BERKELEY, Calif.—Aduro Biotech Inc. recently highlighted two posters presented at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CRI-AACR) in New York. The preclinical data demonstrate positive changes in the tumor microenvironment and induction of a tumor-specific immune response by Aduro’s LADD (Listeria-based immunotherapy construct) and STING (stimulator of interferon genes) Pathway Activator immunotherapy platform technologies. Importantly, adding a PD-1 blockade to either immunotherapy regimen significantly bolstered antitumor efficacy, according to the company.
“These preclinical data demonstrate the underlying mechanisms by which our LADD and STING immunotherapy platforms activate the immune system and induce robust innate immunity, facilitating a change in the tumor microenvironment which results in effective destruction of cancer cells in several preclinical models,” said Dr. Thomas Dubensky Jr., chief scientific officer of Aduro. “Importantly, the combination data are even more impressive, showing increased efficacy when our LADD and STING platforms are combined with an anti-PD1 checkpoint inhibitor to combat the tumor’s ability to hide from the immune system. These data support our strategy to combine our immunotherapy regimens with checkpoint inhibitors for greater anti-tumor activity, looking toward the ultimate goal of better, more effective patient care.”
Aduro presented the following posters at the CRI-AACR meeting:
- Poster A013: Favorable changes in the tumor microenvironment following intravenous dosing with live attenuated Listeria monocytogenes-based immunotherapy—These data demonstrated that a combination of LADD with an anti-PD1 checkpoint inhibitor results in improved anti-tumor efficacy in multiple tumor models. In addition, analyses of biopsies from patients given CRS-207, a LADD immunotherapy, showed enhancement of infiltrating CD8+ T cells, mature dendritic cells, macrophages and natural killer cells.
- Poster B020: STING activation in the tumor microenvironment using a synthetic human STING-activating cyclic dinucleotide induces potent anti-tumor immunity—The data from this work show that STING Pathway Activator ADU-S100 stimulates the production of interferon-beta by all human STING alleles. Importantly, the results showed that injecting ADU-S100 directly into the tumor microenvironment induced T cells with tumor-specific antigenic repertoire, leading to durable antitumor immunity.
LADD is Aduro’s proprietary platform of live, attenuated double-deleted Listeria monocytogenes strains that have been engineered to generate a potent innate immune response and to express tumor-associated antigens to induce tumor-specific T cell-mediated immunity. CRS-207 is one of a family of product candidates based on Aduro’s LADD immunotherapy platform that has been engineered to express the tumor-associated antigen mesothelin, which is over-expressed in many cancers, including mesothelioma and pancreatic, non-small cell lung, ovarian, endometrial and gastric cancers.
Aduro’s proprietary STING Pathway Activator product candidates, including ADU-S100 (MIW815), are synthetic small-molecule immune modulators that are designed to target and activate human STING, which is generally expressed at high levels in immune cells, including dendritic cells. Once activated, the STING receptor initiates a profound innate immune response through multiple pathways, inducing the expression of a broad profile of cytokines, including interferons and chemokines. This subsequently leads to the development of a systemic tumor antigen-specific T cell adaptive immune response.
In addition to this Aduro news, following are some other stories of recent preclinical data presentations by other companies.
PS-targeting antibodies enhance activity of multiple checkpoint targeting agents in TNBC model
TUSTIN, Calif.—Peregrine Pharmaceuticals Inc., a biopharmaceutical company committed to improving patient lives by manufacturing high-quality products for biotechnology and pharmaceutical companies and advancing its proprietary R&D pipeline, recently announced the presentation of preclinical study data demonstrating that phosphatidylserine (PS)-targeting antibodies similar to bavituximab are able to enhance the antitumor activity of multiple checkpoint targeting agents, including anti-PD-1 and anti-LAG3 therapies, in a model of triple-negative breast cancer (TNBC). Data showed that eight of the 10 animals receiving the preclinical bavituximab equivalent (ch1N11) combined with anti-PD-1 and anti-LAG3 therapies (triple combination) experienced complete tumor regressions, whereas there were no animals in the anti-PD-1 and anti-LAG3 combination treatment arm that had a complete regression.
Additional data demonstrated that the triple combination featuring ch1N11 led to a 99-percent reduction in total tumor volume at the interim analysis point (day 25) across all animals as compared to the control arm. In addition, the triple combination showed a statistically significant increase in tumor growth inhibition as compared to the anti-PD-1 and anti-LAG3 combination treatment (99 percent vs. 62 percent).
Peregrine’s Dr. Michael J. Gray, the study’s lead scientist, presented the study findings at the recent CRI-AACR meeting. The presented study evaluated various combinations of ch1N11, anti-PD-1 and anti-LAG3 therapy in the well-characterized E0771 murine model of TNBC.
Other key study findings included:
- Treatment with triple combination therapy led to a significant increase in tumor infiltrating lymphocytes (TILs), particularly CD8+ T cells, as compared with anti-PD-1 and anti-LAG3 combination treatments.
- Treatment with triple combination therapy resulted in a reduction in immunosuppressive cell types, including CD4+ cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). These results show that the triple combination therapy is capable of significantly altering the tumor microenvironment from highly immunosuppressive to highly immuno-stimulatory. Other treatment combinations evaluated in the study lacked a statistically significant reduction in immunosuppressive cells.
“These data offer compelling evidence for the therapeutic potential of including PS-targeted therapies in combination with multiple checkpoint inhibitors in the treatment of TNBC. This is highlighted by the dramatic distinction in complete tumor regression rates seen between the triple combination and anti-PD-1/anti-LAG3 treatment arms, combined with the significant difference in tumor growth inhibition percentages witnessed for these groups,” stated Dr. Jeff T. Hutchins, Peregrine’s vice president of preclinical research. “In addition to its impact on tumor growth, we saw very important changes in the tumor microenvironment with the triple combination treatment with a significant reduction in cell types that contribute to immune suppression such as CD4+ cells, Tregs and MDSCs coupled with the expansion of tumor-fighting cells such as CD8+ T cells. These data offer mechanistic evidence that highlight the manner by which the combination of ch1N11/anti-PD-1/anti-LAG3 may be eliciting such antitumor responses.”
Bavituximab is an investigational monoclonal antibody that targets PS. Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab is believed to override PS-mediated immunosuppressive signaling by blocking the engagement of PS with its receptors as well as by sending an alternate immune activating signal. Previous studies demonstrated PS-targeting antibodies shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor responses. Peregrine evaluates the preclinical equivalent of bavituximab, ch1N11, in animal model studies to guide clinical development.
Peregrine’s clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments. This approach includes the recently announced grants by the National Comprehensive Cancer Network to support three different clinical trials of bavituximab treatment combinations. Those trials will evaluate novel bavituximab combinations in glioblastoma, head and neck cancer and hepatocellular carcinoma, including an immunotherapy combination. Additionally, Peregrine continues to advance its preclinical collaboration with Memorial Sloan Kettering Cancer Center with the goal of evaluating combinations of bavituximab with other checkpoint inhibitors and immune stimulatory agents.
Idera presents new third-generation antisense data
CAMBRIDGE, Mass. & EXTON, Pa.—Idera Pharmaceuticals Inc., a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel nucleic acid-based therapeutics for oncology and rare diseases, in late September announced the presentations of new preclinical data on the mechanism of action supporting selective targeting of single point mutations. Also, data were presented on third-generation antisense (3GA) therapies targeting the NLRP3 gene for the treatment of inflammatory disorders.
“The understanding we have gained of the mechanism of action of 3GA is providing insights into the increased potency and specificity of its gene silencing. This data has illustrated to us a way in which 3GA could be used to target point mutations,” stated Dr. Sudhir Agrawal, president of research at Idera. “We are continuing to employ 3GA technology to target multiple genes, including NLPR3, with a goal of prioritizing a candidate for clinical development.”
In the oral presentation, entitled “Selective Targeting of Point Mutations by Third Generation Antisense Oligonucleotides,” Dr. Reina Improgo, a research scientist in Idera’s Discovery Team, presented an overview of the novel mechanism of action of 3GA technology. These preclinical studies were conducted both in cell-based assays as well as in-vivo models. The novel mechanism of action of 3GA leads to excision of the targeted RNA in the central region. Insertion of a single mismatch led to significant loss of gene-silencing activity. Based on this data, 3GAs were designed to target single point mutations.
These proof-of-concept studies were conducted using the BRAF V600E and MYD88 L265P mutations. The 3GA targeted to BRAF V600E showed mutation-specific inhibition, whereas a 3GA targeted to wild-type BRAF showed minimal activity. Similarly, 3GA targeted to MYD88 L265P showed mutation-specific inhibition, and had insignificant impact on wild-type MYD88 expression. Based on the specificity in targeting RNA the data indicates that 3GA could be used to successfully treat diseases that require allele-specificity.
Additionally, Dr. Fugang Zhu and Dr. Wayne Jiang, scientists from Idera’s Discovery Team, presented a poster entitled, “Third generation antisense (3GA) targeting NLRP3 (NOD-like receptor family, pyrin domain containing protein 3) for the treatment of inflammatory disorders.” In the presentation, they showed that 3GA targeting NLRP3 led to the suppression of the NLRP3 mRNA and protein and inhibition of the downstream cascade, including IL-1β and IL-18. The data also demonstrated that 3GA targeting of NLRP3 resulted in marked improvement in disease-associated parameters in both interstitial cystitis and uveitis preclinical models.
Previously, the company had announced the identification of NLRP3 and DUX4 (double homeobox 4) as initial gene targets to advance into IND-enabling activities, which will occur throughout 2016.
Potential disease indications related to these targets include, but are not limited to, interstitial cystitis, lupus nephritis, uveitis and facioscapulohumeral muscular dystrophy. The company is currently conducting clinical, regulatory and commercial analysis activities and conducting IND-enabling studies with the plan to enter the clinic in 2017 for the first clinical development program. In addition to these activities, over the first half of 2016, Idera generated 3GA compounds for a series of additional gene targets. These will enable the company to continue to expand both its future pipeline opportunities for internal development as well as its opportunities for partnerships in areas outside of Idera’s focus. Additionally, Idera is party to a collaboration and license agreement with GlaxoSmithKline to research, develop and commercialize compounds from its 3GA technology for the treatment of undisclosed, selected renal targets.
Nuevolution presents tox data on its BET BD1 program at Discovery on Target 2016
STOCKHOLM, Sweden—Nuevolution AB in September presented preclinical and preliminary toxicology data from its BET BD1 program at Discovery on Target 2016 in Boston.
Jimmi G. Seitzberg, a project manager with Nuevolution, gave an oral presentation reporting the key findings from the poster “NUE7770—A BET-BD1 selective chemical probe with potent cellular and in vivo anti-inflammatory activity,” also including preliminary data from the first comparative animal toxicology study with NUE7770, a selective BET BD1 inhibitor.
The preliminary data from a two-week mouse toxicology study with NUE7770 showed no mortality and no loss in body weight even at high doses of the compound, whereas the non-selective BET control compound, JQ1, showed a high mortality already at lower doses.
The final conclusion from this toxicology study is not yet available, as further studies still are ongoing. A full characterization and conclusion from this comparative animal toxicology study will be available in the fourth quarter of 2016.
NUE7770 is also being tested in mouse models of systemic lupus erythematosus and idiopathic lung fibrosis, both of which are severe inflammatory diseases. Data from these studies will be reported later in 2016.
BET bromodomain proteins play an important role in regulation of gene expression, which thereby affect inflammatory responses and the ability of cancer cells to sustain growth and survive. The human proteome comprises 46 bromodomain-containing proteins, many of which are thought to be involved in cancer, inflammation and cardiovascular disease.
F-star shares encouraging data on lead bispecific program FS118
CAMBRIDGE, U.K.—F-star, a biopharmaceutical company developing novel bispecific antibodies with a focus on immuno-oncology, recently presented preclinical data on its lead bispecific program FS118 at several oncology-oriented conferences.
FS118 is currently in preclinical development and reportedly has the potential to be a first-in-class antagonist targeting both LAG-3 (lymphocyte-activation gene 3) and PD-L1 (programmed death-ligand 1), two immune checkpoint receptors strongly implicated in allowing cancers to evade the host immune system.
According to the company, the FS118 bispecific program “harnesses the full potential of F-star’s Modular Antibody Technology by introducing an anti-LAG-3 Fcab (Fc-domain with antigen binding activity) into an antibody targeting PD-L1, generating a so-called mAb2.” As a full-length IgG, FS118 is said to retain the characteristics of conventional antibodies, with comparable structure, functionality and manufacturing properties.
F-star plans to file an IND application for FS118 in 2017 to advance the program into clinical development. Initial proof-of-concept studies in syngeneic mouse models have demonstrated the potential for FS118 to deliver greater efficacy and favorable tolerability compared to monotherapy combinations in a range of cancers.
“By combining two activities in a single drug, FS118 represents the next generation of immunotherapies and we look forward to progressing it into clinical development,” said Neil Brewis, chief scientific officer of F-star. “This is an important step for F-star as we continue to exploit our Modular Antibody Technology platform to provide more efficient immunotherapies for cancer patients.”
F-star also presented data on FS101, an earlier-stage mAb2 directed against EGFR (epidermal growth factor receptor) and HGF (hepatocyte growth factor). This first-in-class bispecific antibody in oncology has shown encouraging activity in mouse xenograft models and a decreased skin toxicity compared with monotherapies, demonstrating further the potential of the Modular Antibody Technology, according to F-star.
Events at which F-star presented its data on these pipeline candidates were the CRI-AACR meeting noted in two other stories in this roundup article, as well as Phacilitates Immunotherapy Europe 2016 in Berlin, the World Bispecific Antibody Summit in Boston and the American Association of Cancer Research’s Tumor Immunology and Immunotherapy meeting in Boston.