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Juno Therapeutics Announces Data Presentations at the American Association for Cancer Research Annual Meeting

On April 14, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, reported the Company, in partnership with its collaborators, will present clinical and pre-clinical data from multiple product candidates at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana from April 16-20 (Press release, Juno, APR 14, 2016, View Source;p=RssLanding&cat=news&id=2157199 [SID:1234510814]).

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There will be two presentations with clinical updates. On April 18th, Dr. Terry Fry will present the pre-clinical and clinical rationale as well as updated data from the ongoing Phase I trial of JCAR018, a chimeric antigen receptor (CAR) T cell product candidate targeting CD22, in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r ALL). On April 20th, Dr. Phil Greenberg will present the pre-clinical rationale as well as the first clinical data in patients with solid organ tumors for JTCR016, a T cell receptor (TCR) cell product candidate targeting Wilms tumor-1 (WT-1).

Dr. Hy Levitsky, Juno’s Executive Vice President, Research and Chief Scientific Officer, will discuss pre-clinical data that informed the rationale and design of the ongoing Phase 1 trial for JCAR024, a CAR T cell product candidate targeting ROR-1, in ROR-expressing tumors. Additionally, two Juno-sponsored posters will be presented and Juno’s investigational CAR T cell product candidates will be featured in three additional presentations.

Clinical and Pre-Clinical Updates

CD22 CAR Update and Novel Mechanisms of Leukemic Resistance
Presenter: Terry J. Fry, M.D., Investigator, Pediatric Oncology Branch and Head of Hematologic Malignancies Section, National Cancer Institute, National Institutes of Health
Date: Monday, April 18, 2016: 12:35 – 12:58 p.m. Eastern Time
Location: Room 243

Targeting Cancer with Engineered T Cells
Presenter: Phil Greenberg, M.D., Head of Program in Immunology at the Fred Hutchinson Cancer Research Center and Professor, Medicine/Oncology and Immunology, University of Washington
Date: Wednesday, April 20, 2016: 10:55 – 11:20 a.m. Eastern Time
Location: New Orleans Theater B

Pre-Clinical Updates
ROR1 Targeted by CAR T Cells
Presenter: Hy Levitsky, M.D., Juno’s Executive Vice President, Research and Chief Scientific Officer
Date: Tuesday, April 19, 2016: 1:05 – 1:30 p.m. Eastern Time
Location: New Orleans Theater C

Toxicity and Efficacy Probability Intervals Design for Phase I Dose-Finding in Oncology Trials
Authors: Daniel Li, Ph.D., et al., Juno Department of Clinical Statistics
Date: Sunday, April 17, 2016: 1:00 – 5:00 p.m. Eastern Time
Location: Section 20, Poster Board #29

Comprehensive TIL Profiling by Simultaneous DNA Barcoding of Proteins, RNA and Natively Paired Immune Receptors from Millions of Single Cells
Authors: Katherine Connor, Ph.D., et al., Juno Department of Research, Receptor Discovery
Date: Monday, April 18, 2016: 8:00 a.m. – 12:00 p.m. Eastern Time
Location: Section 24, Poster Board #3

Educational and Major Symposia Sessions
The New T Cell Engineering Arsenal: CARs, CCRs, iCARs, and More
Presenter: Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering & Gene Transfer and Gene Expression Laboratory; Stephen and Barbara Friedman Chair, Memorial Sloan Kettering Cancer Center
Date: Saturday, April 16, 2016: 2:00 – 2:25 p.m. Eastern Time
Location: New Orleans Theater A

Novel Designs and Targets for CAR T Cells
Presenter: Stan Riddell, M.D., Member, Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Professor of Oncology, University of Washington School of Medicine
Date: Tuesday, April 19, 2016: 10:40 – 11:05 a.m. Eastern Time
Location: La Nouvelle Orleans Ballroom

Turbo Charged CAR T Cells
Presenter: Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering & Gene Transfer and Gene Expression Laboratory; Stephen and Barbara Friedman Chair, Memorial Sloan Kettering Cancer Center
Date: Tuesday, April 19, 2016: 11:40 a.m. – 12:05 p.m. Eastern Time
Location: La Nouvelle Orleans Ballroom

About Juno’s Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) Technologies

Juno’s CAR and TCR technologies genetically engineer T cells to recognize and kill cancer cells. Juno’s CAR T cell technology inserts a gene for a particular CAR into the T cell, enabling it to recognize cancer cells based on the expression of a specific protein located on the cell surface. Juno’s TCR technology provides the T cells with a specific T cell receptor to recognize protein fragments derived from either the surface or inside the cell. When either type of engineered T cell engages the target protein on the cancer cell, it initiates a cell-killing response against the cancer cell. JCAR018, JTCR016, and JCAR024 are investigational product candidates and their safety and efficacy have not been established.

Versatility of Particulate Carriers: Development of Pharmacodynamically Optimized Drug-Loaded Microparticles for Treatment of Peritoneal Cancer.

Intraperitoneal (IP) chemotherapy confers significant survival benefits in cancer patients. However, several problems, including local toxicity and ineffectiveness against bulky tumors, have prohibited it from becoming a standard-of-care. We have developed drug-loaded, tumor-penetrating microparticles (TPM) to address these problems. TPM comprises two components and uses the versatile PLGA or poly(lacticco-glycolic acid) copolymer to provide tumor-selective adherence and pharmacodynamically optimized fractionated dosing to achieve the desired tumor priming (which promotes particle penetration into tumors) plus immediate and sustained antitumor activity. Preclinical studies show that TPM is less toxic and more effective against several IP metastatic tumors with different characteristics (fast vs. slow growing, porous vs. densely packed structures, wide-spread vs. solitary tumors, early vs. late stage, with or without peritoneal carcinomatosis or ascites), compared to the intravenous paclitaxel/Cremophor micellar solution that has been used off-label in previous IP studies. TPM further requires less frequent dosing. These encouraging preclinical results have motivated the follow-up clinical development of TPM. We are working with National Institutes of Health on the IND-enabling studies.

A novel monoclonal antibody to a defined peptide epitope in MUC16.

The MUC16 mucin is overexpressed and aberrantly glycosylated in ovarian carcinomas. Immunodetection of circulating MUC16 is one of the most used cancer biomarker assays, but existing antibodies to MUC16 fail to distinguish normal and aberrant cancer glycoforms. Although all antibodies react with the tandem-repeat region, their epitopes appear to be conformational dependent and not definable by a short peptide. Aberrant glycoforms of MUC16 may constitute promising targets for diagnostic and immunotherapeutic intervention, and it is important to develop well-defined immunogens for induction of potent MUC16 immunity. Here, we developed a MUC16 vaccine based on a 1.7TR (264 aa) expressed in Escherichia coli and in vitro enzymatically glycosylated to generate the aberrant cancer-associated glycoform Tn. This vaccine elicited a potent serum IgG response in mice and we identified two major immunodominant linear peptide epitopes within the tandem repeat. We developed one monoclonal antibody, 5E11, reactive with a minimum epitope with the sequence FNTTER. This sequence contains potential N- and O-glycosylation sites and, interestingly, glycosylation blocked binding of 5E11. In immunochemistry of ovarian benign and cancer lesions, 5E11 showed similar reactivity as traditional MUC16 antibodies, suggesting that the epitope is not efficiently glycosylated. The study provides a vaccine design and immunodominant MUC16 TR epitopes.
© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

A common variation of the PTEN gene is associated with peripheral insulin resistance.

Phosphatase and tensin homologue (PTEN) reduces insulin sensitivity by inhibiting the phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (Akt) pathway. This study investigated how a common single nucleotide polymorphism near PTEN, previously associated with fasting levels of plasma insulin and glucose, influences in vivo glucose metabolism and insulin signalling. The primary outcome measure was the gene variant’s association with peripheral glucose disposal rate and, secondarily, whether this association was explained by altered activities of PTEN targets PI3K and Akt.
A total of 183 normoglycaemic Danes, including 158 twins and 25 singletons, were genotyped for PTEN rs11202614, which is in complete linkage disequilibrium with rs2142136 and rs10788575, which have also been reported in association with glycaemic traits and type 2 diabetes (T2D). Hepatic and peripheral insulin sensitivity was measured using tracer and euglycaemic-hyperinsulinaemic clamp techniques; insulin secretion was assessed by intravenous glucose tolerance test; and muscle biopsies were taken during insulin infusion from 150 twins for measurement of PI3K and Akt activities.
The minor G allele of PTEN rs11202614 was associated with elevated fasting plasma insulin levels and a decreased peripheral glucose disposal rate, but not with the hepatic insulin resistance index or insulin secretion measured as the first-phase insulin response and disposition index. The single nucleotide polymorphism was not associated with either PI3K or Akt activities.
A common PTEN variation is associated with peripheral insulin resistance and subsequent risk of developing T2D. However, the association with insulin resistance is not explained by decreased proximal insulin signalling in skeletal muscle.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.

TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells.

TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). In this study, we investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The anti-tumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity. In summary, we showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation.