On April 17, 2018 Aduro Biotech, Inc. (NASDAQ:ADRO) reported that data from three of the company’s programs were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) this week (Press release, Aduro Biotech, APR 17, 2018, View Source;p=RssLanding&cat=news&id=2343034 [SID1234525429]). The poster presentations detailed:

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Updated preclinical data for ADU-S100, a first-in-class small molecule therapeutic in Phase 1 studies targeting the STimulator of INterferon Genes (STING) pathway;
New preclinical data for ADU-1604, an anti-CTLA-4 antibody scheduled to enter clinical development in the second half of 2018; and,
Preclinical data for BION-1301, an anti-APRIL antibody currently in a Phase 1/2 study for the treatment of patients with multiple myeloma.

"These robust and new data continue to elucidate the diverse mechanisms by which our immunotherapies may provide new therapeutic alternatives for the large majority of patients that do not currently benefit from available cancer immunotherapies," said Andrea van Elsas, Ph.D., chief scientific officer of Aduro. "For ADU-S100, we’ve confirmed in preclinical models that signaling through the STING pathway is critical to elicit tumor-reactive CD8+ T cells, the cornerstone of effective, durable and systemic anti-tumor immunity as evident from rejection of distant tumors. Importantly, these preclinical data show that adding checkpoint inhibitors to an ADU-S100 treatment regimen can eradicate tumors unresponsive to anti-PD-1 immunotherapy."

Dr. van Elsas continued, "We also reported data on our anti-CTLA-4 antibody, ADU-1604, and expect to initiate clinical studies based on this data. In addition, our first-in-class antibody BION-1301 blocks APRIL from binding to both BCMA and TACI and may provide a differentiated approach to treating patients with multiple myeloma who do not benefit from or are resistant to current therapies. We look forward to confirming these data through our ongoing Phase 1/2 clinical study."
Presentation Title (Abstract #631): Intratumoral activation of STING with a synthetic cyclic dinucleotide elicits antitumor CD8+ T cell immunity that effectively combines with checkpoint inhibitors
On Sunday, April 15, 2018, Sarah McWhirter of Aduro Biotech presented updated preclinical data demonstrating that an optimized dosing regimen of ADU-S100 administered intratumorally activates acute innate immunity as well as adaptive CD8+ T cells necessary and sufficient for systemic and durable anti-tumor immunity. The data show that activation of the STING pathway by ADU-S100 mediates local induction of type I interferon and TNFα and subsequently CD8+ T cell induction to stimulate an immune response sufficient to reduce or eliminate both the injected and distal tumors.

In addition, combining ADU-S100 with checkpoint inhibitors enhances the durable immunity even in tumors that are resistant to anti-PD-1 treatment. Aduro and Novartis are evaluating ADU-S100 in ongoing Phase 1 clinical studies, both as monotherapy for cutaneously accessible tumors and in combination with PDR001, an anti-PD-1 compound in advanced metastatic solid tumors and lymphomas. Additional studies combining ADU-S100 and other checkpoint inhibitors are planned.

Presentation Title (Abstract #1702): Assessment of pharmacology and toxicology of anti-CTLA-4 antibody (ADU-1604) in non-human primates and evolution of local and anti-CTLA-4 application
On Monday, April 16, 2018, Maaike Hendriks of Aduro Biotech presented preclinical data demonstrating that ADU-1604 binds a unique epitope on human CTLA-4 and was well-tolerated, enhanced T cell activation and inhibited tumor growth. Based on these data, Aduro plans to initiate a Phase 1 study in patients with advanced melanoma in the second half of 2018.

Presentation Title (Abstract #3780): Preclinical pharmacokinetics, pharmacodynamics and safety of BION-1301, a first-in-class antibody targeting APRIL for the treatment of multiple myeloma

On Tuesday, April 17, 2018, John Dulos of Aduro Biotech presented preclinical pharmacokinetic and pharmacodynamic data initially announced at the American Society of Hematology (ASH) (Free ASH Whitepaper) demonstrating that BION-1301 was well-tolerated. In addition, the binding of BION-1301 to APRIL (A Proliferation Inducing Ligand), a ligand for the receptors BCMA and TACI, resulted in decreased IgA, IgG and IgM production in a dose-dependent fashion. Aduro is evaluating BION-1301 in an ongoing Phase 1/2 study in patients with multiple myeloma.

About STING Pathway Activator Platform
The Aduro-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. STING 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.

Aduro’s lead molecule, ADU-S100/MIW815, is the first therapeutic in development specifically targeting STING. In collaboration with Novartis, it is being tested in a Phase 1 monotherapy clinical trial and in a Phase 1b combination study with PDR001, an anti-PD-1 compound. Both studies are enrolling patients with cutaneously accessible, advanced/metastatic solid tumors or lymphomas. The trials are evaluating the ability of ADU-S100 to activate the immune system and recruit specialized immune cells to attack the injected tumor, leading to a broad immune response that seeks out and kills non-injected distant metastases. Initial clinical data are expected in the second half 2018.

About ADU-1604
Cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) is a negative regulator of T cell responses and is an immune checkpoint. Blocking CTLA-4 using antibodies may produce an anti-tumor response by enhancing T cell activation and their cancer cell killing activity in the tumor. This therapeutic target has been clinically validated by others in advanced melanoma. Aduro is developing a proprietary humanized anti-CTLA-4 antibody called ADU-1604 that binds to a unique epitope and its potency has been demonstrated in vitro and in vivo. Based on preclinical studies, Aduro believes that ADU-1604 when combined with innate and adaptive immune cell stimulators such as STING agonists and cancer vaccines, can display an amplified anti-tumor effect against poorly immunogenic tumors. ADU-1604 is anticipated to enter clinical development in the second half of 2018.

About BION-1301
Aduro is currently evaluating BION-1301, its most advanced proprietary B-select monoclonal antibody, as a novel therapy for multiple myeloma. Despite new treatments recently approved in multiple myeloma, this disease remains incurable as patients relapse, or become resistant to, currently-available therapies. In preclinical studies, Aduro has established that A PRoliferation-Inducing Ligand (APRIL) plays a crucial part in the protective bone marrow tumor microenvironment. In these studies, APRIL, through the B cell maturation antigen (BCMA), was shown to be critically involved in the survival, proliferation and chemoresistance of multiple myeloma, and upregulates mechanisms of immunoresistance, including PD-L1 upregulation. BION-1301, a humanized antibody that blocks APRIL from binding to its receptors, has been shown in preclinical studies to halt tumor growth and overcome drug resistance. In addition, BION-1301 also demonstrated the ability to inhibit immune suppressive effects of regulatory T cells via TACI but not BCMA in multiple myeloma blood and bone marrow. BION-1301 is currently being evaluated in a Phase 1/2 clinical study.

On April 17, 2018 amcure, a biopharmaceutical company developing first-in-class cancer therapeutics, reported pre-clinical results of its lead drug candidate, AMC303 (Press release, amcure,APR 17, 2018, View Source [SID1234525445]). The data showed the strong anti-tumor and anti-metastatic effects in various epithelial tumor cells by binding of AMC303 to the extracellular domain of CD44v6. The research was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in a poster entitled ‘The allosteric inhibitor of CD44v6 AMC303 blocks c-MET, Ron and VEGFR-2 dependent signaling and cellular processes’.

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"The results presented in this study emphasize the importance of CD44v6 inhibition in cancer and the potential of this approach to improve the chances against this disease," said Klaus Dembowsky, MD, PhD, CEO of amcure. "Not only did we show strong anti-cancer effects for AMC303, but we gained new mechanistic insights into the role of AMC303 in inhibition of one of the key drivers of metastasis, Epithelial-Mesenchymal-Transition (EMT). We look forward to substantiating the strong preclinical data sets for AMC303 with results from our current and future clinical trials."

The CD44 family of transmembrane glycoproteins comprises several variants that are involved in many cellular processes. The isoform CD44v6 has been shown to play a major role in tumor growth and metastasis. In this study, the amcure research team has shown that blocking CD44v6, an essential coreceptor for the receptor tyrosine kinases VEGFR-2, c-MET and RON by AMC303, interferes with several key steps in tumor progression and metastasis including EMT, cell migration and invasion. This novel mode of action results in strong anti-tumor and anti-metastatic effects of AMC303.

About AMC303
amcure’s lead compound, AMC303, is being developed as a potential treatment for patients with advanced and metastatic epithelial tumors, e.g. pancreatic cancer, head and neck cancer, gastric cancer, colorectal cancer, breast cancer and lung cancer. AMC303 has a high specificity for inhibiting CD44v6, a co-receptor required for signaling through multiple cellular pathways (c-Met, VEGFR-2, RON) involved in tumor growth, angiogenesis and the development and regression of metastases.

AMC303 has demonstrated strong effects in various in vitro and in vivo assays.

On April 17, 2018 GRAIL, Inc., a life sciences company focused on the early detection of cancer, reported initial results from its Circulating Cell-Free Genome Atlas (CCGA) Study (Press release, Grail, APR 17, 2018, View Source [SID1234525517]). Data from three prototype genome sequencing assays showed it may be feasible to develop a blood test for early detection of multiple cancer types with greater than 99 percent specificity.

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"We are excited that early results with our prototype assays suggest we can develop blood tests for early detection of cancer with a very low rate of false-positive results," said Alexander Aravanis, MD, PhD, Vice President of Research and Development at GRAIL. "These data will be used to inform development of a blood test for early detection of multiple cancer types. Our next steps are to analyze additional data sets from CCGA, including validating these results in an independent data set, and to continue optimizing our assays."

The data were presented today by Dr. Aravanis in a late-breaking research minisymposium at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago (Abstract LB-343).

Specificity Analyses

When developing early detection tests, high specificity is important to minimize false-positive results. Across all three of the assays evaluated, a "cancer-like" signal was found in less than one percent of participants who entered the study without a cancer diagnosis (5 of 580), suggesting a test with a specificity greater than 99 percent is feasible. Through longitudinal follow-up in the study, it has since been confirmed that two of the five participants who had a cancer-like signal have been diagnosed with cancer. This suggests the signal indicated presence of undiagnosed cancer. Follow-up of the other three participants continues.

Clonal hematopoiesis of indeterminate potential (CHIP) is a known confounding signal present in cell-free DNA (cfDNA) of white blood cells that could increase false-positive results. This CHIP signal is likely due to natural aging processes. Therefore, in this study, paired sequencing of white blood cells and cfDNA was performed to identify these non-cancer mutations. Somatic (non-inherited) mutations from the white blood cells accounted for 66 and 78 percent of all mutations identified in participants with and without cancer, respectively.

Sensitivity Analyses

Initial analyses showed all three prototype assays detected a strong biological signal in cancer types that are typically not screened for and have low survival rates (five-year cancer-specific mortality rate of greater than 50 percent1). These included lung, ovarian, pancreatic, liver, and esophageal cancers. The signal was detected across all stages of cancer, and increased with stage across all three of the assays. The assays evaluating the whole genome performed best, and the whole-genome bisulfite assay showed the strongest detection rates. Additional data showing detection rates for specific cancer types will be presented at an upcoming medical meeting.

In this pre-planned sub-study of CCGA, three prototype sequencing assays were evaluated as potential methods for a blood-based test for early cancer detection. Blood samples from 878 participants with newly diagnosed cancer who had not yet received treatment and 580 participants without diagnosed cancer were sequenced with all three prototype assays. Twenty different cancer types across all stages were included in the sub-study.

The prototype sequencing assays included:

Targeted sequencing of paired cfDNA and white blood cells to detect somatic mutations such as single nucleotide variants and small insertions and/or deletions;
Whole-genome sequencing of paired cfDNA and white blood cells to detect somatic copy number changes; and
Whole-genome bisulfite sequencing of cfDNA to detect abnormal cfDNA methylation patterns.
About CCGA

CCGA is a prospective, observational, longitudinal study designed to characterize the landscape of cell-free nucleic acid (cfNA) profiles in people with and without cancer. The planned enrollment for the study is more than 15,000 participants across 141 sites in the United States and Canada. Approximately 70 percent of participants will have cancer at the time of enrollment (newly diagnosed, have not yet received treatment) and 30 percent will not have a known cancer diagnosis. The groups are demographically similar and representative of a real-world population. The group of participants without cancer includes individuals with conditions that are known to increase cfNA signal, such as inflammatory or autoimmune diseases. Planned follow-up for all participants is at least five years to collect clinical outcomes.

Presentation Details
Abstract LB-343

Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas (CCGA)

Alexander M. Aravanis et al. Tuesday, April 17, 2018: 4:20-4:35pm CDT, Session LBMS01 – Minisymposium: Late-Breaking Research, Room S101 – McCormick Place South (Level 1).

On April 17, 2018 Torque, an immuno-oncology company developing Deep Primed cellular therapies with pharmacologic control to direct immune power deep within the tumor microenvironment, reported preclinical data for the company’s Deep-Primed IL-15 and Deep-Primed IL-12 programs demonstrating their activity compared to systemically administered IL-15 and IL-12 (Press release, Torque Therapeutics, APR 17, 2018, View Source [SID1234525537]). These data were presented at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago.

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Torque is developing a new class of Deep-Primed immune cell therapeutics to dramatically expand cell therapy cures for cancer. Deep-Priming uses advanced material engineering to anchor immune-stimulatory drugs directly to the surface of multi-targeted, antigen-primed T cells to activate both the adaptive and innate immune system with pharmacologic control in the tumor microenvironment. This approach does not require genetic engineering and enables tunable loading of precise doses of cytokines onto the surface of T cells to deliver sustained and controlled immune activation.

"Both Il-15 and IL-12 are potent cytokines capable of inducing strong anti-tumor immune responses, yet their clinical use as systemic therapies is limited by the potential for severe toxicities," said Thomas Andresen, PhD, Chief Scientific Officer of Torque. "Anchoring these powerful immune activators to the surface of T cells that traffic to tumors is a unique approach to direct immune power in the tumor microenvironment. These preclinical studies demonstrate superior efficacy for this approach compared to systemic administration of these same cytokines and are the foundation for the first clinical trials that will begin later this year for Deep IL-15."

Highlights of the three preclinical presentations follow, and copies of the posters are available for download on the Torque website: https://bit.ly/2FZtPOW

Abstract 3575 / Poster 13: "Cell therapy with surface-tethered IL-12 provides immune system priming and strong anti-tumor activity"
Presenter: Jon Nardozzi, PhD, Torque; Session: Adoptive Cell Therapy 3
Key findings from the study:

Deep IL-12 Priming technology enables high loading of IL-12 doses on the surface of tumor-specific T cells.
Deep IL-12 Priming substantially increases tumor killing survival with adoptively transferred tumor-specific T cells in an aggressive solid tumor model and is superior to systemically administered IL-12.
Administration of repeat doses of Deep IL-12 Primed T cells without pre-conditioning (lymphodepletion) further increases tumor killing and survival with adoptively transferred T cells in this aggressive solid tumor model.
Deep IL-12 Primed T cells activate an endogenous immune response but do not induce overt toxicities such as weight loss or sustained systemic cytokine release.
Abstract 3577 / Poster 15: "Deep IL-15 provides autocrine stimulation and expansion of autologous T cells driven by controlled concentrated release of IL-15"
Presenter: Pengpeng Cao, PhD, Torque; Session: Adoptive Cell Therapy 3
Key findings from the study:

Deep IL-15 Priming technology loads IL-15 on T cells with a highly controlled dose per cell and provides slow release of IL-15 for autocrine stimulation and sustained adoptive T cell therapy expansion.
In contrast to systemically delivered IL-15, Deep IL-15 substantially increases target CD8 T cell concentration in the tumor, without significant systemic IFNg levels or endogenous CD8 and NK cell expansion, due to lack of systemic exposure.
Torque’s fully closed manufacturing process that uses a proprietary dendritic cell priming process generates several billion, antigen-primed human T cells with an average of 20% reactivity and >95% T cell purity (demonstrated with autologous cells from healthy human donors).
Clinical trials using this manufacturing process for Deep IL-15 Primed multi-target T cells are expected to initiate in 2018.

Also at AACR (Free AACR Whitepaper), the Irvine Lab of the Koch Institute at MIT presented data on IL-12 and IL-15 formulated in nanogels and anchored to T cells using technology developed in the Irvine Lab. Torque has built upon the Irvine Lab’s work to create the Deep-Priming technology platform. The Irvine Lab is directed by Darrell Irvine, PhD, who is a co-founder of Torque and Chairman of Torque’s Scientific Advisory Board, Professor at the Massachusetts Institute of Technology, and an Investigator of the Howard Hughes Medical Institute.

Abstract 3565 / Poster 3: "T cell receptor signaling-responsive single chain IL-12 and IL-15 superagonist nanogel ‘backpacks’ to enhance adoptive cell therapy in solid tumors"
Presenter: Michael Fichter, PhD, Koch Institute for Integrative Research at MIT; Session: Adoptive Cell Therapy 3
Key findings from the study:

IL-15 nanogels anchored to tumor-targeted T cells induces significant and specific expansion of the adoptively transferred T cells in tumors and lymph nodes that is superior to systemic IL-15.
IL-15 nanogels anchored to T cells substantively improved the efficacy of an adoptive T cell therapy against solid tumors while reducing cytokine-induced side effects triggered by systemically administered IL-15.
In a separate experiment, IL-12 nanogels anchored to CD8 effector cells induced substantial cell activation.
About Deep-Primed Immune Cell Therapeutics
Torque’s Deep-Priming platform is based on 10 years of research and development to combine very potent immunomodulatory drugs with T cells to drive a powerful immune response with pharmacologic control in the tumor microenvironment. We are developing Deep-Primed T cells using a focused set of immunomodulators—initially IL-15, IL-12, and TLR agonists—that activate both innate and adaptive immunity. Administering these immunomodulators systemically to a patient can cause lethal toxicity by activating immune cells throughout the body. Deep-Primed therapeutics are designed to activate T cells and focus the immune response to target the tumor, without systemic exposure. This is achieved by:

Anchoring the immunomodulators to the surface of T cells to activate and direct the immune response in the tumor microenvironment
Modular antigen priming of T cells to target multiple, tumor-associated antigens using a proprietary cell-processing technology
In hematologic cancers, this new class of immune therapeutics has the potential to improve on the initial success of single-target CAR-T therapeutics. For solid tumors, Deep-Primed T-cells have the potential to enable efficacy against tumors with heterogeneous antigens protected by hostile microenvironments, which are not readily addressable with the first generation of immune cell therapies.

On April 17, 2018 Advaxis, Inc. (NASDAQ: ADXS), a late-stage biotechnology company focused on the discovery, development and commercialization of immunotherapy products, reported the presentation of ADXS-HOT preclinical data in a poster discussion entitled "Targeting Shared Hotspot Cancer Mutations with a Listeria monocytogenes Immunotherapy Induce Potent Anti-Tumor Immunity" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting underway in Chicago (Press release, Advaxis, APR 17, 2018, View Source [SID1234525430]). The discussion, held yesterday, was led by Daniel O. Villarreal, Ph.D., Principal Scientist at Advaxis. The ADXS-HOT franchise leverages the Company’s proprietary Lm Technology to target common mutations in tumor driver genes.

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This study’s objective was to identify and target common (public or shared) mutations (hotspots) and to determine if the ADXS-HOT platform could effectively target those hotspots and control tumor growth. Results indicate that ADXS-HOT could achieve this in preclinical models against single and multi-target constructs. The full abstract is available here: View Source
"The results of this preclinical work with ADXS-HOT represent an exciting opportunity that may allow us to develop disease-specific immunotherapies that have the potential to be effective against multiple targets, capable of generating high-avidity T cells against shared of public mutations, as well as multiple proprietary highly immunogenic cancer-testes and oncofetal antigens for multiple tumor types," said Robert G. Petit, Ph.D., Executive Vice President and Chief Scientific Officer of Advaxis. "Additionally, the results show increased functionality and resiliency in CD8 T cells upon restimulation, indicating the potential not only to increase the number and frequency of CD8 T cells, but to strengthen them."

About ADXS-HOT
ADXS-HOT leverages the Company’s proprietary Lm technology to target common "hotspot" mutations. ADXS-HOT products are designed to target acquired shared or "public" mutations in tumor driver genes along with cancer-testes and oncofetal tumor-associated antigens that are shared by multiple patients. Although ADXS-HOT has not been tested in patients, in theory, products would be designed to treat all patients with a particular type of cancer, without the need for pre-treatment testing, biopsy, DNA sequencing or diagnostic testing.