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Harpoon Therapeutics Unveils ProTriTAC Platform: A Novel, Protease-Activated T Cell Engager Platform Designed to Access a Broad Landscape of Solid Tumor Targets

On November 9, 2018 Harpoon Therapeutics, Inc. ("Harpoon"), a clinical-stage immunotherapy company developing a novel class of T cell engagers that harness the power of the body’s immune system to treat patients suffering from cancer and other diseases, reported preclinical data supporting the development of a new Protease-activated Tri-specific T cell Activating Construct ("ProTriTAC") platform (Press release, Harpoon Therapeutics, NOV 9, 2018, View Source [SID1234531108]). The new ProTriTAC platform is based on Harpoon’s Tri-specific T cell Activating Construct ("TriTAC") technology, which is designed to bind a patient’s immune cells to cancer cells. This binding leads to activation of the immune cell, which then attacks and kills the cancer cell. Data were presented at the 2018 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in Washington, D.C., held November 9-11, 2018.

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Therapeutics derived from the new ProTriTAC platform are intended to be administered as T cell inactive prodrugs and are optimized for serum exposure to ensure delivery to solid tumor tissues. At the site of the tumor, these prodrugs can be locally activated by tumor-associated proteases. This induces T cells to kill tumor cells expressing target antigen without affecting other tissues.

"We are very pleased to launch our ProTriTAC platform, which retains the advantages of our TriTAC platform, including activity at low levels of target expression, extended serum half-life and conventional manufacturing. Our ProTriTAC platform allows us to access tumor-associated antigens that have been historically challenging because they are expressed in both tumors and non-tumor tissues. ProTriTAC therapeutics are designed to be serum half-life extended, but do not engage T cells until they are clipped by tumor-associated proteases. Once clipped, a T cell activator is released at the site of the tumor. However, this T cell activator now has a short half-life and is quickly removed from circulation before it can impact non-tumor tissues," said Holger Wesche, PhD, Chief Scientific Officer of Harpoon. "Harpoon plans to bring its first ProTriTAC product candidate into IND-enabling studies in 2019."

"ProTriTAC is an important extension of Harpoon’s proprietary TriTAC platform, a T cell engager platform designed to harness the natural power of the patient’s own immune system to fight cancer and other diseases," said Jerry McMahon, PhD, President and CEO of Harpoon. "ProTriTAC product candidates have the potential to increase the number of possible tumor antigen targets for Harpoon’s emerging pipeline."

The poster entitled "ProTriTAC: A Protease-Activatable T Cell Engager Platform That Links Half-Life Extension to Functional Masking" can be found on the Publications page of Harpoon’s website. Key proof-of-concept data include:

Biological Activity Dependent on Protease Activation

Intact ProTriTAC proteins can block binding to T cells by more than 500-fold, but they can become fully active after a single proteolytic cleavage event, enabling T cell binding and activity in the tumor microenvironment.

Potent Anti-Tumor Activity In Vivo Is Protease-Dependent

When administered to tumor-bearing mice, ProTriTAC molecules can completely inhibit tumor growth with doses as low as 0.03 mg/kg. These data imply that this activity depends on proteolytic activation of the ProTriTAC in the tumor.

Reduced T Cell Binding and Rapid Clearance of the Active Drug in Non-Human Primates

Pharmacokinetic data derived from non-human primates confirm that ProTriTACs exhibit long serum half-life and support that T cells are not being engaged by the prodrug form.

Obsidian Presents Preclinical Data Demonstrating Precise Regulation of Cytokines and CAR in T cells with Destabilizing Domain Technology using FDA-Approved Drugs

On November 9, 2018 Obsidian Therapeutics, Inc., a biotechnology company developing cell therapies with pharmacologic operating systems, reported the presentation of preclinical data demonstrating fine-tuned regulation of cytokine production and CAR-T function using Destabilizing Domains (DDs) paired with FDA-approved small molecule drugs (Press release, Obsidian Therapeutics, NOV 9, 2018, View Source [SID1234531107]). Obsidian will reveal a suite of novel human DDs and showcase their application in CAR-T therapy at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 33rd Annual Meeting in Washington, DC, November 7-11, 2018.

DDs are small, fully-human protein domains that confer conditional stability to a fused payload protein. These regulated cassettes can be readily added to a cell or gene therapy product. CAR-T cells are engineered to find and destroy tumor cells and can be armed with powerful cytokines, such as IL12 and IL15, to further enhance anti-tumor immunity. However, these potent immune modulators require precise control to optimize their therapeutic benefit.

"Pharmacologic regulation of CAR-T therapies is a critical next step in the advancement of adoptive immunotherapy for cancer," said Steve Shamah, Ph.D., Senior Vice President and Head of Research for Obsidian, who will present one of the posters at SITC (Free SITC Whitepaper)’s 33rd Annual Meeting. "By designing pharmacologic operating systems that use FDA-approved small molecules for regulation, we believe we have opened a new set of opportunities for next-generation cell therapies."

Highlights of the two preclinical presentations describing Obsidian’s enhanced CAR-T therapies include:

Abstract Number P271: Titratable and reversible regulation of IL12 or IL15 with FDA-approved drugs for enhanced CAR-T therapy
Presenter: Steve Shamah, Ph.D.
Date and Time: Friday, November 9, from 12:45 – 2:15 pm and 6:30 – 8 pm

Our discovery process yields a wide array of fully human DD variants with performance characteristics that can be matched to specific applications.
We have achieved titratable, fine-tuned regulation of IL12 and IL15 in human T cells in vitro and in vivo with clinically translatable DDs and FDA-approved drugs.
Abstract Number P238: Regulation of in vivo anti-tumor activity of adoptively transferred CAR-T cells using FDA-approved small molecule drugs
Presenter: Jennifer Gori, Ph.D., Associate Director, Head of In Vivo Pharmacology, Obsidian
Date and Time: Saturday, November 10, from 12:20 – 1:50 pm and 7:00 – 8:30 pm

DDs provide small molecule regulation of CAR expression and activity in T cells.
We have demonstrated on-demand anti-tumor activity of a clinically translatable DD-CAR in T cells with drug dosing in vivo.
These studies show Obsidian’s ability to achieve precise kinetic and dose-responsive control over transgene-derived protein expression, fueling the development of CAR-T cell therapies that are potentially safer and more efficacious.

About Destabilizing Domains

Obsidian uses Destabilizing Domains (DDs) to enable pharmacologic regulation of protein activity for next-generation cell and gene therapies. Obsidian’s DDs are small, fully-human protein domains that confer conditional stability to a fused payload protein. In the absence of a specific small-molecule ligand, the fusion protein is rapidly degraded, whereas in the presence of the ligand the fusion protein becomes stable and functional. Obsidian uses this approach to equip engineered cells with controllable functions that can be precisely tuned by the administration of non-immunosuppressive, small-molecule medicines that are readily available and dispensed by the treating physician.

Vaxart Announces Third Quarter 2018 Financial Results and Provides Corporate Update

On November 9, 2018 Vaxart, Inc., a clinical-stage biotechnology company developing oral recombinant vaccines that are administered by tablet rather than by injection, reported financial results for the third quarter ended September 30, 2018 and provided a corporate update (Press release, Vaxart, NOV 9, 2018, View Source [SID1234531106]).

"As our first year as a public company comes to a close, Vaxart’s main focus continues to be the development of our oral tablet vaccine for the prevention of norovirus infection. Due to a manufacturing issue, our norovirus GI.1 vaccine tablets failed release testing, and we now expect to initiate our Phase 1 bivalent study and Phase 2 monovalent challenge study in the first half of 2019," said Wouter Latour, M.D., chief executive officer of Vaxart. "Besides our norovirus program, we are also advancing our first therapeutic vaccine for the treatment of human papillomavirus (HPV)–associated cancer and dysplasia and we are on track to file an IND for our HPV vaccine in 2019."

"Norovirus causes up to 20 million cases of acute gastroenteritis in the U.S. each year, with significant morbidity and mortality in vulnerable populations like the very young and elderly," Dr. Latour continued. "Norovirus outbreaks are notorious in long-term care facilities, schools, hospitals, restaurants and cruise ships. In all, norovirus disease costs society an estimated $5.5 billion annually in the United States, according to a prominent health economics study published in 2012. At IDWeek in October of this year, we presented breakthrough data demonstrating that our oral H1 flu vaccine primarily protected through mucosal immunity. Our oral norovirus vaccine is based on the same platform, and we expect it to provide superior protection compared to injectable alternatives."

Third Quarter 2018 and Recent Highlights:

Corporate:

The Company’s Phase 1 bivalent and Phase 2 challenge norovirus studies are now expected to begin in the first half of 2019 due to a manufacturing issue affecting the norovirus GI.1 vaccine tablets. Vaxart is working diligently to resolve the issue.
On October 6, 2018, the Company presented data from its H1 influenza Phase 2 challenge study demonstrating that its oral H1 flu vaccine, while providing 39% reduction in flu illness compared to 27% for Fluzone, protected primarily through mucosal immunity, in contrast to Fluzone which primarily protected through serum antibodies. This finding confirmed that Vaxart’s oral vaccines are uniquely suited to provide protection against mucosal pathogens such as influenza, norovirus and respiratory syncytial virus (RSV). A copy of this presentation can be found on the Investor Relations page on the Company’s website.
On October 4, 2018, the Company presented preclinical data on its human papillomavirus (HPV) vaccine trial in a poster presentation at the 32nd International Papillomavirus Conference in Sydney, Australia. As described in the poster, the Vaxart HPV vaccine created CD8 tumor-infiltrating T cells and eliminated or significantly reduced the majority of tumors with or without a checkpoint inhibitor. Preparations to advance the program into the clinic in 2019 are underway. A copy of this presentation can be found on the Investor Relations page on the Company’s website.
Following the completion of the 3-month follow-up assessment of the Phase 2 clinical trial evaluating teslexivir, a small-molecule antiviral for the treatment of condyloma that Vaxart obtained in the acquisition of Aviragen in 2018, analysis of the data showed there was no improvement compared to the topline results reported in June 2019.
Third Quarter 2018 Financial Results

Vaxart reported a net loss of $6.5 million for the third quarter of 2018 compared to a net loss of $2.2 million for the third quarter of 2017. For the nine months ended September 30, 2018, the net loss was $13.1 million compared to a net loss of $8.5 million for the same period in 2017.
Vaxart ended the quarter with cash and cash equivalents of $17.9 million compared to $23.9 million at June 30, 2018. The decrease was primarily due to cash used in operations.
Revenue for the quarter was $0.3 million compared to $0.9 million in the third quarter of 2017. The decrease was due to lower revenues from the contract with BARDA, which ended on September 30, 2018.
Research and development expenses were $4.4 million for the quarter compared to $2.2 million for the third quarter of 2017. The increase was due to higher clinical and manufacturing costs incurred in the Company’s norovirus program, clinical costs incurred in completing the teslexivir trial, and the amortization of intangible assets acquired in the merger with Aviragen, offset by lower expenditures incurred under the BARDA contract.
General and administrative expenses were $1.7 million for the quarter compared to $0.6 million for the third quarter of 2017. The increase was a result of a higher headcount and additional expenses relating to operating as a public company, including expenses required for regulatory compliance, additional insurance, director fees and other professional expenses.

Veracyte to Present at the Canaccord Genuity Medical Technologies & Diagnostics Forum

On November 9, 2018 Veracyte, Inc. (Nasdaq: VCYT) reported that Bonnie H. Anderson, chairman and chief executive officer, will present at the Canaccord Genuity Medical Technologies & Diagnostics Forum on Thursday, November 15, 2018, at 9:00 a.m. Eastern Time (ET) (Press release, Veracyte, NOV 9, 2018, View Source [SID1234531105]).

A live audio webcast of the company’s presentation will be available by visiting Veracyte’s website at View Source A replay of the webcast will be available for 90 days following the conclusion of the live presentation broadcast.

Alpine Immune Sciences Advances Oncology Programs with New ALPN-202 Preclinical Data and Key Additions to Scientific Advisory Board

On November 9, 2018 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading immunotherapy company focused on developing innovative treatments for cancer, autoimmune/inflammatory, and other diseases, reported advancements in the company’s oncology program (Press release, Alpine Immune Sciences, NOV 9, 2018, View Source [SID1234531104]). Following promising preclinical data presented today at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 33rd Annual Meeting in Washington, D.C., the company remains on track to initiate human clinical trials of ALPN-202, a PD-L1/CTLA-4 dual antagonist with PD-L1 dependent CD28 costimulation, in the fourth quarter of 2019. Additionally, Alpine has strengthened its Scientific Advisory Board with the addition of key oncology leaders – Rafi Ahmed, Ph.D., James Welsh, M.D., and John Thompson, M.D.

ALPN-202 Preclinical Study Results Presented at SITC (Free SITC Whitepaper)’s 33rdAnnual Meeting

Alpine presented the results of a preclinical study of ALPN-202 in a poster session today, strongly supporting the proposed mechanism of action of ALPN-202 via activation of the immune system in a differentiated way from current checkpoint therapies. ALPN-202 is a novel molecule designed to block the inhibitory immune checkpoints PD-L1 and CTLA-4 while providing PD-L1 dependent T cell activation via the CD28 costimulatory pathway. It has previously been demonstrated to have efficacy in an MC38-based colorectal cancer model, superior to the FDA-approved PD-L1 inhibitor durvalumab. Today’s poster correlates these findings with superior intratumoral immune cell infiltration and effector gene signatures, as well as favorable changes in T cell receptor profiles, consistent with ALPN-202’s proposed multi-modal mechanism of action.

"ALPN-202 is differentiated from currently approved checkpoint inhibitors by providing T cell costimulation in addition to dual checkpoint antagonism. We believe that the provision of costimulation, such as via CD28, will be critical to improving response rates during checkpoint inhibition," said Stanford Peng, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Alpine. "In this way, ALPN-202 could result in superior monotherapy efficacy over single or even dual checkpoint antagonists. We anticipate initiating human clinical trials of ALPN-202 for the treatment of advanced malignancies in the fourth quarter of 2019."

The preclinical study evaluated the anti-tumor responses of ALPN-202 compared with durvalumab in mice implanted with human PD-L1 transduced MC38 tumors. Results showed ALPN-202:

Produced dose-dependent anti-tumor responses, including potent single-dose activity
Induced a greater tumor inflammation gene signature than durvalumab
Induced increased T cell infiltration and T cell-related effector gene signatures compared to durvalumab
Promoted both increased T cell receptor clonality and richness, consistent with ALPN-202’s multiple mechanisms of action
NKp30/ICOSL vIgD-Fc program demonstrates tumor-localized costimulation

In a second preclinical study, Alpine used its variant immunoglobin domain (vIgD) platform to engineer novel NKp30/ICOSL vIgD fusion proteins. The resulting therapeutic is designed to agonize two T cell costimulatory receptors ICOS and CD28 only in the presence of B7-H6, a tumor antigen overexpressed in certain cancer types such as some forms of esophageal, kidney, rectal, and stomach cancers.

Results showed the NKp30-ICOSL vIgD-Fc fusion proteins:

Conferred potent T cell costimulation in vitro, with enhanced T cell proliferation and cytokine production only in response to B7-H6-expressing target cells. In contrast, ICOSL and NKp30 vIgDs alone in the absence of B7-H6 were not inflammatory.
Demonstrated efficacy in a B7-H6-positive CT26 mouse colon cancer model, especially when administered in combination with a PD-1 inhibitor. The proteins were not effective on a B7-H6-negative parental CT26 tumors, demonstrating target specificity.
Dr. Peng added, "These results are encouraging because they indicate that NKp30/ICOSL vIgD-Fc fusion proteins in particular may provide a novel therapeutic strategy to provide tumor-specific immunomodulation in a B7-H6-dependent fashion and support the utility of Alpine’s platform in developing novel targeted agents in oncology."

Scientific Advisory Board Appointments

Drs. Rafi Ahmed, James Welsh, and John Thompson have been appointed to the Alpine Immune Sciences Scientific Advisory Board. They join a team of distinguished translational and clinical scientists including Andrew Scharenberg, M.D, Scientific Advisory Board Chair, Manish Butte, M.D, Ph.D, and Paul Tumeh, M.D.

"We welcome Rafi, James, and John to the Alpine Scientific Advisory Board," said Andy Scharenberg, M.D. "The support of these scientific leaders and their belief in Alpine’s vision to bring novel molecules to patients will be important as we work to advance our oncology programs into the clinic next year."

Dr. Rafi Ahmed, Ph.D. is a highly respected researcher who has contributed significant influential work over the past decade in shaping the current understanding of memory T cell differentiation and anti-viral T and B cell immunity. He is the Charles Howard Candler Professor of Microbiology and Immunology at Emory University, where he is also Director of the Emory Vaccine Center, and a Georgie Research Alliance Eminent Scholar in Vaccine Research. He is also a member of the National Academy of Sciences.

"I am looking forward to working with the Alpine team as they have a unique approach of targeting T cells," said Dr. Ahmed. "My lab previously published research showing how CD28/B7 pathway costimulation is required for anti PD-1 antibody efficacy, so I’m particularly excited work with Alpine on their ALPN-202 program."

Dr. James Welsh, M.D. is a Tenured Physician Scientist at The University of Texas MD Anderson Cancer Center, where he serves as the Head of the Immune Radiation program with the goal of using radiation to turn the tumor into an "in-situ" vaccine in order to prime T cells, turning radiation into a systemic therapy. Dr. Welsh and his team recently developed the first mouse model of PD-1 resistance to investigate the mechanisms how cancer cells adapt to evade the immune system.

Dr. John Thompson, M.D. is the Medical Director of the Phase 1 Clinical Trials Program and Co-Director of the Melanoma Clinic at the Seattle Cancer Care Alliance. He also serves as a Professor in the Medical Oncology Division at the University of Washington School of Medicine and is a member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center. Dr. Thompson is a member of several medical societies, including the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), the American Association for Cancer Research (AACR) (Free AACR Whitepaper), the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), and the National Kidney Cancer Association. He has authored or co-authored more than 150 articles, appearing in the Journal of Immunology, Blood Leukemia, Journal of Clinical Oncology, and Clinical Cancer Research, among others.