Objective. The study was undertaken to evaluate the antidepressant activity of ethanolic extract of Ferula asafoetida oleo gum resins. Materials and Methods. Five groups of rats (180-200g) and mice (20-30g) of both genders, each group comprising six animals, were used (i.e., normal, positive control, standard, FAEE 200mg/kg, and FAEE 400mg/kg treated groups). Forced swimming test (FST), Tail suspension test (TST), Potentiation of Norepinephrine-Induced Toxicity (PNEIT), Haloperidol-Induced Catalepsy (HIC), and Reserpine-Induced Hypothermia (RIH), were used as the validate models of depression in rodents. The study was confirmed by brain monoamines estimation (i.e. Dopamine, Norepinephrine and 5-HT), MAO levels and invivo antioxidant studies (CAT and SOD). Results. FAEE treated animals showed a significant and dose dependent effect on a decrease in immobility time in FST, TST, and decrease in catalepsy time in HIC. FAEE and imipramine (15mg/kg) showed a significant increase in body temperature in RIH, and also showed a potent lethality in PNEIT. FAEE treated animals showed a significant increase in the levels of brain monoamines, in vivo antioxidants, and a significant decrease in MAO levels. Conclusion. Results of present study indicate that FAEE has potent antidepressant-like activity, and this effect may be due to the anti-oxidant property of Ferulic acid and umbelliferone, or may be due to neuroprotective activity of other major phytoconstituents, e.g. flavonoids, phenolic acids and polysulfide compounds. To identify the particular compound responsible for the antidepressant-like activity required further molecular level studies.

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Objective. The study were undertaken to evaluate anti-fibrotic activity of ethanolic extract of Nelumbo nucifera seed (NNSEE) against doxorubicin and Unilateral Ureter Obstruction-induced renal fibrosis. Materials and method. Animals were divided into five groups with six animals in each group, i.e. Normal, Positive control, Standard (Pirfenidone 200mg/kg), Test-I (NNSEE 200mg/kg), and Test-II (NNSEE 400mg/kg). Renal fibrosis was developed by doxorubicin and UUO-induced methods. After induction of renal fibrosis, profibrotic responses in biochemical parameters were observed, e.g. BUN, serum creatinine levels were elevated, while total protein and GFR levels decreased. Antioxidant (SOD and CAT) levels are also attenuates and hyalinized glomeruli cells, damage to tubular cells were noted in histopathology, which are all responsible for the development of renal fibrosis. Results. The result showed that the anti-fibrotic activity of NNSEE at a dose of 200 and 400mg/kg b.wt was comparable with the standard treatment 200mg/kg b.wt of pirfenidone (anti-fibrotic drug). These data supplemented with histopathological studies of rat kidney sections. NNSEE had reversed all the manifestation of renal fibrosis. Conclusion. Results of the study indicate that the NNSEE has potent anti-fibrotic activity, as well as antioxidant property, in dose dependent manner that may be due to the presence of major phytochemical constituents such as alkaloids, polyphenols.

BackgroundMALT1 protease is a promising target in aggressive lymphomas1, and two phase 1 clinical trials in hematological cancers are ongoing (NCT03900598, NCT04876092). More recently, MALT1 protease inhibition was also shown to reprogram regulatory T cells (Treg) in solid tumors, causing them to lose their immunosuppressive function and secrete interferon-gamma (IFN).2 Changes in Treg metabolism in the tumor microenvironment (TME) may account for their destabilization and selective susceptibility to reprogramming in tumor tissue.3 4 5 While strong MALT1 inhibition can cause Treg depletion in blood and induce autoimmune toxicity,6 a therapeutic window for a differentiated MALT1 inhibitor that reprograms destabilized Treg in the TME before affecting Treg in healthy tissue may exist.2 MPT-0118 is an orally dosed MALT1 inhibitor developed to reprogram destabilized Treg in the TME without causing autoimmune symptoms. A Phase 1/1b dose-escalation and cohort-expansion clinical trial evaluating MPT-0118 is underway (NCT04859777).MethodsHuman xenograft models of lymphoma were used to assess the direct activity of MPT-0118 on MALT1-dependent (but not not MALT1-independent) hematologic tumors. Effects of MPT-0118 on solid tumors were determined in syngeneic cancer models. Human and mouse tumor tissues were evaluated for Treg reprogramming by in situ hybridization or flow cytometry. Patient-derived organotypic tumor spheroids were assessed for immune-mediated cell killing. Studies in rodents and dogs assessed pharmacokinetics (PK) and safety.ResultsMPT-0118 was selective and effective in preventing growth of aggressive MALT1 protease-dependent lymphomas. Beyond direct activity on hematologic malignancies, MPT-0118 also increased anti-tumor immune responses as single-agent or in combination with anti-PD-1 in syngeneic tumor models that are otherwise unresponsive to immune checkpoint blockade (ICB). MPT-0118-treated syngeneic tumors showed an increase in IFN-secreting Treg, associated with decelerated tumor growth. PK studies reveal that MPT-0118 has a high volume of distribution, and effective inhibitor concentrations are reached in the murine tumors upon oral dosing. The drug candidate caused tumor-associated Treg to produce IFN without changing the frequency of Treg circulating in the blood. Ex vivo, MPT-0118 induced Treg reprogramming in tumors resected from patients with colorectal and endometrial cancers and cell killing in spheroids derived from patients with colorectal cancer.ConclusionsThe MALT1 inhibitor MPT-0118 is a clinical candidate for treating MALT1-expressing lymphomas and Treg-infiltrated solid tumors. MPT-0118 exploits the therapeutic opportunity presented by destabilized Treg in the TME. Treg reprogramming represents a novel strategy with the potential to improve responses to ICB therapy in a broad range of solid tumors.ReferencesNagel D, Spranger S, Vincendeau M, Grau M, Raffegerst S, Kloo B, Hlahla D, Neuenschwander M, Peter von Kries J, Hadian K, Dörken B, Lenz P, Lenz G, Schendel DJ, Krappmann D. Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell 2012 December 11;22(6):825–37.Di Pilato M, Kim EY, Cadilha BL, Prüßmann JN, Nasrallah MN, Seruggia D, Usmani SM, Misale S, Zappulli V, Carrizosa E, Mani V, Ligorio M, Warner RD, Medoff BD, Marangoni F, Villani AC, Mempel TR. Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy. Nature 2019 June;570(7759):112–116.Lim SA, Wei J, Nguyen TM, Shi H, Su W, Palacios G, Dhungana Y, Chapman NM, Long L, Saravia J, Vogel P, Chi H. Lipid signalling enforces functional specialization of Treg cells in tumours. Nature 2021 March;591(7849):306–311.Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, Watson MJ, Leftin A, Maniyar R, Verma S, Lubin M, Ko M, Mane MM, Zhong H, Liu C, Ghosh A, Abu-Akeel M, Ackerstaff E, Koutcher JA, Ho PC, Delgoffe GM, Blasberg R, Wolchok JD, Merghoub T. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature 2021 March;591(7851):652–658.Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, Shuai Y, Normolle DP, Kirkwood JM, Ferris RL, Delgoffe GM, Bruno TC, Workman CJ, Vignali DAA. Interferon-γ drives Treg fragility to promote anti-tumor immunity. Cell 2017 June 1;169(6):1130–1141.e11.Martin K, Junker U, Tritto E, Sutter E, Rubic-Schneider T, Morgan H, Niwa S, Li J, Schlapbach A, Walker D, Bigaud M, Beerli C, Littlewood-Evans A, Rudolph B, Laisney M, Ledieu D, Beltz K, Quancard J, Bornancin F, Zamurovic Ribrioux N, Calzascia T. Pharmacological inhibition of MALT1 protease leads to a progressive IPEX-Like pathology. Front Immunol 2020 April 30;11:745.

Background Despite transforming effects of immune checkpoint blockade (ICB) therapy, objective response rates are low for most solid tumors. In the tumor microenvironment (TME), regulatory T cells are functionally unstable, likely due to changes in Treg metabolism seen in the tumor milieu. Destabilized Treg are susceptible to reprogramming wherein they can be induced to lose their immunosuppressive function and to secrete interferon-gamma (IFN-g). Thus, Treg reprogramming offers a novel strategy to sensitize unresponsive tumors to ICB. Notably, blockade of MALT1 protease induces Treg reprogramming in the TME but without affecting Treg in healthy tissue. MPT-0118, an orally dosed MALT1 inhibitor, was developed to reprogram Treg in the TME and is currently being assessed in patients with advanced tumors. Approach Treatments included MPT-0118 and anti-PD-1. In vivo studies in mice assessed anti-tumor effects using D4M.3A, B16F10, and MC38 syngeneic tumors. Human and mouse tumor tissues were evaluated for Treg reprogramming by in situ hybridization or flow cytometry. Studies in rats and dogs assessed pharmacokinetics and safety. Results MPT-0118 demonstrated dose-dependent in vivo anti-tumor activity. Consistent with the hypothesis that Treg reprogramming supports anti-tumor immunity by initiating IFN-g-driven tumor inflammation, the effect was strongest in combination with anti-PD-1 and in models that are not responsive to ICB alone. MPT-0118-treated tumors showed an increase in IFN-g-secreting Treg, associated with decelerated tumor growth. Ex vivo, MPT-0118 induced Treg reprogramming in tumors resected from patients with colorectal and endometrial cancers. While MPT-0118 caused Treg to produce IFN-g, no changes in the frequencies of Treg circulating in blood were detected in rats. Modeling of the human effective dose and toxicology studies demonstrate a >2x therapeutic window in patients. Conclusions MPT-0118 Treg reprogramming represents a novel strategy with the potential to improve responses to ICB therapy in solid tumors. A Phase 1/1b dose-escalation and cohort-expansion clinical trial evaluating MPT-0018 is underway. Citation Format: Peter Keller, Irina Mazo, Yun Gao, Vijayapal Reddy, Francisco Caballero, Sam Kazer, Dannah Miller, Roberto Gianani, James E. Marvin, Bret Stephens, Gregory L. Beatty, Ulrich H. von Andrian, Thorsten R. Mempel. Reprogramming regulatory T cells (Treg) using a MALT1 inhibitor for cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P106.