remain unclear. Here we report the contents of serum exosomes to assess their possible roles as indicators of systemic immunity, and alternatively, tumor formation. We examined the RNA and protein content of serum exosomes from CVI988 (Rispens)-vaccinated and protected chickens (VEX), and unvaccinated tumor-bearing chickens (TEX), via deep-sequencing and mass spectrometry, respectively. Bioinformatic analyses of microRNAs (miRNAs) and predicted miRNA targets indicated a greater abundance of tumor suppressor miRNAs in VEX compared to TEX. Conversely, oncomiRs originating from cellular (miRs 106a-363) and MDV miRNA clusters were more abundant in TEX compared to VEX. Most notably, mRNAs mapping to the entire MDV genome were identified in VEX, while mRNAs mapping to the repeats flanking the unique long (IRL/TRL) were identified in TEX. These data suggest that long-term systemic vaccine-induced immune responses may be mediated at the level of VEX which transfer viral mRNAs to antigen presenting cells systemically. Proteomic analyses of these exosomes suggested potential biomarkers for VEX and TEX. These data provide important putative insight into MDV-mediated immune suppression and vaccine responses, as well as potential serum biomarkers for MD protection and susceptibility.

Broadening the Message: A Nanovaccine Co-loaded with Messenger RNA and α-GalCer Induces Antitumor Immunity through Conventional and Natural Killer T Cells.

Messenger RNA encoding tumor antigens has the potential to evoke effective antitumor immunity. This study reports on a nanoparticle platform, named mRNA Galsomes, that successfully co-delivers nucleoside-modified antigen-encoding mRNA and the glycolipid antigen and immunopotentiator α-galactosylceramide (α-GC) to antigen-presenting cells after intravenous administration. By co-formulating low doses of α-GC, mRNA Galsomes induce a pluripotent innate and adaptive tumor-specific immune response in mice, with invariant natural killer T cells (iNKT) as a driving force. In comparison, mRNA Galsomes exhibit advantages over the state-of-the-art cancer vaccines using unmodified ovalbumin (OVA)-encoding mRNA, as we observed up to seven times more tumor-infiltrating antigen-specific cytotoxic T cells, combined with a strong iNKT cell and NK cell activation. In addition, the presence of suppressive myeloid cells (myeloid-derived suppressor cells and tumor-associated macrophages) in the tumor microenvironment was significantly lowered. Owing to these antitumor effects, OVA mRNA Galsomes significantly reduced tumor growth in established E.G7-OVA lymphoma, with a complete tumor rejection in 40% of the animals. Moreover, therapeutic vaccination with mRNA Galsomes enhanced the responsiveness to treatment with a PD-L1 checkpoint inhibitor in B16-OVA melanoma, as evidenced by a synergistic reduction of tumor outgrowth and a significantly prolonged median survival. Taken together, these data show that intravenously administered mRNA Galsomes can provide controllable, multifaceted, and effective antitumor immunity, especially when combined with checkpoint inhibition.

Donor lymphocyte infusion for prevention of relapse after unmanipulated haploidentical PBSCT for very high-risk hematologic malignancies.

Unmanipulated haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) has been an established treatment to cure high-risk leukemia/lymphoma. Relapse is the main cause of treatment failure for patients with relapsed/refractory disease or with very high-risk gene mutations such as TP53, TET2, and DNMT3a. In this study, we aimed to establish the tolerance and efficacy of prophylactic donor lymphocyte infusion (DLI) with G-CSF-primed peripheral blood progenitors for prevention of relapse in these very high-risk patients after haplo-PBSCT. The prophylactic DLI was given at a median of 77 days after transplantation in 31 of 45 consecutive patients with very high-risk leukemia/lymphoma. The median dose of CD3+ cells for infusion was 1.8 × 107/kg. The 100-day incidences of acute graft-versus-host disease (GVHD) grades 2-4 and 3-4 after DLI were 55.3% and 10.2%. The 2-year incidences of chronic GVHD and severe chronic GVHD were 52.0% and 18.2%. The 2-year incidences of non-relapse mortality and relapse were 33.1% and 32.5%. The 2-year probabilities of overall survival and relapse-free survival were 40.1% and 31.9%. Poor-risk gene mutations (p = 0.029), disease in non-remission status prior to transplantation (p = 0.005), and donors older than 40 years of age (p = 0.043) were associated with relapse after DLI. In multivariate analysis, disease in non-remission status prior to transplantation was an independent risk factor of relapse (hazard ratio = 4.079; p = 0.035). These data showed the feasibility of the prophylactic DLI in the haplo-PBSCT setting and the anti-leukemic efficacy in very high-risk leukemia/lymphoma.

Early antiviral therapy reduces the risk of lymphoma in patients with chronic hepatitis C infection.

BACKGROUND: Chronic hepatitis C infection is linked to lymphoma development. AIM: To investigate whether antiviral therapy prevents the risk of HCV-related lymphoma. METHODS: Patients diagnosed with chronic hepatitis C were retrieved from the Taiwan National Health Insurance Research Database during 2004-2012. We included patients who received pegylated interferon and ribavirin (PegIFN/RBV) antiviral therapy for ≥24 weeks (PegIFN/RBV cohort) or hepatoprotectants for ≥90 days without antiviral therapy (HCV-untreated cohort). Both cohorts were matched by age, sex, and comorbidities through propensity scores and followed for newly diagnosed lymphoma or non-Hodgkin's lymphoma (NHL). RESULTS: In total, 24 133 patients were included in both the PegIFN/RBV and HCV-untreated cohort. The lymphoma incidence was significantly higher in the untreated than in the treated cohort (66.48 vs 43.34 per 100 000 person-years, P = 0.029). After adjusting for confounders, the patients who received PegIFN/RBV therapy were at a lower risk of developing lymphoma compared with the untreated patients (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.43-0.96, P = 0.030). Moreover, this beneficial effect was mainly observed in patients with chronic hepatitis C <60 years old with a relative risk reduction of 51% for all lymphoma (HR: 0.49, 95% CI: 0.29-0.82, P = 0.007) and 48% for non-Hodgkin's lymphoma (HR: 0.52, 95% CI: 0.30-0.91, P = 0.022). The risk of all lymphoma or non-Hodgkin's lymphoma development after antiviral therapy was lowered to that of subjects without HCV. CONCLUSIONS: PegIFN/RBV-based antiviral therapy significantly reduced the risk of lymphoma, especially non-Hodgkin's lymphoma; the reduction was mostly among patients <60 years old. Early antiviral therapy for chronic hepatitis C is suggested.

Preventive Effects of Fermented Brown Rice and Rice Bran on Spontaneous Lymphomagenesis in AKR/NSlc Female Mice

Fermented brown rice and rice bran with Aspergillus oryzae (FBRA) is known to possess potentials to prevent chemical carcinogenesis in multiple organs of rodents. In the present study, possible chemopreventive effect of FBRA against spontaneous occurrence of lymphomas was examined using female AKR/NSlc mice. Four-week-old female AKR/ NSlc mice were divided into three groups, and fed diets containing FBRA for 26 weeks at a dose level 0% (Group 1), 5% (Group 2) or 10% (Group 3). At the termination of experiment, the incidence of thymic malignant lymphoma of Group 3 was significantly lower than of Group 1 (p < 0.05). The average number of apoptotic cells of the thymic lymphoma of Group 3 was significantly larger than that of Group 1 (p < 0.05). In addition, the incidences of malignant lymphoma arising from body surface and abdominal lymph nodes, and the frequencies of lymphoma cell invasion to liver, kidney, spleen, and ovary of Group 3 were relatively lower than those of Group 1. These results indicate that FBRA inhibits spontaneous development of the lymphoma in female AKR/NSc mice and the inhibition of lymphomagenesis may relate to the induction of apoptosis by exposure of FBRA, suggesting that FBRA could be a protective agent against development of human lymphoma.

Cationic lipid-assisted nanoparticles for delivery of mRNA cancer vaccine.

Message RNA-based vaccines with prominent advantages such as facile production, no requirement for nuclear entry and high safety without the need for integration into host genome have been shown to be potent activators of the cytotoxic immune system. However, wider applications of mRNA-based therapeutics have been hindered because of their intrinsically high vulnerability to expressed nucleases and difficulty while entering antigen-presenting cells (APCs) directly. Here, we investigated the potential of cationic lipid-assisted nanoparticles (CLAN), which form a clinically translatable nucleic acid delivery system working as a carrier of an mRNA vaccine. We found that CLAN encapsulating mRNA encoding antigen could effectively stimulate the maturation of dendritic cells (DCs) and promote the activation and proliferation of antigen-specific T cells both in vitro and in vivo. Intravenous immunization of mice with CLAN containing mRNA encoding ovalbumin (OVA) provoked a strong OVA-specific T-cell response and slowed tumor growth in an aggressive E·G7-OVA lymphoma model. Collectively, CLAN proved to be a promising platform for mRNA vaccine delivery.

Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma.

Epstein-Barr virus (EBV) is associated with several B and epithelial cell cancers. EBV-encoded latent membrane protein 2A (LMP2A) contributes to cellular transformation by mimicking B cell receptor signaling. LMP2A/MYC double transgenic mice develop splenomegaly and B cell lymphoma much faster than MYC transgenic mice do. In this study, we explored the potential therapeutic efficacy of a novel spleen tyrosine kinase (SYK) and FLT3 inhibitor TAK-659 for development of a treatment option for EBV-associated malignancies. In our transgenic model, TAK-659 treatment totally abrogated splenomegaly and tumor development in LMP2A/MYC mice in both pretumor and tumor cell transfer experiments. TAK-659 treatment killed tumor cells, but not host cells within the spleen and tumors. Furthermore, TAK-659 treatment abrogated metastasis of tumor cells into bone marrow. Our data also show that TAK-659 inhibits SYK phosphorylation and induces apoptosis in LMP2A/MYC tumor cells at low nanomolar concentrations. Therefore, TAK-659 may provide an effective therapeutic option for treatment of LMP2A-positive EBV-associated malignancies and should be explored further in clinical trials.IMPORTANCE The novel SYK and FLT3 inhibitor TAK-659 prevents the enlargement of spleen and tumor development in a mouse model of EBV-associated lymphoma by counteracting the activation of cellular kinase SYK through the viral LMP2A gene by inducing cell death in tumor cells but not in nontumor cells. These findings indicate that TAK-659 may be a very effective nontoxic therapeutic molecule especially for EBV-positive hematologic malignancies.

Small-Molecule Inhibition of PD-1 Transcription Is an Effective Alternative to Antibody Blockade in Cancer Therapy.

The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase, GSK-3α/ß, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small-molecule inhibitors of GSK-3α/ß (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PD-L1-blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Furthermore, the conditional genetic deletion of GSK-3α/ß reduced PD-1 expression on CD8+ T cells and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor-infiltrating lymphocytes, while increasing Tbx21 (T-bet) transcription, and the expression of CD107a+ (LAMP1) and granzyme B (GZMB) on CD8+ T cells. Finally, the adoptive transfer of T cells treated ex vivo with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti-PD-1 pretreatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1-blocking antibodies.Significance: These findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies, offering a next-generation approach in the design of immunotherapeutic approaches for cancer management. Cancer Res; 78(3); 706-17. ©2017 AACR.