On April 18, 2016 Biothera Pharmaceuticals, Inc. reported research providing new insights into the ability of the Company’s Phase 2 cancer immunotherapy to coordinate innate and adaptive immune responses and enhance the effectiveness of combination therapies (Press release, Biothera, APR 18, 2016, View Source [SID:1234511022]). The findings were presented today at the AACR (Free AACR Whitepaper) annual meeting, which is taking place in New Orleans, LA, April 16-20, 2016.

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AACR logoThe company is presenting five poster presentations at the AACR (Free AACR Whitepaper) meeting focusing on the unique therapeutic mechanisms of action for Imprime PGG, a Pathogen Associated Molecular Patterning molecule, or PAMP. Imprime PGG acts as an immunological "ignition switch" enlisting the innate immune system to enhance the therapeutic efficacy of tumor targeting, anti-angiogenic, and immune checkpoint inhibitor antibodies.

"These data provide compelling new evidence demonstrating in vivo that Imprime PGG can re-orient the immunosuppressive tumor microenvironment, especially in concert with anti-VEGF or anti-VEGF2 antibodies," said Jeremy Graff, Ph.D., Chief Scientific Officer and Senior Vice President, Research, at Biothera Pharmaceuticals. "Imprime PGG also effectively binds to dendritic cells, enhancing the maturation of these professional antigen presenting cells, which is key to enabling robust T cell-mediated anti-cancer immune responses and to driving therapeutic synergy with immune checkpoint inhibitors."

The Biothera Pharmaceuticals presentations, including three appearing in the late-breaking immunology research poster session, advance understanding of the mechanisms by which Imprime PGG augments immune responses:

Imprime PGG significantly enhances the efficacy of both anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors in preclinical in vivo Fully 83% of mice treated with Imprime PGG and anti-PD-L1 antibody were tumor-free after 29 days, compared with 33% of mice treated with anti-PD-L1 antibody alone. The tumor-free mice were re-injected in the opposite flank with cancer cells and remained tumor-free, indicating the establishment of immunological memory against the tumor.
Imprime PGG also upregulates expression of the critical co-stimulatory marker CD86, as well as PD-L1, on peripheral blood mononuclear cells (PBMCs) isolated from the blood of Imprime PGG-treated colon cancer patients, providing the first evidence from human clinical trials that Imprime elicits the critical immune changes in humans previously recognized in preclinical studies.
Additionally, Imprime PGG has been shown to trigger the direct tumor-killing functions of the innate immune system, dramatically reducing metastatic burden in concert with a tumor-targeting antibody in a model of melanoma metastases to lung.
By promoting myeloid-derived suppressor cell (MDSC) differentiation and repolarization of suppressive M2 macrophages, Imprime PGG re-educates the immune microenvironment and enhances the therapeutic efficacy of anti-angiogenic antibodies.
Further, Imprime PGG enables the activation and maturation of dendritic cells – the body’s professional antigen presenting cells – to facilitate T cell-mediated, antigen-specific immune responses.
The posters will be available on the Biothera Pharmaceuticals website, as they are presented today and tomorrow.

On April 18, 2016 Foundation Medicine, Inc. (NASDAQ:FMI) reported new data from more than 1,200 pediatric tumors across 51 cancer subtypes that were analyzed using the company’s comprehensive genomic profiling assays, FoundationOne and FoundationOne Heme (Press release, Foundation Medicine, APR 18, 2016, View Source [SID:1234511021]). The dataset reveals novel and potentially targetable genomic alterations identified during pediatric cancer clinical care that offer the possibility for new research towards novel therapeutics. In a separate but related announcement at the White House Precision Medicine Initiative Summit in February, Foundation Medicine made this data set publically available for research to motivate and accelerate development of new therapies to fight pediatric cancer.

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These findings were presented in a late-breaking poster titled "Genomic profiling of 1239 diverse pediatric cancers identifies novel discoveries across tumors" by Juliann Chmielecki, Ph.D., associate director, cancer genomics at Foundation Medicine, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 taking place April 16-20 in New Orleans.

The poster presentation details genomic profiles from 1,239 pediatric tumors (ages 0-18). Multiple studies are actively investigating clinically relevant genomic alterations in common tumor subtypes for therapeutic exploitation. As demonstrated by the identification of novel fusions and mutations, this data set offers significant discovery potential and can be used to generate hypotheses, validate rare findings, and investigate the genomic landscape of rare tumors in a pediatric population for which only small studies currently exist. Key findings include:

Genomic profiles from 51 disease subtypes representing sarcomas (26.6 percent), other blastomas (22.4 percent), brain tumors (20.4 percent), hematological malignancies (19.5 percent), carcinomas (9.8 percent) and gonadal tumors (1.4 percent).

Alterations with proven clinical actionability in pediatric cancers (BRAF V600E and ALK, NTRK1 and ABL1 fusions) were found in 3.9 percent of samples across brain, sarcoma and hematologic cases.

Three novel ALK fusions were identified in a neuroblastoma (BEND5-ALK), a soft tissue sarcoma (IGFBP5-ALK) and an astrocytoma (PPP1CB-ALK), respectively. Two novel BRAF fusions were also found in an astrocytoma (BCAS1-BRAF) and a ganglioglioma (TMEM106B-BRAF).

This large data set also challenges the paradigm of "disease-specific" alterations as previously characterized fusions involving ALK, NTRK1 and PAX3 were observed in novel diseases from which they were originally reported.

Pediatric cancers are a rare and diverse collection of diseases. Childhood cancer rates have been rising slightly for the past few decades, with The American Cancer Society estimated 10,380 children in the U.S. were diagnosed with cancer in 2015. Pediatric cancer remains the leading cause of death by disease among children. Despite advances in detection and treatment of childhood cancer, over 1,900 pediatric patients in the United States succumb to disease each year.1

A phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), efficacy and pharmacogenetic characteristics of clofarabine in seven Japanese pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients in Cohort 1 received clofarabine 30 mg/m(2)/day for 5 days, followed by 52 mg/m(2)/day for 5 days in subsequent cycles. Cohort 2 patients were consistently treated with 52 mg/m(2)/day for 5 days. No more than six cycles were performed. Every patient had at least one ≥Grade 3 adverse event (AE). AEs (≥Grade 3) related to clofarabine were anaemia, neutropenia, febrile neutropenia, thrombocytopenia, alanine aminotransferase increased, aspartate aminotransferase increased, haemoglobin decreased, and platelet (PLT) count decreased. C max and AUC of clofarabine increased in a dose-dependent fashion, but its elimination half-life (T 1/2) did not appear to be dependent on dose or duration of treatment. Clofarabine at 52 mg/m(2)/day shows similarly tolerable safety and PK profiles compared to those in previous studies. No complete remission (CR), CR without PLT recovery, or partial remission was observed. Since clofarabine is already used as a key drug for relapsed/refractory ALL patients in many countries, the efficacy of clofarabine in Japanese pediatric patients should be evaluated in larger study including more patients, such as by post-marketing surveillance.

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On April 18, 2016 AstraZeneca reported new data from multiple molecules in its industry-leading DNA Damage Response (DDR) pipeline at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA (Press release, AstraZeneca, APR 18, 2016, View Source [SID:1234511011]). These agents use a variety of different pathways to disrupt tumour cells’ natural ability to repair themselves as they replicate, eventually causing the tumour cells to die.7,8 Illustrating the unique breadth of AstraZeneca’s approaches to DDR, presentations at AACR (Free AACR Whitepaper) featured molecules that disrupt multiple tumour cell repair processes, including single-strand break repair, double-strand break repair, and cell cycle regulation.1-6

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Susan Galbraith, Head of AstraZeneca’s Oncology Innovative Medicines Unit said, "Taken together with the positive Phase II results of olaparib in patients with metastatic, castration-resistant prostate cancer published early this year,9 we are encouraged by the potential of PARP inhibition in multiple tumour types beyond ovarian cancer. The breadth of our pipeline showcases DDR monotherapies and combinations that could attack cancer in a multitude of novel ways – our first priority, as demonstrated here at AACR (Free AACR Whitepaper), is to follow the science to identify and quickly advance those molecules that have the potential to address the greatest unmet medical needs."

PARP Inhibition and Lynparza (olaparib): Beyond Ovarian Cancer

The PARP inhibitor olaparib is the cornerstone of AstraZeneca’s pipeline of personalised treatments targeting DDR mechanisms in cancer cells. Olaparib was combined with the investigational AKT inhibitor AZD5363 in a new Phase I trial of germline (g) BRCA and non-BRCA mutant (m) advanced cancer patients with ovarian, breast, prostate and bile duct cancers.1 Results showed that the olaparib-AZD5363 combination was well-tolerated with multiple responses, including 10 RECIST complete or partial responses (out of 37 evaluable patients) in both gBRCA and non-BRCAm tumours, as well as prior PARP inhibitor-treated cancers.1

Olaparib disrupts the repair of single-strand DNA breaks, a mode of action that has potential to work in a range of tumour types beyond ovarian cancer.10 AstraZeneca is researching how several different compounds can be combined with DDR molecules to provide a dual threat to tumour cells. For example, treatments such as AZD5363 that selectively inhibit the PI3K / AKT signalling pathway may complement olaparib’s interference with tumour DNA repair.1

Additional Mechanisms of DDR: Cell Cycle Disruption & Double-Strand Break Repair

AstraZeneca presented data on a variety of investigational compounds acting on different aspects of the DDR pathway, both in monotherapy and in combination. Most significant were early results from a Phase Ib open-label study of AZD1775, a novel small molecule designed to inhibit the Wee1 kinase.2 Wee1 is a protein kinase that helps regulate the cell cycle.5 In many tumours, Wee1 overexpression stops the cell cycle after DNA damage occurs, allowing tumour cells time to repair any damage.5,11 By inhibiting Wee1, the cell cycle continues despite damage, which can lead to tumour cell death.5 Assessing the safety, tolerability, pharmacokinetics and anti-tumour activity of AZD1775, the Phase Ib safety run-in included patients with small-cell lung, non-small cell lung, head and neck, ovarian, breast, pancreas and unknown primary tumours.2 Early results demonstrated a partial or stable response in a third of patients (4/12), and AstraZeneca has initiated expansion cohorts in ovarian, breast and small-cell lung cancer.2 Other studies currently recruiting include a Phase I multi-centre, dose escalation study of AZD1775 combined with olaparib in refractory solid tumours.12

Several other new molecules in the clinical pipeline are entering Phase I development, including the first-in-class Ataxia telangiectasia mutated (ATM) kinase inhibitor AZD0156.3 Pre-clinical in vivo activity of AZD0156 presented at AACR (Free AACR Whitepaper) demonstrated that inhibition of ATM during the DNA damage response enhanced the efficacy of a range of DNA-damaging agents, including olaparib, and support its further study in the clinical setting.3 AstraZeneca is now recruiting for a Phase I trial of AZD0156 as monotherapy or in combination with olaparib in patients with advanced solid tumours.13

Other ongoing DDR-focused studies include additional Phase I trials of the Aurora B kinase inhibitor AZD281114 and ATR inhibitor AZD6738 in solid tumours.15

On April 17, 2016 Precision Biologics, a NantWorks affiliated clinical stage biotechnology company focused on developing therapeutic and diagnostic products for the early detection and treatment of cancer and a participant in the Cancer MoonShot 2020 program, reported it will present a poster titled, "Identification of target and cytotoxicity of novel monoclonal antibody NEO-201 in ovarian and uterine cancer subtypes" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (Press release, Precision Biologics, APR 18, 2016, View Source [SID:1234511010]).

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"With better identification of cancer subtypes that express the NEO201 target, we are taking a step closer to personalized medicine for women diagnosed with ovarian and uterine cancer," said Philip M. Arlen, M.D., President & Chief Executive Officer of Precision Biologics, Inc. of Rockville, MD. "Without the visionary support of NantWorks and Dr. Patrick Soon-Shiong, tumor-specific and neo-epitope cytotoxicity research would face a much slower development path, potentially impacting cancer morbidity and mortality rates."

At AACR (Free AACR Whitepaper), Precision Biologics will present preclinical data on the cytotoxic effects of NEO-201 in uterine and ovarian cancers. NEO-201 is an investigational, humanized monoclonal antibody that targets a novel neo-antigen with sequence homology to the tumor-associated antigens (TAA) CEACAM-5 and CEACAM-6, but highly sensitive to epithelial tumors with little cross reactivity to normal tissue. It is being explored as a potential therapy for epithelial malignancies. NEO-201 demonstrates antibody-dependent cellular cytotoxicity and specifically targets cancer tissues with minimal reactivity in normal tissues.

"Accelerating clinical development of neo-epitopes is a key focus of our immunotherapy initiative. Given the complexity of ovarian and uterine cancer and the great unmet need to overcome these cancers which strike women in the prime of their lives, the work that Precision Biologics is doing with NEO-201 to drive combination immunotherapy reinforces why NantWorks and Cancer MoonShot 2020 supports this program," said Patrick Soon-Shiong, M.D., founder of NantWorks and leader of the Cancer MoonShot 2020 program.

Results from in vitro cytotoxicity assays and inhibition of tumor growth in nude mice will be reported, both as single agents and in combination with a Natural Killer cell line. The preclinical data indicate that NEO-201 demonstrates tumor-specific cytotoxicity and provides promise for the development of TAA-directed therapy for ovarian and uterine malignancies.

Presentation Information: Identification of target and cytotoxicity of novel monoclonal antibody NEO-201 in ovarian and uterine cancer subtypes

Monday, April 18, 2016 at 8:00am-12:00pm in Section 25, Poster Board 27, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, Ernest N. Morial Convention Center, New Orleans, LA.

Abstract Title: # 1496

Author: M. K. Neuman1, L. Hernandez1, X. P. Wang2, O. Saric2, A. Dubeykovskiy2, P. Arlen1,2 and C. M. Annunziata1,1 National Cancer Institute, Bethesda, MD, 2Precision Biologics, Rockville, MD

About Cancer MoonShot 2020
The Cancer MoonShot 2020 Program is one of the most comprehensive cancer collaborative initiative launched to date, seeking to accelerate the potential of combination immunotherapy as the next generation standard of care in cancer patients. This initiative aims to explore a new paradigm in cancer care by initiating randomized Phase II trials in patients at all stages of disease in 20 tumor types in 20,000 patients within the next 36 months. These findings will inform Phase III trials and the aspirational MoonShot to develop an effective vaccine-based immunotherapy to combat cancer by 2020.