The escalating environmental concerns regarding plastic waste necessitate innovative strategies for waste management and resource utilization. This study presents a novel approach for synthesizing high surface area activated carbon (AC) through a single-step process, using polyethylene terephthalate (PET) plastic waste as the precursor and potassium hydroxide (KOH) as the activating agent. The optimal activation conditions were established using a weight ratio of 1:1 of PET to KOH and annealing for 15 min at 700 °C. The conversion efficiency of PET plastic trash into AC exceeded 20

Tables S1-S3, Figures S1-S5

Abstract The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5′-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant in vivo efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in in vivo xenograft models. Mutation of PTEN is associated with reduced apoptosis in vitro and diminished efficacy in vivo in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.

The main aim of this study was to synthesize an innovative magnetic CuFe2O4@porphyrin nanofiber hybrid material via one-step re-precipitation self-assembly of freebase-tetracarboxy-porphyrin (TCPP), in the presence of CuFe2O4 nanoparticles. The resultant hybrid materials were thoroughly characterized using scanning electron microscopy, energy-dispersive X-ray mapping, X-ray diffractometry, and Fourier-transform infrared, and UV-vis spectroscopy. Results showed well-integration of CuFe2O4 nanoparticles into TCPP nanofiber network, with the average size of CuFe2O4 being less than 100 nm and diameter and length of TCPP aggregate being approximately 20 nm and several mu m, respectively. The as-prepared hybrid material possessed strong magnetic properties with a saturated magnetization value of approximately 25 emu/g. This photocatalyst was highly efficient in the removal of rhodamine B (RhB) dye, with the rate constant reaching 2.1 x 10(-2) min(-1). This paper describes in detail a plausible photocatalytic mechanism for RhB removal by CuFe2O4@porphyrin nanofiber hybrid material.

Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates cap-dependent protein synthesis. The flavagline class of natural products (i.e., rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation-incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity. A focused effort was undertaken utilizing a ligand-based design strategy to identify a chemotype with optimized physicochemical properties. Also, detailed mechanistic studies were undertaken to further elucidate mRNA sequence selectivity, key regulated target genes, and the associated antitumor phenotype. This work led to the design of eFT226 (Zotatifin), a compound with excellent physicochemical properties and significant antitumor activity that supports clinical development.

Dysregulated messenger RNA (mRNA) translation drives the pathogenesis of multiple hematological malignancies. In lymphoma this includes the upregulation of key driver oncogenes and anti-apoptotic proteins (e.g., MYC, CCND1/3, BCL2 and MCL1) that contain a highly structured 5’-untranslated region (UTR) in their mRNA requiring enhanced eIF4A helicase activity for translation. eIF4A is a component of the eIF4F translation initiation complex and catalyzes the ATP-dependent unwinding of RNA duplexes and facilitates 43S ribosome scanning within the 5’-UTR. The activation of oncogenic signaling pathways, including RAS and PI3K, enhance eIF4A activity through phosphorylation of eIF4B, eIF4G and PDCD4 which facilitates formation of eIF4F and full activation of eIF4A. The PI3K/AKT/mTOR pathway is frequently activated in lymphoma, promoting the translation of oncogenes with complex 5’-UTRs that are required for tumor cell proliferation, survival and metastasis. eFT226 is a potent and sequence selective eIF4A1 inhibitor that promotes eIF4A1 binding to specific 5’-UTR polypurine and/or G-quadraplex recognition motifs leading to a selective block in ribosome mRNA scanning. The sequence dependency of eFT226 translational inhibition was evaluated in cell-based reporter assays demonstrating >100-fold greater sensitivity for reporter constructs containing a polypurine motif in the 5’-UTR (IC50 ~2 nM). Direct binding studies also confirmed the formation of a stable ternary complex with increased drug residence time between eFT226, eIF4A1 and RNA oligonucleotides containing polypurine motifs. The ability of eFT226 to inhibit MYC or MCL1 expression was found to be dependent on the presence of their respective 5’-UTR supporting a translational regulation mechanism dependent on recognition elements within the 5’-UTR. eFT226 shows potent anti-proliferative activity (GI50 < 15 nM) against a panel of B-cell lymphoma cell lines. Treatment with eFT226 leads to coordinated inhibition of MYC, CCND1/3, BCL2 or MCL1 protein expression resulting in significant anti-tumor activity. eFT226 has good pharmacokinetic properties and exhibits significant in vivo activity across a panel of diffuse large B cell lymphoma (DLBCL), and Burkitt lymphoma tumor models with ≤1 mg/kg/week IV administration. Further evaluation of predictive markers of sensitivity or resistance has shown that tumors with mTOR mediated activation of eIF4A are most sensitive to eFT226. In addition, tumors with PTEN mutations do not exhibit activated eIF4A and are generally resistant to induction of apoptosis by eFT226, resulting in reduced in vivo efficacy. The association of eFT226 activity with PI3K/mTOR pathway activation and mutational status provides a means to identify patient subsets during clinical development. Clinical trials in patients with lymphoma and other malignancies are planned. Citation Format: Peggy A. Thompson, Boreth Eam, Nathan P. Young, Sarah Fish, Joan Chen, Maria Barrera, Haleigh Howard, Eric Sung, Ana Parra, Jocelyn Staunton, Gary G. Chiang, Christopher J. Wegerski, Andres Nevarez, Jeff Clarine, Samuel Sperry, Alan Xiang, Chinh Tran, Christian Nilewski, Garrick K. Packard, Theodore Michels, Paul A. Sprengeler, Justin T. Ernst, Siegfried H. Reich, Kevin R. Webster. eFT226, a potent and selective inhibitor of eIF4A, is efficacious in preclinical models of lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2698.

Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.

Direct-acting antiviral inhibitors have revolutionized the treatment of hepatitis C virus (HCV) infected patients. Herein is described the discovery of velpatasvir (VEL, GS-5816), a potent pan-genotypic HCV NS5A inhibitor that is a component of the only approved pan-genotypic single-tablet regimens (STRs) for the cure of HCV infection. VEL combined with sofosbuvir (SOF) is Epclusa®, an STR with 98% cure-rates for genotype 1-6 HCV infected patients. Addition of the pan-genotypic HCV NS3/4A protease inhibitor voxilaprevir to SOF/VEL is the STR Vosevi®, which affords 97% cure-rates for genotype 1-6 HCV patients who have previously failed another treatment regimen.

Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

Abstract eFT226: A Selective and Highly Potent Inhibitor of Eukaryotic Initiation Factor 4A (eIF4A), a Novel Approach for the Treatment of Cancer Siegfried H Reich, Peggy A Thompson, Justin T Ernst, Boreth Eam, Nathan P Young, Sarah Fish, Joan Chen, Maria Barrera, Haleigh Howard, Ana Parra, Eric Sung, Jocelyn Staunton, Ivy NJ Hung, Gregory S Parker, Gary G Chiang, Christopher J Wegerski, Andres Nevarez, Jeff Clarine, Samuel Sperry, Alan Xiang, Chinh Tran, Christian Nilewski, Garrick K Packard, Theodore Michels, Paul A Sprengeler, and Kevin R Webster Effector Therapeutics, San Diego, CA Oncoprotein expression is tightly controlled at the level of RNA translation which is largely regulated by the eukaryotic translation initiation factor 4F (eIF4F). eIF4A1, a component of the eIF4F complex, catalyzes the ATP dependent unwinding of RNA duplexes and facilitates 43S ribosome complex scanning within the 5'-untranslated region (UTR). eIF4A1 is required for efficient translation of key oncogenes that contain complex secondary structures within the 5'-UTR. eFT226 is a novel, potent and selective eIF4A small molecule inhibitor with excellent physicochemical and pharmaceutical properties. The design of eFT226 involved ab initio ligand-based methods coupled with small molecule crystal structure analysis. eFT226 inhibits eIF4A1 through a reversible sequence-selective enhancement of eIF4A1 binding to mRNA with specific polypurine motifs within the 5'-UTR. The formation of a stable ternary complex [eIF4A1/eFT226/mRNA] with specific sequence recognition motifs leads to a block in ribosome scanning of select mRNAs. Treatment of lymphoma, AML, breast, colorectal, lung and hepatocellular tumor cell lines with eFT226 led to a dose dependent translational down regulation (IC50 of ~5-20 nM) of key oncogenes that drive tumor cell survival and proliferation (i.e., c-MYC, CCND1, BCL2 and MCL-1). Oncogene down regulation results in potent inhibition of cellular proliferation (GI50 of ~2-30 nM) across a panel of tumor cell lines. Enhanced anti-tumor sensitivity and a rapid induction of apoptosis was observed in hematological cell lines including lymphoma and AML. Inhibition of tumor cell proliferation and survival with eFT226 treatment results in significant antitumor activity in vivo in multiple human tumor models of DLBCL, Burkitt's lymphoma, acute myeloid leukemia (AML), and solid tumors following ≤ 1 mg/kg/week IV administration. eFT226 regulates the protein expression of multiple metabolic markers (i.e. c-MYC, HK2, TXNIP and GLUT1) that result in inhibition of tumor glucose uptake supporting the use of 18F-FDG-PET imaging as a measure of eFT226 target engagement in the clinic. These data demonstrate that eFT226 is a sequence-selective translational repressor of key oncogenic drivers that are essential for tumor cell proliferation and survival and support the clinical development of eFT226 in cancer patients. Citation Format: Siegfried H. Reich, Peggy A. Thompson, Justin T. Ernst, Boreth Eam, Nathan P. Young, Sarah Fish, Joan Chen, Maria Barrera, Haleigh Howard, Ana Parra, Eric Sung, Jocelyn Staunton, Ivy Nj Hung, Gregory S. Parker, Gary G. Chiang, Christopher J. Wegerski, Andres Nevarez, Jeff Clarine, Samuel Sperry, Alan Xiang, Chinh Tran, Christian Nilewski, Garrick K. Packard, Theodore Michels, Paul A. Sprengeler, Kevin R. Webster. eFT226: A selective and highly potent inhibitor of eukaryotic initiation factor 4A (eIF4A), a novel approach for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr DDT02-05.

Purpose: This study was designed to evaluate the potential of eFT508 to selectively regulate key immune signaling pathways and enhance anti-tumor immunity as a monotherapy or in combination with checkpoint blockade in immunocompetent syngeneic cancer models. Methods: eFT508 and its effect on mRNA translation, effector protein production, immune cell signaling and tumor infiltrating lymphocytes was evaluated in vitro using normal human T cells and in vivo utilizing immunocompetent syngeneic models. The mechanism of translational regulation of specific target genes was further evaluated in these model systems. Results: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple solid tumors and hematological malignancies. MNK1 and MNK2 integrate signals from several oncogenic and immune signaling pathways (including RAS, p38 and toll-like receptors) by phosphorylating eukaryotic initiation factor 4E (eIF4E) and other key effector proteins including hnRNPA1 and PSF. Phosphorylation of these RNA-binding proteins by MNK1 and MNK2 selectively regulates the stability and translation of a subset of cellular mRNA that control tumor/stromal cell signaling and the tumor microenvironment. eFT508 inhibits both MNK1 and MNK2 through a reversible, ATP-competitive mechanism of action with an IC50 of 2 and 1 nM against MNK1 and MNK2 respectively. eFT508 is highly selective (≥100-fold) for MNK1 and MNK2 relative to over 400 other protein and lipid kinases. Ribosome profiling has demonstrated that inhibition of MNK1 and MNK2 by eFT508 selectively regulates the translational efficiency and mRNA stability of a subset of genes that include inflammatory cytokines/chemokines, regulators of reactive oxygen species (ROS), and effectors of anti-tumor immune response. Given the importance of both RAS signaling and translational control to immune cell function the immunological effect of eFT508 was evaluated in both normal human T cells in vitro and immunocompetent syngeneic cancer models in vivo. eFT508 treatment of normal donor T cells has no deleterious effect on CD3/CD28 activation of IL-2 production, T cell proliferation or on T cell viability. However, eFT508 selectively down regulates the induction of IL-10 and specific immune checkpoint mechanisms. The effect of eFT508 on IL-10 protein production corresponded with reduced mRNA stability. The in vivo antitumor effect of eFT508 was assessed in the CT26 BALB/C syngeneic tumor model. CT26 mouse tumor cell proliferation and survival are insensitive to eFT508 in vitro. In vivo, daily oral treatment with 1 mg/kg eFT508 results in significant anti-tumor activity and establishment of immune memory. In addition, combination of daily oral treatment of 1 mg/kg eFT508 with either anti-PD-1 or anti-PD-L1 monoclonal antibodies increases the number of responder animals and results in synergistic activity that corresponds to the modulation of tumor infiltrating lymphocyte populations. Conclusions: eFT508 is a selective, orally bioavailable small molecule inhibitor of MNK1 and MNK2 that can decrease the production of key immune checkpoint regulators and immunosuppressive cytokines. This novel mechanism of action triggers anti-tumor immune response in immunocompetent syngeneic animal models as a monotherapy and in combination with established immune checkpoint antibodies. eFT508 is currently under evaluation in two phase I clinical trials for patients with advanced solid tumors and patients with advanced lymphoma respectively. These findings support further clinical evaluation of eFT508 in combination with checkpoint blockade. This abstract is also being presented as Poster B29. Citation Format: Kevin R. Webster, Vikas K. Goel, Jocelyn Staunton, Ivy NJ Hung, Gregory S. Parker, Craig R. Stumpf, Jolene Molter, Gary G. Chiang, Christopher J. Wegerski, Samuel Sperry, Joan Chen, Vera Huang, Peggy A. Thompson, Chinh Tran, Justin T. Ernst, Stephen E. Webber, Paul A. Sprengeler, Siegfried H. Reich. eFT508: An oral, potent and highly selective inhibitor of MNK1 and MNK2, promotes anti-tumor immunity as a monotherapy and in combination with immune checkpoint blockade. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr PR11.

Translational control of oncoprotein expression has been implicated in the pathogenesis of multiple solid tumors and hematological malignancies. Protein synthesis is tightly regulated largely at the initiation stage through the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, an RNA helicase, is an essential component of the translation initiation complex and selectively regulates a subset of mRNAs based on the sequence and structure of the 5‘-untranslated region (UTR). B-cell receptor signaling activates eIF4A resulting in the selective upregulation of oncogenes involved in cell proliferation, survival and metastasis. B-cell malignancies are often associated with dysregulation of oncogenes or anti-apoptotic proteins (e.g., c-MYC, CCND1/3, BCL2 and MCL-1) that contain structured 5‘-UTRs and require enhanced eIF4A activity for translation.

Abstract Purpose: This study was designed to evaluate the potential of eFT508 to selectively regulate key immune signaling pathways and enhance anti-tumor immunity as a monotherapy or in combination with checkpoint blockade in immunocompetent syngeneic cancer models. Methods: eFT508 and its effect on mRNA translation, effector protein production, immune cell signaling and tumor infiltrating lymphocytes was evaluated in vitro using normal human T cells and in vivo utilizing immunocompetent syngeneic models. The mechanism of translational regulation of specific target genes was further evaluated in these model systems. Results: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple solid tumors and hematological malignancies. MNK1 and MNK2 integrate signals from several oncogenic and immune signaling pathways (including RAS, p38 and toll-like receptors) by phosphorylating eukaryotic initiation factor 4E (eIF4E) and other key effector proteins including hnRNPA1 and PSF. Phosphorylation of these RNA-binding proteins by MNK1 and MNK2 selectively regulates the stability and translation of a subset of cellular mRNA that control tumor/stromal cell signaling and the tumor microenvironment. eFT508 inhibits both MNK1 and MNK2 through a reversible, ATP-competitive mechanism of action with an IC50 of 2 and 1 nM against MNK1 and MNK2 respectively. eFT508 is highly selective (≥100-fold) for MNK1 and MNK2 relative to over 400 other protein and lipid kinases. Ribosome profiling has demonstrated that inhibition of MNK1 and MNK2 by eFT508 selectively regulates the translational efficiency and mRNA stability of a subset of genes that include inflammatory cytokines/chemokines, regulators of reactive oxygen species (ROS), and effectors of anti-tumor immune response. Given the importance of both RAS signaling and translational control to immune cell function the immunological effect of eFT508 was evaluated in both normal human T cells in vitro and immunocompetent syngeneic cancer models in vivo. eFT508 treatment of normal donor T cells has no deleterious effect on CD3/CD28 activation of IL-2 production, T cell proliferation or on T cell viability. However, eFT508 selectively down regulates the induction of IL-10 and specific immune checkpoint mechanisms. The effect of eFT508 on IL-10 protein production corresponded with reduced mRNA stability. The in vivo antitumor effect of eFT508 was assessed in the CT26 BALB/C syngeneic tumor model. CT26 mouse tumor cell proliferation and survival are insensitive to eFT508 in vitro. In vivo, daily oral treatment with 1 mg/kg eFT508 results in significant anti-tumor activity and establishment of immune memory. In addition, combination of daily oral treatment of 1 mg/kg eFT508 with either anti-PD-1 or anti-PD-L1 monoclonal antibodies increases the number of responder animals and results in synergistic activity that corresponds to the modulation of tumor infiltrating lymphocyte populations. Conclusions: eFT508 is a selective, orally bioavailable small molecule inhibitor of MNK1 and MNK2 that can decrease the production of key immune checkpoint regulators and immunosuppressive cytokines. This novel mechanism of action triggers anti-tumor immune response in immunocompetent syngeneic animal models as a monotherapy and in combination with established immune checkpoint antibodies. eFT508 is currently under evaluation in two phase I clinical trials for patients with advanced solid tumors and patients with advanced lymphoma respectively. These findings support further clinical evaluation of eFT508 in combination with checkpoint blockade. This abstract is also being presented as Poster B29. Citation Format: Kevin R. Webster, Vikas K. Goel, Jocelyn Staunton, Ivy NJ Hung, Gregory S. Parker, Craig R. Stumpf, Jolene Molter, Gary G. Chiang, Christopher J. Wegerski, Samuel Sperry, Joan Chen, Vera Huang, Peggy A. Thompson, Chinh Tran, Justin T. Ernst, Stephen E. Webber, Paul A. Sprengeler, Siegfried H. Reich. eFT508: An oral, potent and highly selective inhibitor of MNK1 and MNK2, promotes anti-tumor immunity as a monotherapy and in combination with immune checkpoint blockade. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr PR11.

Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple solid tumors and hematological malignancies. MNK1 and MNK2 integrate signals from several oncogenic and immune signaling pathways (including RAS, Toll-like receptors and T cell receptor) by phosphorylating eukaryotic initiation factor 4E (eIF4E) and other key effector proteins including hnRNPA1 and PSF. Phosphorylation of these RNA-binding proteins by MNK1 and MNK2 selectively regulates the stability and translation of a subset of cellular mRNA that control tumor/stromal cell signaling, the tumor microenvironment and immune cell function. eFT508 is a potent and highly selective inhibitor of both MNK1 and MNK2. Ribosome profiling has demonstrated that inhibition of MNK1 and MNK2 by eFT508 selectively regulates the translational efficiency and mRNA stability of a subset of genes that include inflammatory cytokines/chemokines, regulators of stress response, and effectors of anti-tumor immune response. Given the importance of MAPK signaling and translational control to immune cell activation and differentiation, the immunological effect of eFT508 was further evaluated in both normal human immune cells in vitro and immunocompetent syngeneic cancer models in vivo. eFT508 treatment of normal donor T cells has no deleterious effect on αCD3/αCD28 stimulated IL-2 production, T cell proliferation or T cell viability. However, eFT508 selectively down regulates the induction of IL-10 and specific immune checkpoint receptors, including PD-1 and LAG3. Further evaluation of the mechanism of translational regulation has shown LAG3 mRNA contains specific sequence elements in the 5’-untranslated region (UTR) that confer sensitivity to eFT508. In addition, IL-10 mRNA is destabilized upon treatment with eFT508 leading to significant inhibition of IL-10 production in activated T cells. Furthermore, eFT508 treatment results in upregulation of MHC class II molecules on tumor cells, macrophage and dendritic cells through an IL-10/MARCH1 dependent mechanism. The in vivo antitumor effect of eFT508 was assessed in the CT26 BALB/C syngeneic tumor model. CT26 mouse tumor cell proliferation and survival are insensitive to eFT508 in vitro. In vivo, daily oral treatment with 1 mg/kg eFT508 results in significant anti-tumor activity, modulation of tumor infiltrating lymphocytes and establishment of immune memory. In addition, combination of eFT508 with either anti-PD-1 or anti-PD-L1 monoclonal antibodies results in marked efficacy, significantly increasing the percentage of responder animals. eFT508 is currently under evaluation in two phase I/II clinical trials for patients with advanced solid tumors and patients with advanced lymphoma respectively. These findings support further clinical evaluation of eFT508 in combination with checkpoint blockade. Citation Format: Kevin R. Webster, Vikas K. Goel, Jocelyn Staunton, Craig R. Stumpf, Rajesh Sharma, Ivy N. Hung, Gregory S. Parker, Jolene Molter, Gary G. Chiang, Christopher J. Wegerski, Samuel Sperry, Vera Huang, Joan Chen, Peggy A. Thompson, Chinh Tran, Justin T. Ernst, Paul A. Sprengeler, Siegfried H. Reich. eFT508, a potent and highly selective inhibitor of MNK1/2 regulates immune checkpoint and cytokine expression promoting anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 596. doi:10.1158/1538-7445.AM2017-596