Novartis inks $750 million deal with Aduro Biotech By Steven Ross Johnson| March 30, 2015 Pharmaceutical maker Novartis is broadening its footprint in the cancer drug treatment market. The Swiss company announced plans Monday to enter a multiyear partnership with Berkeley, Calif.-based Aduro Biotech, valued at $750 million, to develop next-generation immunotherapies against the disease. The terms of the agreement will see Novartis pay $200 million upfront to Aduro with an additional $500 million to be paid if development milestones are met. In addition, Novartis has agreed to make a $25 million investment in Aduro for a 2.7% equity share in the firm, with a promise to pay an additional $25 million investment at a later date. The collaboration will focus on the development of treatments designed to activate the Stimulator of Interferon Genes, or STING, receptors, which have been found to generate an effective immune response against infectious organisms."Immunotherapy is one of the exciting frontiers in oncology today," Mark Fishman, president of the Novartis Institutes for BioMedical Research, said in a released statement. "STING agonists have the potential to fully activate the immune system to attack a broader range of tumors." Under the agreement, Aduro will lead commercialization activities and will book sales in the U.S. for any products developed, with Novartis leading commercialization activities internationally. The companies will share profits, if any, in the U.S., Japan and major European countries, with Novartis paying Aduro royalties for any sales in the rest of the world."We are extremely pleased to enter into this relationship with Novartis as their strong commitment and spirit of collaboration was evident early in our conversations," Stephen Isaacs, chairman, president and CEO of Aduro, said in a released statement. In March, Novartis won FDA approval to market its cancer drug Zarxio, making it the first "biosimilar" to be sold in the U.S. The drug was designed as a cheaper alternative to Amgen's biologic medication Neupogen, with experts estimating it could be sold at a discount of up to 35% of Neupogen's current price.
$$$ Aduro's platform technology is our proprietary LADD method of engineering Listeria mononcytogenes bacteria into therapeutic agents that stimulate targeted immune response to specific tumor antigens.LADD technology is designed to enable the safe administration of Listeria by deleting two genes critical to the bacterium's natural virulence – internalin B and act A, which control infection of hepatocytes and spread of bacterial DNA. The attenuated strain of bacteria is then modified with new genetic material to encode and express specific tumor antigens. The engineered Listeria is designed to be absorbed by the patient's antigen presenting cells, including dendritic cells, which are primary initiators of both the innate and adaptive immune responses. Once absorbed, the LADD-engineered bacterium releases genetic material and antigens into the dendritic cell cytosol. The dendritic cell immediately launches an innate immune response (by releasing cytokines and other signaling proteins) and then processes the tumor antigen genes from the LADD bacterium. These antigens are presented on the dendritic cell surface where they are "read" by CD4 and CD8 T cells, which then initiate an adaptive immune response specific to the target antigen.
LADD-based therapies have several attractive characteristics: Listeria is well understood and characterized after more than 50 years as a research tool in immunology The double attenuated methodology has a well-characterized safety profile in multiple clinical trials. Unlike therapeutic virus vectors, LADD-engineered bacteria are not neutralized by antibodies and can be administered repeatedly LADD-based agents have potential therapeutic effect both as a monotherapy and in combination with other conventional and emerging therapies, including GVAX*, chemotherapy, radiotherapy and checkpoint inhibitors. The first LADD therapeutics are engineered to stimulate an immune response to mesothelin, a tumor-associated antigen expressed by multiple tumor types. The company is currently conducting trials treating mesothelin-expressing tumors in pancreatic cancer and mesothelioma. Additional studies are anticipated in non-small cell lung and ovarian cancers, which also frequently express mesothelin. Aduro is also developing other LADD strains to target other known tumor antigens.
* GVAX is a portfolio of irradiated tumor cell lines that express GM-CSF, a key immune cell recruitment factor, and can stimulate a broad-based, highly potent immune response. In 2013, Aduro acquired rights to the GVAX portfolio.
$$$ 李斯特菌（學名：Listeria monocytogenes），又名單核細胞增生性李斯特菌、李氏菌，是一種兼性厭氧細菌，為李斯特菌症的病原體。它主要以食物為傳染媒介，是最致命的食源性病原體之一，造成二至三成的感染者死亡。李斯特菌在美國每年約引起2500份病例、500人死亡，其中李斯特菌症是導致死亡的主要病因，其致死率甚至高過沙門氏菌及肉毒桿菌。李斯特菌是革蘭氏陽性菌，屬厚壁菌門，取名自約瑟夫·李斯特。它在30°C以下的環境中具能動性，但通常不耐超過37°C的高溫；而除了以鞭毛運動之外，李斯特菌也能透過肌動蛋白絲狀物的爆炸性聚合（簡稱爆聚），藉真核細胞進行活動，即所謂的「彗尾」（comet tails）或「肌動蛋白火箭」（actin rockets）研究顯示，約一成的人類消化系統內滋長有李斯特菌[5]。然而，獸醫才是碰上以李斯特菌為禍首之臨床病例的大宗，而病例中又以反芻動物感染腦膜腦炎的情況最為顯見。李斯特菌具有相當的致病性，能經由婦女的陰部感染腹中胎兒、引發腦膜炎，因此懷孕婦女通常不建議食用未經低溫殺菌的軟質乳酪，如：布利乳酪、卡門培爾乳酪、菲達乳酪、克索布蘭可乳酪等。近期，李斯特菌則在疾病生物科技領域被用作模式生物來解釋相關學說。
$$$ Glutathione activates virulence gene expression of an intracellular pathogen Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA Michelle L. Reniere, Sonya M. John & Daniel A. Portnoy Graduate Group in Infectious Diseases and Immunity, School of Public Health, University of California, Berkeley, California 94720, USA Aaron T. Whiteley Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina 27710, USA Keri L. Hamilton & Richard G. Brennan Aduro BioTech, Inc. Berkeley, California 94710, USA Peter Lauer School of Public Health, University of California, Berkeley, California 94720, USA Daniel A. Portnoy Nature 517, 170–173 (08 January 2015) doi:10.1038/nature14029 Received 25 June 2014 Accepted 03 November 2014 Published online 07 January 2015
Abstract Abstract• References• Author information• Extended data figures and tables Intracellular pathogens are responsible for much of the world-wide morbidity and mortality due to infectious diseases. To colonize their hosts successfully, pathogens must sense their environment and regulate virulence gene expression appropriately. Accordingly, on entry into mammalian cells, the facultative intracellular bacterial pathogen Listeria monocytogenes remodels its transcriptional program by activating the master virulence regulator PrfA. Here we show that bacterial and host-derived glutathione are required to activate PrfA. In this study a genetic selection led to the identification of a bacterial mutant in glutathione synthase that exhibited reduced virulence gene expression and was attenuated 150-fold in mice. Genome sequencing of suppressor mutants that arose spontaneously in vivo revealed a single nucleotide change in prfA that locks the protein in the active conformation (PrfA*) and completely bypassed the requirement for glutathione during infection. Biochemical and genetic studies support a model in which glutathione-dependent PrfA activation is mediated by allosteric binding of glutathione to PrfA. Whereas glutathione and other low-molecular-weight thiols have important roles in redox homeostasis in all forms of life, here we demonstrate that glutathione represents a critical signalling molecule that activates the virulence of an intracellular pathogen.
$$$ Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes–Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer Dung T. Le, Andrea Wang-Gillam, Vincent Picozzi, Tim F. Greten, Todd Crocenzi, Gregory Springett, Michael Morse, Herbert Zeh, Deirdre Cohen, Robert L. Fine, Beth Onners, Jennifer N. Uram, Daniel A. Laheru, Eric R. Lutz, Sara Solt, Aimee Luck Murphy, Justin Skoble, Ed Lemmens, John Grous, Thomas Dubensky Jr, Dirk G. Brockstedt, and Elizabeth M. Jaffee J Clin Oncol 33.
Purpose GVAX pancreas, granulocyte-macrophage colony-stimulating factor–secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes– expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. Patients and Methods Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response.
Results A total of 90 patients were treated (arm A, n 61; arm B, n 29); 97% had received prior chemotherapy; 51% had received two regimens for metastatic disease. Mean number of doses ( standard deviation) administered in arms A and B were 5.5 4.5 and 3.7 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. Conclusion Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.
There is increasing evidence that immunotherapy can be effective in patients with solid tumors. Sipuleucel-T (Provenge; Dendreon, Seattle, WA) is the first US Food and Drug Administration– approved immunotherapeutic for prostate cancer.1 Ipilimumab (Yervoy; Bristol-Myers Squibb, New York, NY), an antagonist antibody to cytotoxic T-lymphocyte antigen-4, is approved for melanoma.2 Promising results in multiple tumor types have been observed with an agent that inhibits the anti–programmed death-1 (PD-1) receptor.3 Evidence also is emerging for activity of immunotherapy in pancreatic ductal adenocarcinoma (PDA).4-6 GVAX and CRS-207 are cancer vaccines that have been evaluated in PDA. GVAX is composed of two irradiated, granulocyte-macrophage colonystimulating factor (GM-CSF) –secreting allogeneic PDA cell lines administered 24 hours after treatment with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells.7 GVAX induces T cells against a broad array of PDA antigens, and mesothelin-specific T-cell responses have been shown to correlate with survival.5,8 Mesothelin is a tumor-associated antigen overexpressed in most PDAs. In a prior study, patients with previously treated advanced PDA who received Cy/GVAX had better induction of mesothelin-specific CD8
T cells than those treated with GVAX alone. Median survival was 4.3 and 2.3 months, respectively.7 CRS- 207 is recombinant live-attenuated, double-deleted Listeria monocytogenes (LADDLm), engineered to secrete mesothelin into the cytosol of infected antigen presentation cells, which subsequently gets processed and presented in the context of major histocompatibility complex molecules.9,10 In PDA mouse models, a heterologous prime/boost using GVAX and LADD Lm–expressing mesothelin demonstrated synergistic activity in both antigen-specific T-cell induction and antitumor activity (Appendix Fig A1, online only). In the CRS-207 phase I study, patients with PDA who received GVAX before entering the study lived a median of 17 months, compared with 5 months for those who did not receive prior GVAX.10 Following up on these observations, a phase II randomized, multicenter study was conducted comparing Cy/GVAX followed by CRS-207 with Cy/ GVAX alone in patients with metastatic PDA.
$$$ Killed but metabolically active microbes: a new vaccine paradigm for eliciting effector T-cell responses and protective immunity Nature Medicine 11, 853 - 860 (2005) D G Brockstedt1,5, K S Bahjat1,5, M A Giedlin1,5, W Liu1, M Leong1, W Luckett1, Y Gao1, P Schnupf2, D Kapadia1, G Castro1, J Y H Lim1, A Sampson-Johannes1, A A Herskovits2, A Stassinopoulos1, H G Archie Bouwer2, J E Hearst1, D A Portnoy2,4, D N Cook1 & T W Dubensky Jr.1
Abstract We developed a new class of vaccines, based on killed but metabolically active (KBMA) bacteria, that simultaneously takes advantage of the potency of live vaccines and the safety of killed vaccines. We removed genes required for nucleotide excision repair (uvrAB), rendering microbial-based vaccines exquisitely sensitive to photochemical inactivation with psoralen and long-wavelength ultraviolet light. Colony formation of the nucleotide excision repair mutants was blocked by infrequent, randomly distributed psoralen crosslinks, but the bacterial population was able to express its genes, synthesize and secrete proteins. Using the intracellular pathogen Listeria monocytogenes as a model platform, recombinant psoralen-inactivated Lm ΔuvrAB vaccines induced potent CD4+ and CD8+ T-cell responses and protected mice against virus challenge in an infectious disease model and provided therapeutic benefit in a mouse cancer model. Microbial KBMA vaccines used either as a recombinant vaccine platform or as a modified form of the pathogen itself may have broad use for the treatment of infectious disease and cancer.
$$$ Selective Targeting of Antitumor Immune Responses with Engineered Live-Attenuated Listeria monocytogenes Cancer Res 2006; 66: (2). January 15, 2006 Kiyoshi Yoshimura,1,3 Ajay Jain,1,2 Heather E. Allen,4 Lindsay S. Laird,1 Christina Y. Chia,1 Sowmya Ravi,1 Dirk G. Brockstedt,4 Martin A. Giedlin,4 Keith S. Bahjat,4 Meredith L. Leong,4 Jill E. Slansky,5 David N. Cook,4 Thomas W. Dubensky,4 Drew M. Pardoll,1 and Richard D. Schulick1,2 1 Immunology and Hematopoiesis Division, Department of Medical Oncology, Sidney Kimmel Cancer Center; 2 Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland; 3 Department of Surgery II, Yamaguchi University School of Medicine, Yamaguchi, Japan; 4 Cerus Corp., Concord, California; and 5 Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado
Abstract Improved immunization and ex vivo T-cell culture strategies can generate larger numbers and more potent tumor-specific effector cells than previously possible. Nonetheless, the capacity of these cells to eliminate established tumors is limited by their ability to efficiently enter tumor-bearing organs and mediate their effector function. In the current study, we show that the administration of an engineered organ-homing microbe selectively targets tumor-specific immune responses to metastases within that organ. Specifically, an attenuated Listeria monocytogenes strain, which preferentially infects the liver following systemic administration, dramatically enhances the activity of a cancer vaccine against liver metastases but not metastases in the lung. This enhanced activity results from both local recruitment of innate immune effectors as well as concentration and increased activation of vaccine-induced antitumor T cells within the liver. These findings show a general approach to focus systemic cancer immunotherapies to specific organs bearing tumor metastases by taking advantage of differential tropisms and the proinflammatory nature of microbes. (Cancer Res 2006; 66(2): 1096-104)
Introduction There are three requirements for a therapeutically effective immune response against systemic cancer. First, a sufficient number of tumor-specific lymphocytes must be generated within the host. Second, these lymphocytes must traffic to sites of metastases. Third, the lymphocytes at the tumor site must execute the appropriate effector functions to destroy the cancer cells. Although significant numbers of circulating T cells capable of recognizing cancer antigens can be generated with various vaccination strategies or adoptive transfer of tumor-specific lymphocytes grown ex vivo, this typically does not result in tumor regression, particularly in the setting of bulky disease. Failure of these cells to efficiently home to sites of tumor metastases is becoming appreciated as an important limitation in this setting. In this report, we explore a novel strategy to enhance the homing and activity of tumor-specific T cells into tumor deposits by administering a microbe that selectively targets an organ affected by metastases. We chose hepatic metastases for this proofof-concept because the liver is one of the most important and often the sole site of metastatic cancer. This is particularly true for gastrointestinal cancers. For example, the majority of patients with advanced colorectal cancer will have metastatic disease limited only to the liver during some period of their illness, and one third of patients dying of colorectal cancer have metastatic disease limited to the liver on autopsy. Less than 20% of these patients with isolated hepatic metastases will have disease resectable for potential cure. Of the patients who undergo complete resection, 30% to 40% of these patients will survive 5 years and half will be with evidence of disease. As a means of regulating the inflammatory milieu of the liver, we have used engineered attenuated strains of Listeria monocytogenes, a bacterium that preferentially infects the liver. When administered by any of several routes, L. monocytogenes will initially be found in many organs but concentrates into the liver where they infect the hepatocytes and Kupffer cells and less so into the spleen. This process results in a transient hepatitis associated with the induction of multiple proinflammatory cytokines and chemokines. We reasoned that this proinflammatory milieu could enhance the trafficking and activity of T cells within the liver. Using a model of hepatic metastases of colorectal cancer, we show that administration of L. monocytogenes significantly enhances the antitumor activity of a cancer vaccine. This enhanced activity is not observed for metastases in the lung. The immunologic mechanisms for this liver-specific effect result from both increased intrahepatic innate immunity and enhanced activity of tumor-specific T cells.
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