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 Alligator Bioscience (Nasdaq Stockholm: ATORX), a biotechnology company developing antibody-based pharmaceuticals for tumor-directed immunotherapy, reported preclinical data on the immune activating antibody ATOR-1015 at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 taking place in Chicago, Illinois American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 taking place in Chicago, Illinois. ATOR-1015 is a first-in-class bispecific tumor-directed antibody, targeting CTLA-4 and OX40, designed to selectively activate the immune system in the tumor, without increasing systemic toxicity.

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The preclinical data demonstrate that ATOR-1015 physically localizes to the tumor and selectively activates the immune system in the tumor area, confirming the intended ATOR-1015 mechanism of action.

ATOR-1015 is primarily designed for combination therapy with a PD-1 blocking antibody, and the potential of this approach is supported with preclinical data reporting enhanced anti-tumor effect of ATOR-1015 in combination with an anti-PD-1 antibody, as compared to anti-PD-1 monotherapy. In addition, ATOR-1015 demonstrated superior efficacy compared to mono-targeting CTLA-4 and OX40 antibodies.

"The results presented in Chicago confirm that our CTLA-4 bispecific antibody ATOR-1015 selectively activates the immune system in the tumor area. 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", said Per Norlén CEO of Alligator Bioscience.

Alligator is planning to initiate an ATOR-1015 Phase I study during the second half of 2018.

A poster with the title "CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation" is showcased today at 8-12 a.m. EDT and is also available on the company web page View Source

For further information, please contact:
Cecilia Hofvander, Director Investor Relations & Communications
Phone +46 46 286 44 95
E-mail: [email protected]

The information was submitted for publication, through the agency of the contact person set out above, at 3 p.m. CEST on 17 April 2018.

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 Elios Therapeutics, a biopharmaceutical company developing innovative particle-delivered, dendritic cell vaccines in oncology, reported initial open-label results from the ongoing Phase 2b clinical trial of the TLPLDC (tumor lysate, particle-loaded, dendritic cell) vaccine in patients with stage III and IV (resected) melanoma (Press release, Orbis Health Solutions, APR 17, 2018, View Source [SID1234529911]). Results were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting held April 14-18, 2018 in Chicago, Illinois.

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"We are encouraged by these initial open-label results from our Phase 2b trial which demonstrate a compelling safety profile and provide early evidence that the TLPLDC vaccine may enhance the efficacy of commonly used FDA-approved systemic therapies, including checkpoint inhibitors," said George E. Peoples, M.D., chief medical officer at Elios Therapeutics. "We look forward to continuing our assessment of the TLPLDC vaccine in this ongoing study as we evaluate opportunities for further clinical development of combination therapies."

In an ongoing prospective, randomized, double-blind, placebo-controlled Phase 2b trial, patients with resected Stage III and IV melanoma were randomized (2:1) to received either TLPLDC vaccine or placebo to prevent recurrence. All patients who recurred on the trial (met study endpoint) were then offered open-label TLPLDC along with standard of care therapy as determined by the patient’s treatment team.

The initial open-label results presented were from 22 patients. Seven patients had their recurrences resected and were treated with the TLPLDC vaccine to prevent a second recurrence. At 12.5 months of median follow-up, only one patient has recurred.

The remaining 15 patients were on a variety of FDA-approved systemic therapies for their non-resectable recurrences. Of these patients, two patients withdrew from the study and one was not treated. In the remaining 12 patients treated with the TLPLDC vaccine in combination with their standard of care systemic therapy, two patients had a complete response (median follow-up 8.6 months), seven had stable disease and two had progressive disease. One patient progressed initially on TLPLDC vaccine alone but was converted to a complete response once checkpoint inhibitor therapy was initiated. Importantly, the addition of the TLPLDC vaccine did not increase the toxicity of checkpoint inhibitors, BRAF/MEK inhibitors, or TVEC in these patients.

To view the full abstract, please visit the AACR (Free AACR Whitepaper) website at View Source

About TLPLDC
The TLPLDC (tumor lysate, particle-loaded, dendritic cell) vaccine is an autologous, personalized, therapeutic cancer vaccine designed to stimulate the immune system to recognize tumor cells and fight a patient’s specific cancer. TLPLDC is made from the patient’s own tumor cells and dendritic cells – the most potent antigen-presenting cells in the body. Once TLPLDC is injected, the tumor lysate-loaded dendritic cells present the tumor antigens to the immune system, stimulating the induction of tumor-specific, activated T cells that are able to find and destroy tumor cells that may remain in the body. TLPLDC is currently being studied as a monotherapy and in combination with standard of care checkpoint inhibitor therapy in a Phase 2b clinical trial for the treatment of late-stage melanoma at leading academic cancer centers in the United States.