On April 17, 2018 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading immunotherapy company focused on developing treatments for cancer and autoimmune/inflammatory diseases, reported preclinical study results of its ALPN-202 immuno-oncology program (Press release, Alpine Immune Sciences, 17 17, 2018, View Source [SID1234525447]). ALPN-202 will be the second product candidate to come out of the company’s proprietary scientific platform following ALPN-101, which is projected for an IND filing in the fourth quarter of 2018.

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ALPN-202 is designed to antagonize PD-L1 and CTLA-4 while also providing CD28 costimulation. Recent literature suggests the lack of CD28 costimulatory signaling may be a principal reason why many tumors do not respond to PD-L1 or CTLA-4 blockade. ALPN-202’s ability to agonize the costimulatory receptor CD28 potentially improves the immune system’s response to cancer.

Alpine used its proprietary scientific platform to engineer Variant Ig Domains (vIgDs) based on CD80. Single vIgD proteins were created capable of binding PD-L1, CTLA-4, and CD28. These vIgDs were then fused to an Fc backbone and used in various in vitro and in vivo studies to characterize functional activity and assess anti-tumor activity in mice implanted with human PD-L1 transduced tumors. Results showed:

ALPN-202 eliminated tumors in most mice (73% or 8/11 tumor free) compared to durvalumab, an FDA-approved anti PD-L1 antibody (18% or 2/11 tumor free), and controls (0/11 tumor free).
Importantly, those mice tumor free after receiving ALPN-202 were re-challenged with tumor and 100% of them were resistant to the newly-implanted cells without receiving additional doses of therapy, suggesting the potential for ALPN-202 to induce anti-tumor memory.
ALPN-202 elicited CD28 costimulation only in the presence of PD-L1.
Scientific Support and Rationale for ALPN-202
PD-1/PD-L1 inhibitors likely are most effective only when sufficient T cell activating signals, such as via CD28 costimulation, are present. Indeed, recent research demonstrated CD28 costimulation appears to be required for PD-1 inhibition to rescue exhausted T cells in some settings (Science 355:1423, 2017), yet the CD28 ligands CD80 and/or CD86 are often poorly expressed in tumor microenvironments. Because it provides both checkpoint blockade and CD28 costimulation, the ALPN-202 program is therefore well positioned to potentially be a more potent and broadly applicable therapeutic.

"Previously published data suggest PD-1 blockade requires CD28 costimulation to work, at least in some cancers. The preclinical data we are presenting at AACR (Free AACR Whitepaper) indicate the ALPN-202 program proteins are capable of delivering both with a single molecule," said Stanford Peng, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Alpine. "Additionally, these data demonstrate we can modulate three targets (PD-L1, CTLA-4, and CD28) with a single domain (in contrast to the need for multiple targeting domains for other therapeutic formats like bi- or tri-specific antibodies), demonstrating the potential promise of our versatile scientific platform."

"Our goal in oncology is to develop paradigm-shifting therapeutics that meaningfully improve upon existing therapies like PD-1/PD-L1 inhibitors," said Mitchell H. Gold, M.D., Executive Chairman and Chief Executive Officer of Alpine. "The preclinical data presented at AACR (Free AACR Whitepaper) show ALPN-202 antagonizes PD-1 and CTLA-4, and provides a CD28 costimulatory signal, resulting in a potent anti-tumor response. As we drive the ALPN-202 program towards the clinic in 2019, we believe we can create the next generation of immuno-oncology therapeutics with novel mechanisms of action using our proprietary scientific platform."

On April 17, 2018 Apexian Pharmaceuticals, a clinical-stage biotechnology company focused on developing safe and effective therapy for patients with high unmet medical needs, reported that it will present two key poster sessions at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Meeting, which will be held at McCormick Place in Chicago, Illinois from April 14 – 18, 2018 (Press release, Apexian Pharmaceuticals, APR 17, 2018, View Source [SID1234525431]). Dr. Mark Kelley, Apexian’s Chief Scientific Officer, along with the research team will available at the posters session. The company will present two posters on combination therapy of APX3330 in pancreatic cancer and APE1 signaling pathway.

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The titles and locations for these sessions are:
"Combination Therapy in PDAC Involving Blockade of the APE1/Ref-1 Signaling Pathway: An Investigation into Drug Synthetic Lethality and Anti-Neuropathy Therapeutic Approach"
Session Date and Time: Tuesday, April 17, 2018 from 1:00 – 5:00 PM
Location: McCormick Place South, Exhibit Hall A, Poster Section 37
"APE1/Ref-1 Redox Signaling Regulates HIF1a-mediated CA9 Expression in Hypoxic Pancreatic Cancer Cells: Combination Treatment in Patient-derived Pancreatic Tumor Models"
Session Date and Time: Monday, April 16, 2018 from 1:00 – 5:00 PM
Location: McCormick Place South, Exhibit Hall A, Poster Section 41
The poster sessions will add significant new information gathered on the effectiveness of Apexian’s lead clinical candidate, APX3330, and the ongoing research on the APE1/Ref-1 target.

On April 17, 2018 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) reported the presentation of preclinical data exploring the mechanism of action of APTO-253, the company’s clinical stage product candidate (Press release, Aptose Biosciences, APR 17, 2018, View Source;p=RssLanding&cat=news&id=2343016 [SID1234525432]). The data, demonstrating heightened sensitivity of BRCA1 or BRCA2 mutated cancer cells to APTO-253, were presented in a poster Tuesday, April 17 at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held April 14-18, in Chicago, IL.

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The poster, entitled APTO-253 is a new addition to the repertoire of drugs that can exploit DNA BRCA1/2 deficiency, explored the mechanism of action of APTO-253, a small molecule with anti-proliferative activity against cell lines derived from a wide range of human malignancies. This study investigated the mechanism of action of APTO-253 to identify synthetic lethal interactions that can guide combination drug studies.

The research team found that APTO-253 stabilizes certain quadruplex DNA structures, causes DNA damage, and exhibits synthetic lethality comparable to olaparib – an FDA-approved targeted therapy that acts against cancers in people with hereditary BRCA1 or BRCA1 mutations, including some ovarian, breast and prostate cancers – albeit through a different mechanism. Unlike other drugs for which loss of this DNA repair function results in hypersensitivity, APTO-253 does not produce myelosuppression even at the maximum tolerated dose. The observations reported also identify γH2AX as a potential biomarker of clinical effect and open the window to more detailed studies of how APTO-253 promotes DNA damage and how it might be used clinically to treat patients with tumors harboring deficiencies in DNA repair.

The presentation will be published in the AACR (Free AACR Whitepaper) Conference Proceedings. The poster can also be accessed here or at the Publications & Presentations section of the Aptose website, www.aptose.com.
"We have clarified the mechanism of APTO-253 during the past year or so, including its mechanism to inhibit expression of the MYC gene, an oncogene that promotes tumor growth and resistance to drugs in AML and other cancers," said William G. Rice, Ph.D., Chairman, President and Chief Executive Officer. "AML remains our primary focus for APTO-253, and we hope to re-initiate dosing of AML patients with APTO-253 in an open phase Ib trial during the 2nd quarter of 2018. In the current presentation at AACR (Free AACR Whitepaper), we report that cancer cells deficient in the BRCA1/2 DNA repair functions are hyper-sensitive to APTO-253, analogous to the FDA-approved PARP inhibitor olaparib, but acting through a different mechanism. The findings reveal potential new solid tumor indications for APTO-253. Importantly, APTO-253 does not produce myelosuppression even at the maximum tolerated dose, which significantly distinguishes it from other cancer chemotherapies."

About APTO-253
APTO-253 is a clinical-stage small molecule targeted therapeutic agent that inhibits expression of the c-Myc oncogene, leading to cell cycle arrest and programmed cell death (apoptosis) in human-derived solid tumor and hematologic cancer cells, without causing general myelosuppression of the healthy bone marrow. The c-Myc oncogene is overexpressed in hematologic cancers, including acute myeloid leukemia (AML). Aptose researchers have reported the ability of APTO-253 to induce cell death, or apoptosis, in multiple blood cancer cell lines including AML, as well as in vitro synergy with various classes of conventional approved and investigational therapies for AML or myelodysplastic syndromes (MDS). New findings reveal that APTO-253 might also serve certain solid tumor patients with BRCA1/2 mutations, but without causing toxicity to the normal bone marrow functions.

On April 17, 2018 Seres Therapeutics, Inc. (NASDAQ:MCRB) reported that new preclinical data supporting the development of microbiome therapeutics for immuno-oncology (leveraging gut microbiota to impact tumor immunotherapy)1 will be presented today by Sceneay et al in the late breaking poster session at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (AACR) (Free AACR Whitepaper) in Chicago (Press release, Seres Therapeutics, APR 17, 2018, View Source [SID1234530893]). The data presented provide new insights on the potential mechanism by which Seres’ microbiome therapies could improve the outcomes of cancer patients treated with immune checkpoint inhibitors.

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"The data presented at AACR (Free AACR Whitepaper) provide important new models and mechanistic insights that inform our planned development efforts to evaluate the ability of microbiome therapy to augment immune checkpoint inhibitors," said David Cook, Ph.D., Chief Scientific Officer and Executive Vice President of Research at Seres. "The insights described in this presentation will guide the continued development of SER-401, which we expect to enter clinical development later this year. Our objective is to use our microbiome therapeutic approach to improve the efficacy of immunotherapy in patients with life-threatening cancers."

Seres presented results from preclinical studies designed to evaluate the impact of various consortia of bacterial species on the anti-tumor immune response in murine models following treatment with an anti-PD-1 checkpoint inhibitor. Results demonstrated that both germ-free mice lacking a microbiome and antibiotics-treated mice with a dysbiotic microbiome, failed to mount an effective anti-tumor response following treatment with an anti-PD-1 checkpoint inhibitor. The response to anti-PD-1 was restored in germ-free as well as antibiotics-treated mice by introducing a diverse microbiome, and was driven by increased entry of tumor-infiltrating lymphocytes into the tumor; specifically, CD8+ T effector cells. Current pre-clinical efforts are focused on optimizing specific microbiome compositions based on functional and phylogenetic information to inform the development of therapeutic candidates.

Seres is developing SER-401, a preclinical stage oral microbiome therapy comprising a consortium of live bacteria to improve the efficacy and safety of immunotherapy. Through a collaboration with The University of Texas MD Anderson Cancer Center and the Parker Institute for Cancer Immunotherapy, Seres plans to initiate a clinical study in patients with advanced metastatic melanoma later this year. In a 2017 study published in Science, the MD Anderson research team, led by Dr. Jennifer Wargo, described a microbiome signature associated with response to checkpoint inhibitor therapy. A planned clinical trial will evaluate the impact of an anti-PD-1 checkpoint inhibitor with adjunctive microbiome therapy on patient outcomes.

Now in its fourth day, the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 held in Chicago, has had plenty of news, much of it preclinical or early-clinical data (Press release, BioSpace, APR 17, 2018, View Source [SID1234525433]). Here’s a roundup of some of the top stories.

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Compugen and Bayer AG presented efficacy data of BAY 1905254 in cancer immunotherapy. The compound is a first-in-class antibody candidate that targets ILDR2, a novel immune checkpoint discovered by Israeli company Compugen. Bayer expects to move it into human trials sometime this year.

"ILDR2 is a completely new immune checkpoint that we discovered through our computational discovery capabilities," said Anat Cohen-Dayag, Compugen’s president and chief executive officer, in a statement. "This immune checkpoint, together with the discovery of TIGIT and PVRIG, clearly demonstrate the power and value of Compugen’s predictive discovery capabilities in the discovery of new drug targets and pathways, enabling the development of first-in-class product opportunities."
Sierra Oncology, based in Vancouver, presented data for its Checkpoint kinase 1 (Chk1) inhibitor SRA737, as a monotherapy and in combination with a poly ADP-ribose polymerase inhibitor (PARPi) like Tesaro’s Zejula (niraparib). It is being evaluated in an ongoing Phase I/II trial in replication stress-driven cancer. It also plans to initiate a Phase Ib/II trial in metastatic castration-resistant prostate cancer in the fourth quarter.

Tarveda Therapeutics, headquartered in Watertown, Massachusetts, presented preclinical data related to PEN-866. PEN-866 is a miniature drug conjugate to treat patients with solid tumor types that are sensitive to topoisomerase 1 inhibitors like SN-38, which is PEN-866’s payload. It is being evaluated in models of ovarian cancer, lung cancer and colorectal cancer. PEN-866 utilizes the activation of Heat Shock Protein 90 (HSP90) in tumors in order to accumulate and release its payload.

Lycera Corp., located in New York and Ann Arbor, Michigan, released clinical findings from the Phase I part of its Phase I/IIa ARGON trial of the company’s novel immuno-oncology candidate, LYC-55716. LYC-55716 is a first-in-class oral, selective retinoic acid-related orphan receptor-gamma (RORgamma) agonist that reprograms the immune system in solid tumor patients. In the 32 patients enrolled in six dosing cohorts, the drug was well tolerated and no dose-limiting toxicities were seen.
"The promising safety results and early signals of efficacy with LYC-55716 as a monotherapy are very encouraging," said Judy Wang, associate director of Drug Development, Florida Cancer Specialists and Sarah Cannon Research Institute, in a statement. "We are very pleased to be participating in the development of this novel immunotherapeutic, and are actively enrolling patients with advanced solid tumor cancers in the Phase IIa portion of the study."

Lund, Sweden’s Alligator Bioscience presented preclinical data on its immune activating antibody ATOR-1015. ATOR-1015 is a first-in-class bispecific tumor-directed antibody that targets CTLA-4 and OX40. The data shows the compound localizes to the tumor and activates the immune system in the surrounding area, which confirms the drug’s mechanism of action. It is designed mostly for a combo-therapy with PD-1 blocking antibody.
"The results presented in Chicago confirm that our CTLA-4 bispecific antibody ATOR-1015 selectively activates the immune system in the tumor area," said Per Norlen, Alligator’s chief executive officer, in a statement. "This offers great potential for an improved benefit/risk profile for cancer patients. We are more and more excited about the significant prospects for this unique compound, particularly in combination with PD-1 blockers, and are looking forward to initiate clinical development later in the year."
CBT Pharmaceuticals, based in Pleasonton, California, a U.S. and China-based biopharmaceutical company, presented preclinical in-vivo data and animal safety pharmacology studies of CBT-102. This compound is a multi-targeted kinase inhibitor that targets VEGFR, PDGFR, MAPK, B-RAF, C-RAF, C-KIT and CSF1R. It showed tumor regression in 52 patient-derived xenograft models, including non-small cell lung, colorectal, gastric, and hepatocellular carcinoma.
"We are highly encouraged by the preclinical safety and efficacy data of CBT-102," said Sanjeef Redkar, president and chief executive officer of CBT Pharma, in a statement. "Based on this data set, we plan to advance CBT-102 into GLP toxicology studies in 2018 with an aim to enter the clinic in early 2019 in combination with other agents in our portfolio."