On April 2, 2019 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company focused on the development of precision medicines for oncology, reported new findings regarding the mechanism of action of the Company’s lead drug candidate tipifarnib and its potential clinical applications (Press release, Kura Oncology, APR 2, 2019, View Source [SID1234534892]). These findings are being presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 in Atlanta. A copy of the poster is available on Kura’s website at www.kuraoncology.com.

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Tipifarnib is a potent and selective farnesyl transferase inhibitor currently in a registration-directed clinical trial in patients with head and neck squamous cell carcinoma (HNSCC) that carry mutations in HRAS, an exclusively farnesylated oncogene. Tipifarnib has also been shown to downregulate production of the chemokine CXCL12 in tumor models and cancer patients. New findings, presented today, suggest that gene expression of the exclusively farnesylated proteins RHOE (RND3) and PRICKLE2 is strongly associated with CXCL12 expression in bone marrow stroma, which may provide a mechanistic rationale for why the CXCL12 pathway is a therapeutic target of tipifarnib and other farnesyl transferase inhibitors.

In addition, an analysis of a subset of patients from a previously conducted Phase 2 trial of tipifarnib in patients with relapsed and refractory lymphomas identified pre-treatment tumor CXCL12 expression as a potential biomarker of clinical benefit in patients with diffuse large B-cell lymphoma (DLBCL) and mycosis fungoides, the most common form of cutaneous T-cell lymphoma (CTCL). This observation is consistent with similar findings from Kura in other indications such as peripheral T-cell lymphoma (PTCL), acute myeloid leukemia (AML) and pancreatic cancer. CXCL12 and its receptors, CXCR4 and CXCR7, have been implicated in cancer progression and poor prognosis across a large spectrum of solid tumor and hematologic indications.

"The target of farnesyl transferase inhibitors has been elusive for several decades. These findings provide key evidence supporting the inhibition of the CXCL12 pathway as a mechanism of action mediating the activity of tipifarnib in the clinic," said Antonio Gualberto, M.D., Ph.D., Head of Development and Chief Medical Officer of Kura Oncology. "CXCL12-expressing cancers represent a major unmet medical need, and we believe that CXCL12 pathway biomarkers could enable registrational strategies for tipifarnib in multiple hematologic and solid tumor indications."

In December 2018, Kura reported activity from an ongoing Phase 2 trial of tipifarnib in patients with relapsed or refractory PTCL, including a significant association between CXCL12 expression and clinical benefit, as well as proof-of-concept in angioimmunoblastic T-cell lymphoma (AITL), an aggressive form of PTCL often characterized by high levels of CXCL12 expression. The Company anticipates providing an update on this trial, including duration of response data from the AITL cohort and additional data from the CXCL12-high PTCL cohort, in mid-2019.

About Tipifarnib

Kura Oncology’s lead drug candidate, tipifarnib, is a potent and highly selective inhibitor of farnesylation, a key cell signaling process implicated in cancer initiation and development. Tipifarnib was previously studied in more than 5,000 cancer patients and showed compelling and durable anti-cancer activity in certain patient subsets, however no molecular mechanism of action had previously been determined that could explain its activity across a range of diverse clinical indications, including squamous tumors that carry mutant HRAS, as well as in lymphoid, myeloid and solid tumors that do not carry HRAS mutations. Leveraging advances in next-generation sequencing as well as emerging information about cancer genetics and tumor biology, Kura is seeking to identify those patients most likely to benefit from tipifarnib

On April 2, 2019 Dynavax Technologies Corporation (NASDAQ:DVAX), a fully-integrated biopharmaceutical company focused on discovering and developing novel vaccines and immuno-oncology therapeutics, reported results from the ongoing Phase 1b clinical study evaluating the safety of DV281, a novel toll-like receptor (TLR) 9 agonist in combination with nivolumab in patients with advanced or metastatic non-small cell lung cancer (NSCLC) (Press release, Dynavax Technologies, APR 2, 2019, View Source [SID1234534889]). The results were presented today in a poster session at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Exhibit Hall B, Poster Section 17, Poster Board Number: #18, 1:00 pm. – 5:00 p.m. ET).

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DV281 is Dynavax’s proprietary investigational TLR9 agonist designed specifically for focused delivery to tumor-burdened lungs for the treatment of primary lung tumors and lung metastases.

"We are very encouraged by what we’ve seen with the TLR9 agonist DV281 in this safety study, including a favorable safety profile and evidence of target engagement," said Edward B. Garon, MD, associate professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles, and principal investigator for the trial. "Lung cancer is the most common cause of cancer-related death, and new options are needed for this difficult disease. These preliminary results support additional evaluation of inhaled DV281 as a unique treatment option to stimulate the body’s immune system to fight lung cancer."

The Phase 1b clinical study (NCT03326752) is ongoing. Dynavax is currently studying DV281 in this open label, multicenter study to assess the safety and pharmacodynamic activity of inhaled DV281 in combination with nivolumab in patients with advanced or metastatic NSCLC. As of March 5, 2019, 23 heavily pre-treated anti-PD-1/L1 experienced (87% of whom were PD-1/PD-L1 resistant) or naïve advanced NSCLC patients were enrolled in second-line or third-line treatment using a 3+3 design in five dose cohorts.

Key highlights from the clinical data presentation include:

In this safety study, two doses of DV281 monotherapy followed by combination with nivolumab was well tolerated. No immune-related adverse events such as pneumonitis have been reported.

Inhalation of DV281 leads to dose-dependent target engagement as measured by induction of IFN-regulated genes at all evaluated dose levels.

DV281 plus nivolumab demonstrates early signs of antitumor activity in heavily pretreated patients (87% received a prior checkpoint inhibitor +/- chemotherapy.)

Dramatic clinical improvement and clear tumor shrinkage at day 50 in a patient treated at 25 mg who was progressing on pembrolizumab.

Prolonged stable disease (4 to 8 months) has been observed in all cohorts that have sufficient duration of follow-up.

Clear control of target lesions as measured on CT scans and slowing down of tumor growth with significantly extended tumor doubling time.

The dose escalation phase of the study is ongoing.
"In this safety study in heavily pre-treated patients with advanced lung cancer, we were pleased to see that combination of DV281 and nivolumab was well tolerated and exhibited dose-dependent target engagement," said Robert Janssen, M.D., chief medical officer of Dynavax. "We were further encouraged by signs of anti-tumor activity, including patients with prolonged stable disease. In addition, we were pleased to see results demonstrating that the combination slowed tumor growth and significantly extended tumor doubling time."

Activation of dendritic cells through TLR9 in the presence of tumor antigens generates potent T cell-mediated anti-tumor immunity and can substantially improve the response to PD-1 blockade in mouse tumor models.

The combination of an inhaled TLR9 agonist with systemic PD-1 blockade can induce complete clearance of lung tumors as well as distant metastases and provide a long-term survival benefit in mouse models of lung cancer.

The poster titled "Phase Ib, open label, multicenter study of inhaled DV281, a Toll-like receptor 9 agonist, in combination with nivolumab in patients with advanced or metastatic non-small cell lung cancer (NSCLC)" is available on Dynavax’s website at View Source

About DV281
DV281 is Dynavax’s proprietary investigational TLR9 agonist designed specifically for focused delivery to primary lung tumors and lung metastases. DV281 is similar in biological activity and mechanism of action to Dynavax’s Phase 2 immunotherapy candidate, SD-101, but has been optimized for administration as an inhaled therapy. Both SD-101 and DV281 activate plasmacytoid dendritic cells which then stimulate T cells specific for antigens released from dying tumor cells. TLR9 agonists such as DV281 and SD-101 have been shown to stimulate potent Type 1 interferon induction along with maturation of dendritic cells to effective antigen-presenting cells; both activities are important for the induction of effective anti-tumor immunity.

On April 2, 2019 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel cancer immunotherapies based on tumor-infiltrating lymphocyte (TIL) technology, reported that first patient has been dosed in Cohort 4, the pivotal cohort of the innovaTIL-01 (C-144-01) study of lifileucel (Press release, Iovance Biotherapeutics, APR 2, 2019, View Source;p=RssLanding&cat=news&id=2393137 [SID1234534888]). Cohort 4 is designed to enroll 75 patients with advanced melanoma.

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"Dosing of the first patient in Cohort 4, the pivotal arm of our melanoma program, is a significant step toward registration of TIL therapy," commented Maria Fardis, Ph.D., president and chief executive officer of Iovance. "Complete enrollment of this cohort is expected in early 2020 and we remain on track to file a Biologics License Application for regulatory approval of lifileucel in late 2020."

InnovaTIL-01 (NCT02360579) is a pivotal phase 2 global multicenter study evaluating the safety and efficacy of Iovance’s autologous lifileucel TIL therapy for treatment of patients with metastatic melanoma. The study is currently enrolling in the United States and Europe. To date, Iovance has activated 39 clinical sites in the United States and Europe. Additional information on this study is available at View Source

On April 2, 2019 Molecular Templates, Inc., (Nasdaq: MTEM) a clinical stage biopharmaceutical company focused on the discovery and development of Engineered Toxin Bodies (ETBs), a new class of targeted biologic therapies that possess unique mechanisms of action in oncology, reported highlights from the four poster presentations on its pipeline programs that were presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019, taking place March 29 – Apr 3, 2019 at the Georgia World Congress Center in Atlanta, Georgia (Press release, Molecular Templates, APR 2, 2019, View Source [SID1234534887]). Copies of the posters presented at AACR (Free AACR Whitepaper) can be found in the Presentations section of Molecular Templates’ website at View Source

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"We believe that ETBs represent an important advance in immunotoxins as a therapeutic class of drugs. MT-3724 has demonstrated forced internalization of CD20 and has driven responses in heavily pretreated DLBCL patients. While MT-3724 development continues in Phase II, our presentations at AACR (Free AACR Whitepaper) highlight next generation pipeline programs that show key improvements in the ETB platform," said Eric Poma, Ph.D., CEO and CSO of Molecular Templates. "These advances include enhanced potency, improved tolerability, potential to dose weekly or bi-weekly, and the ability to alter the immunophenotype of tumors through antigen seeding to redirect a T-cell response to the tumor."

Poster Title: TAK-169, an Exceptionally Potent CD38 Targeted Engineered Toxin Body, as a Novel Direct Cell Kill Approach for the Treatment of Multiple Myeloma
Poster highlights:

TAK-169 is able to efficiently internalize and directly kill CD38-expressing cells with potency seen at picomolar or sub-picomolar concentrations.
Preclinical data suggest that TAK-169 may provide benefit to patients who have progressed after or are unlikely to respond to CD38-targeted antibody therapy.
TAK-169 has demonstrated potent cytotoxicity across a range of myeloma cell lines with a range of CD38 expression in vitro as well as in patient-derived samples including those with previous exposure to daratumumab.
TAK-169 retains activity in the presence of daratumumab.
In xenograft models, complete regressions were observed using both once-weekly and bi-weekly schedules of TAK-169.
TAK-169 was tolerated in cynomolgus monkeys (highest non-severely toxic dose [HNSTD] of 750 mcg/kg weekly) at doses where evidence of pharmacodynamic effect (NK cell depletion) was observed. In comparison, the HNSTD of MT-3724 was 150 mcg/kg with visible signs of capillary leak syndrome (CLS); dosing MT-3724 at 450 mcg/kg showed severe CLS in cynomolgus monkeys.
Poster Title: The Safety and efficacy Profile of a PD-L1-Directed, Engineered Toxin Body, as a Novel Targeted Direct-Cell Kill Approach for the Treatment of PD-L1-Expressing Cancers
Poster highlights:

Molecular Templates has developed PD-L1-targeting ETBs as an approach to directly target tumor cells and overcome resistance mechanisms against PD-1 and PD-L1 antibodies.
MT-6020, a human and cynomolgus cross-reactive, PD-L1-targeted, ETB binds to cell lines expressing non-human primate PD-L1 and elicits cytotoxic responses comparable to those observed on human tumor target cells.
MT-6035 is built upon the MT-6020 scaffold and can also deliver a viral peptide for cell surface presentation and targeting by a specific antiviral CTL population for a second and complementary mechanism for tumor cell destruction, referred to as antigen seeding.
MT-6020 and MT-6035 represent a novel approach to targeting and destroying tumors expressing PD-L1 that is unlikely to be inhibited by resistance mechanisms to current checkpoint inhibitors, is well tolerated in relevant toxicity models, and has the capacity for activity in indications where standard of care has failed.
Poster Title: Combination of CD20-targeted Engineered Toxin Body, MT-3724, with Chemotherapy or IMiDs for the Treatment of Non-Hodgkin’s Lymphoma
Poster highlights:

MT-3724, a CD20-targeted ETB, has demonstrated single agent anti-tumor activity in heavily pre-treated relapsed/refractory (R/R) non-Hodgkin’s lymphoma (NHL) patients in a Phase I clinical study.
The combination of MT-3724 with chemotherapeutic agents (doxorubicin, gemcitabine, bendamustine, and vincristine) or an immunomodulatory (IMiD) agent (lenalidomide) all demonstrated additive or synergistic cytotoxicity of NHL cell lines.
Clinical studies to evaluate MT-3724 as single agent and in combination with gemcitabine and oxaliplatin (GEMOX) or lenalidomide are underway and expected to generate data in 2019.
Poster Title: Design and Characterization of Bispecific Engineered Toxin Bodies for Targeted Cancer Therapy
Poster highlights:

Bispecific ETBs that target two epitopes on the same receptor, or two distinct cell surface molecules both expressed on cancer cells, may allow for enhanced activity profiles. These possibilities include:
activity in the presence of a competitive binding protein
sustained activity when one target molecule is shed or downregulated
synergistic binding events to increase overall potency
increased specificity towards cancer over normal tissue.
Bispecific ETBs have been generated to engage a variety of target combinations, relevant to both solid and hematologic cancer treatment.
MTEM is exploring therapeutically relevant target combinations to facilitate the development of a bispecific clinical lead.

On April 2, 2019 Pieris Pharmaceuticals, Inc. (NASDAQ: PIRS), a clinical-stage biotechnology company advancing novel biotherapeutics through its proprietary Anticalin technology platform for respiratory diseases, cancer and other indications, reported the presentation of preclinical data for PRS-342, a GPC3/4-1BB immuno-oncology bispecific drug candidate, at a poster session at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Pieris Pharmaceuticals, APR 2, 2019, View Source [SID1234534885]).

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The poster, titled "Costimulatory T-cell engagement by PRS-342, a GPC3/4-1BB bispecific molecule, leads to activation of T cells and tumor growth inhibition in a HCC humanized mouse model," demonstrated that T-cell activation by PRS-342 led to NF-kB activation, increased production of IL-2 and dose-dependent cytolysis of GPC3-expressing tumor cells. PRS-342 also demonstrated a localized increase of tumor-infiltrating lymphocyte (TIL) levels in a humanized hepatocellular carcinoma (HCC) xenograft mouse model. The data presented suggest potent T-cell activation that is strictly dependent on the presence of GPC3-positive tumor cells. A copy of the poster presentation is available on the publications section of the Pieris website.