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Despite recent advances in tumor treatment, reactive oxygen species (ROS)-mediated therapy, such as photodynamic therapy (PDT) and chemical dynamic therapy (CDT), remains challenging mainly due to hypoxia in tumor microenviroment. Relieving the hypoxia of tumor tissue has been considered as an attractive strategy for enhancing efficacy of ROS-based cancer treatment. Herein, one cascaded platform was developed to overcome tumor hypoxia and synergistically enhance the effect of ROSmediated therapy. This platform is based on cleavable bimetallic metal organic polymers (DOX@Fe/Mn-THPPTK-PEG). As an efficient Fenton-like material, it could not only produce cytotoxic •OH by catalyzing the decomposition of intracellular H2O2, but also generate O2 to alleviate tumor hypoxia. In addition, the DOX-loaded metal organic polymers (MOPs could be disrupted after being exposed to laser irradiation or/and treated with H2O2, and then release the DOX for chemotherapy. Overall, 3 therapies (hypoxia-relieved PDT, photo-enhanced CDT, and ROS-mediated chemotherapy) could be achieved simultaneously by such a smart platform. Furthermore, T1-weighted MRI imaging ability of the MOPs could be greatly improved under H2O2 treatment. Therefore, total four robust functions were realized in a simple platform. These findings demonstrate great clinical potentials of the MOPs for cancer theranostics.

Stress caused by pathogens strongly damages plants. Developing products to control plant disease is an important challenge in sustainable agriculture. In this study, a heat-killed endophytic bacterium (HKEB), Bacillus aryabhattai, is used to induce plant defense against fungal and bacterial pathogens, and the main defense pathways used by the HKEB to activate plant defense are revealed. The HKEB induced high protection against different pathogens through the salicylic and jasmonic acid pathways. We report the presence of gentisic acid in the HKEB for the first time. These results show that HKEBs may be a useful tool for the management of plant diseases.

IMPORTANCE: Plinabulin is a novel, non–granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects. OBJECTIVE: To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non–small lung cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine. Participants were adult patients with non–small cell lung cancer whose cancer had progressed after platinum-based chemotherapy. Data were collected from April 2017 through March 2018 and analyzed from August 2019 through February 2020. INTERVENTIONS: All patients received docetaxel 75 mg/m(2) on day 1 and were randomly assigned to 1 of 3 doses of plinabulin (5, 10, or 20 mg/m(2)) on day 1 or to pegfilgrastim 6 mg on day 2. Patients were treated every 21 days for 4 chemotherapy cycles. MAIN OUTCOMES AND MEASURES: The primary end point was the determination of the recommended phase 3 dose of plinabulin based on the days of severe neutropenia during chemotherapy cycle 1. Daily complete blood cell counts and absolute neutrophil counts were drawn during times of anticipated neutropenia during cycle 1. RESULTS: Of the 55 patients randomized and evaluated, the mean (SD) age was 61.3 (10.2) years, and 38 (69.1%) were men. With each escalation of the plinabulin dose, the incidence of any grade of neutropenia decreased. There were no significant differences in mean (SD) days of severe neutropenia among those treated with pegfilgrastim (0.15 [0.38] days) when dosed at day 2 vs plinabulin 20 mg/m(2) (0.36 [0.93] days; P = .76) when dosed at day 1, and no safety signals were detected. CONCLUSIONS AND RELEVANCE: Single dose-per-cycle plinabulin has a similar neutropenia protection benefit as pegfilgrastim. Plinabulin 40 mg fixed dose, which is pharmacologically equivalent to 20 mg/m(2), will be compared with pegfilgrastim 6 mg in the phase 3 portion of this trial. Noninferior days of severe neutropenia will be the primary end point, and bone pain reduction, thrombocytopenia reduction, and quality of life maintenance will be secondary end points. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03102606

Constitutive activation of Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic event in certain types of human cancer and is associated with poor patient survival. Small molecule signaling inhibitors have improved the clinical outcomes of patients with various cancer types but attempts to target KRAS have been unsuccessful. Plinabulin represents a novel class of agents that inhibit tubulin polymerization with a favorable safety profile in clinical trials. In the present study, the potency of plinabulin to inhibit tubulin polymerization and growth of KRAS-driven cancer cells was characterized. In vivo efficacy of plinabulin was tested in two different mouse models; one being the RCAS/t-va gene transfer system and the other being a xenograft model. In vitro cell culture tubulin polymerization assays were used to complement the mouse models. There was improved survival in a KRAS-driven mouse gene transfer glioma model, but lack of benefit in a similar model, without constitutively active KRAS, which supports the notion of a KRAS-specific effect. This survival benefit was mediated, at least in part, by the ability of plinabulin to inhibit tubulin polymerization and disrupt endosomal recycling. It was proposed a mechanism of compromised endosomal recycling of displaced KRAS through targeting microtubules that yields inhibition of protein kinase B, but not extracellular signal regulated kinase (ERK) signaling, therefore lending rationale to combination treatments of tubulin- and ERK-targeting agents in KRAS-driven cancer.

547 Background: Peg is the current standard of care (SoC) for the prevention of CIN, with a low absolute neutrophil (N) count (ANC) week 1 after chemotherapy (chemo) with normalization in week 2. Breakthrough designation agent from FDA, Plin, a novel, non-G-CSF agent for the prevention of CIN, produces a normal ANC in week 1 of cycle (C) 1 by potentially protecting progenitor cells in bone marrow from chemo assault, and also has anticancer activity (Blayney, St Gallen 2019; ASCO 2019). Here we report data from a pre-specified interim analysis from PROTECTIVE-1 (Study 105; NCT03102606). Methods: Breast cancer (BC), lung (NSCLC) and prostate cancer (HRPC) pts with at least 1 risk factor as per NCCN, received docetaxel (Doc) 75 mg/m2 with either Peg 6mg (n=53) or Plin 40 mg (n=52) over 4 cycles, and had ANC blood draws on Day (D) 1, 2,6,7,8,9,10,15 in C1 (Covance Central Laboratory). Plin was given on D1, as a 30 min IV infusion, 30 min after Doc, and Peg, 24 hrs after Doc. Primary objective was to demonstrate non-inferiority (NI) of SA Plin vs SA Peg for duration of severe neutropenia (DSN) in C1. NI of Plin vs Peg would be declared if the upper limit of 95% confidence interval for the mean DSN difference between Plin and Peg would be

546 Background: PN [absolute neutrophil count (ANC) of 1, 48% FN and 50% Infection2. Peg is standard of care for the prevention of CIN. Peg has a slow onset of action with absolute neutrophil count (ANC) recovery occurring in week 2 of the cycle (C), leaving patients (pts) vulnerable in the first week of the Cycle (C), which >75% of negative clinical consequences occur. Plin, which received breakthrough designation from FDA, is a novel, non-G-CSF small molecule agent for the prevention of CIN and has CIN protection in week 1 (Blayney JAMA Onc 2020), which is the rationale for adding Plin to Peg to achieve superior protection against CIN throughout the entire cycle vs Peg alone (Blayney, St Gallen 2019; ASCO 2019). Methods: Plin is given on Day (D)1 after the last Chemo, has a favorable safety profile, and also has anticancer activity. A phase 3 study evaluating Plin as an anticancer agent (DUBLIN-3; NCT02504489) in NSCLC pts, is fully enrolled, with anti-cancer OS results expected in 2021. In PROTECTIVE-2 (Study 106; NCT0329457), we compare the CIN preventive effects of Plin (on D1) added to Peg (on D2) vs Peg alone. Here we report on PN results. Study 106 is a global multicenter randomized (1:1) double-blind study to evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Plac (Arm 2) in early-stage BC (node positive or node negative with a high risk of recurrence) pts (n=221) with ECOG status 0 or 1, receiving docetaxel (75 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) (TAC). Primary objective was to compare the prevention of severe (Gr 4) neutropenia between Plin+Peg and Peg+Plac. As an exploratory objective in C1, we evaluated PN between the Plin/Peg and Peg/Plac. ANC (Covance Central Laboratory) was assessed in Cycle 1 (C1) on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Results: Shown in the table below. Conclusions: In conclusion, Peg still cannot protect patients with the most severe form of neutropenia, PN, at 46.4% in this study. Adding Plin to Peg offers superior protection for the prevention of profound neutropenia by reducing > 50% of PN, and its clinical sequelae in FN and hospitalization as compared to Peg alone. References: 1. Bodey et al. Ann Intern Med 64(2): 328 (1966); 2. Bodey et al. Cancer 41(4): 1610 (1978). Clinical trial information: NCT03531099. [Table: see text]

533 Background: Peg is standard of care (SoC) for the prevention of CIN. Peg’s mechanism of action leaves patients vulnerable to FN in week 1 of the chemo cycle(C), as the absolute neutrophil count (ANC) does not normalize until week 2. Plin is a first-in-class, non-G-CSF small molecule agent, which received breakthrough designation from FDA in CIN. It prevents CIN by protecting progenitor cells in bone marrow from chemo assault and has normal ANC in week 1 (Blayney JAMA Onc 2020). Phase 2 testing showed the combination of Plin and Peg achieved CIN protection throughout the entire cycle vs Peg alone (Blayney: St Gallen 2019, ASCO 2019). Methods: Plin is given on Day (D)1 after Chemo, has a favorable safety profile, and also has anticancer activity. A separate phase 3 study evaluating Plin as an anticancer agent (DUBLIN-3; NCT02504489) in NSCLC pts is underway, with anti-cancer results in OS expected in 2021. In PROTECTIVE-2 (Study 106; NCT0329457), we added Plin (on D1) to Peg (on D2), testing superiority of the combination for CIN prevention vs Peg alone. Study 106, is a global multicenter randomized (1:1) double-blind study to evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Placebo (Plac) (Arm 2) in preventing Severe Neutropenia (N), (defined as ANC

Ferroptosis is attracting significant attention due to its effectiveness in tumor treatment. The efficiency to produce toxic lipid peroxides (LPOs) at the tumor site plays a key role in ferroptosis. A hybrid PFP@Fe/Cu-SS metal organic framework (MOF) is synthesized and shown to increase intratumoral LPO content through redox reactions generating ·OH. In addition, glutathione (GSH) depletion through disulfide-thiol exchange leads to the inactivation of glutathione peroxide 4 (GPX4), which results in a further increase in LPO content. This MOF exhibits high inhibitory effect on the growth of xenografted Huh-7 tumors in mice. The coadministration of a ferroptosis inhibitor reduces the antitumor effect of the MOF, leading to a restoration of GPX4 activity and an increase in tumor growth. Moreover, the construction of Cu into mesoporous PFP@Fe/Cu-SS not only allows the MOF to be used as a contrast agent for T1 -weighted magnetic resonance imaging, but also renders its photothermal conversion capacity. Thus, near-infrared irradiation is able to induce photothermal therapy and transform the encapsulated liquid perfluoropentane into microbubbles for ultrasound imaging.

In this study, interface-assembled carbonyl reductase (IACR) was prepared and used in the synthesis of S-licarbazepine in a toluene/Tris-HCl biphasic system. The carbonyl reductase (CR) was conjugated with polystyrene to form a surfactant-like structure at the interface of the toluene/Tris-HCl biphasic system. The interface-assembled efficiency of IACR reached 83% when the CR (180 U/mg) and polystyrene concentration were 8 × 10² g/ml and 3.75 × 10³ g/ml, respectively. The conversion reached 95.6% and the enantiometric excess of S-licarbazepine was 98.6% when 3.97 × 10⁶ nmol/l oxcarbazepine was converted by IACR using 6% ethanol as a co-substrate in toluene/Tris-HCl (12.5:10) at 30°C and 43 ×g for 6 h. IACR could be reused efficiently five times.

Developing multifunctional phototheranostics with nanoplatforms offers promising potential for effective eradication of malignant solid tumors. In this study, we develop a multifunctional phototheranostic by combining photothermal therapy (PTT) and photoacoustic therapy (PAT) based on a tumor-targeting nanoagent (DBCO-ZnPc-LP). The nanoagent DBCO-ZnPc-LP was facilely prepared by self-assembling of a single lipophilic near-infrared (NIR) dye zinc(II)-phthalocyanine (ZnPc) with a lipid-poly(ethylene glycol) (LP) and following modified further with dibenzyl cyclootyne (DBCO) for introducing the two-step chemical tumor-targeting strategy based on metabolic glycoengineering and click chemistry. The as-prepared DBCO-ZnPc-LP could not only convert NIR light into heat for effective thermal ablation but also induce a thermal-enhanced ultrasound shockwave boost to trigger substantially localized mechanical damage, achieving synergistic antitumor effect both in vitro and in vivo. Moreover, DBCO-ZnPc-LP can be efficiently delivered into tumor cells and solid tumors after being injected intravenously via the two-step tumor-targeting strategy. By integrating the targeting strategy, photoacoustic imaging, and the synergistic interaction between PTT and PAT, a solid tumor could be accurately positioned and thoroughly eradicated in vivo. Therefore, this multifunctional phototheranostic is believed to play an important role in future oncotherapy by the enhanced synergistic effect of PTT and PAT under the guidance of photoacoustic imaging.

e12030 Background: Peg is used for prevention of CIN. Plin, a novel non-GSF small molecule with anti-cancer activity has equal efficacy against CIN as Peg; Plin does not cause bone pain and mitigates thrombocytopenia and the immune suppressive hematologic profile (Blayney ASCO, ESMO, SITC 2018). Plin has a mechanism of action (MoA) consistent with IL-6 -dependent granulocyte progenitor cell expansion, increased neutrophil demargination and transit from the bone marrow (Suwa, Am J Physiol 2000; Blayney SLB/IEIIS 2018). In single agent (SA) Peg and Plin phase (Ph) 2 data, CIN with Peg occurs in the 1st week (~day (D) 7) post Chemo, and with Plin in the 2nd week (~ D15) post Chemo, presumably due to different MoAs (NCT03102606, NCT03294577). We evaluated whether combining these two agents/MoAs would protect against CIN throughout the entire Chemo cycle (C). Methods: Early stage Breast Cancer Ph 2 patients received high febrile neutropenia (FN) risk TAC (docetaxel, doxorubicin, cyclophosphamide) and either SA standard dose Peg 6 mg (Peg; n=22) or SA Plin (20 mg/m2; n= 15), or Peg 6mg combined with Plin 20 mg/m2 (Peg/Plin; n=16). Peg was given ~24 hrs after TAC, and Plin ~30 min after TAC. Blood draws for ANC were taken daily from predose to Day (D)15, and validated bone pain assessments were done from predose D1 to D8 in C1. Results: On D7 (week 1) of C1, Plin but not Peg maintained mean ANC within normal; P

e12017 Background: Peg is used for CIN prevention. Plin, a novel, non-G-CSF agent is in Phase (Ph) 3 trials for CIN prevention and as an anticancer (NSCLC) agent. In contrast to Peg, Plin does not cause bone pain and maintains absolute neutrophil counts (ANC) within the normal range. Furthermore, Peg, but not Plin, increases Neutrophil-to-Lymphocyte Ratio (NLR) and Lymphocyte-to-Monocyte Ratio (LMR) to immune suppressive values; i.e. NLR>5 and LMR 5 and LMR

4 Background: Peg is a long-acting G-CSF used for prevention of Chemotherapy Induced Neutropenia (CIN). Peg stimulates granulopoiesis in bone marrow and causes a temporary overshoot in absolute neutrophil count (ANC). High NLR is a negative prognostic marker in esophageal, renal cancer and melanoma (Zhou, Nature 2016; Ma, Nature 2018). Decreased Lymphocyte-to Monocyte Ratio (LMR) is another negative prognostic marker (Sierzega; Ann Surg Onc 2017). Peg single agent (SA), but not Plin SA, increased NLR, and decreased LMR (Blayney ESMO 2018) after Docetaxel (Doc). We analyzed whether Plin added to Peg would reverse Peg’s immune-suppressive potential by analyzing NLR and LMR with Peg SA and with Plin+Peg. Methods: NLR and LMR were calculated in cycle 1 of Ph2 study BPI-2358-106 with either Peg SA (6 mg; n = 22), Plin SA (20 mg/m2; n = 15) or Peg 6 mg and Plin 20 mg/m2 (Peg+Plin; n = 21). NLR and LMR were calculated after day (D) 8, since Peg increases leukocytes after D8, and were performed through D15. Plin was given D1 of chemotherapy (Doc, Doxorubicin, Cyclophosphamide) in Breast Cancer patients (pts); Peg was given D2. Results: The percentage (%) of pts with grade 4 neutropenia was lowered from 59% with Peg SA to 38% by adding Plin to Peg. The % of pts with an ANC exceeding upper limit of normal (8x10E9/L) was lowered from 50% with Peg SA to 31%, by adding Plin to Peg. The table summarizes the % of patients with NLR ≥ 5 and LMR ≤3.2 over time with Peg SA, Plin SA and Peg+Plin. Peg-induced immune-suppressive NLR and or LMR levels occurred in 50% or more of pts, and in a significantly lower % of pts by adding Plin to Peg (p < 0.0076 for NLR and p < 0.073 for LMR on D13). Conclusions: Peg, but not Plin generates a potentially deleterious NLR and LMR which was significantly reversed by the addition of Plin to Peg. The Peg+Plin combination improves efficacy for CIN and reversed Peg’s potentially immune-suppressive NLR and MLR phenotype. Clinical trial information: NCT03294577. [Table: see text]

2528Background: Plin has clinical anticancer activity in combination with Tax (Mohanlal ASCO-SITC 2017,18). Plin prevented Tax-induced neutropenia in a post-hoc analysis of a φ 2 trial (Blayney ASH...

Kras mutations, particularly at codons 12 and 13, are reported to occur in up to one-third of human cancer cells and are considered to be undruggable targets (Stoize et al, 2015). These mutations are especially prevalent in NSCLC and CRC. Plinabulin is a new chemical entity in Phase 3, with a multi-faceted mechanism of action, including anti-angiogenesis, inhibition of tubulin polymerization and activation of JNK, which is downstream of the Kras pathway. The combination of these vascular mechanisms together with activity downstream from Kras, suggests that plinabulin could express anti-tumor activity in the presence of Kras mutations. The present report summarizes the findings with plinabulin on tumors with Kras mutations (p.12V, p.12D, p.D153V, p.G12A, p.G12C, p.G12D, p.G12V or p.G13D) in vitro and in vivo. In vitro, plinabulin was very potent (IC50 7-33 nM) as a cytotoxic agent against CRC cell lines containing a Kras mutation at p.G13D (LoVo, HCT-15, HCT116) or a BRAF + P53 mutation (HT-29) and against multiple myeloma cell lines (Singh et al, Blood, 2010) with either Nras or p.G12A mutations (IC50 In vivo, plinabulin was tested as a single agent and in combination with SOC in the CRC Kras mutation murine models LoVo and HCT-15 and the P53/Braf mutant model HT-29, the NSCLC Kras mutation model A549, the multiple myeloma Kras mutation model MM.1S and the breast Kras mutation model MDA-MB-231. As a single agent plinabulin was at most moderately active in these models, with the greatest activity seen in the LoVo, HCT-15, and MDA-MB-231 models (TGI 21-43%); the exception was a marked single agent activity observed in the MM.1S model. However, in all cases plinabulin significantly increased the anti-tumor activity of the standard of care agents (TGI 59-84%, with several CRs and increased tolerability as compared to SOC alone). In summary, plinabulin exhibits a potent anti-tumor activity either in vitro, or in vivo as a single agent or in combination with SOC agents. This activity is observed across several tumor types and mutations, but the spectrum of activity does not extend across all tumor types (e.g. inactive in vivo in Kras mutations for pancreatic cancer or melanoma). These findings are encouraging in terms of clinical studies in Kras mutations in MM, NSCLC, CRC and breast cancers. Citation Format: George Kenneth Lloyd, Lihua Du, Gloria Lee, Jessica Dalsing-Hernandez, Kari Kotlarczyk, Paul Gonzales, Steffan Nawrocki, Jennifer Carew, Lan Huang. Activity of plinabulin in tumor models with Kras mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A184.