On November 07, 2015 MacroGenics, Inc. (Nasdaq: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, reported that interim results of an ongoing Phase 1 dose-escalation study of enoblituzumab (MGA271) were presented in the late-breaking abstract session today at the 2015 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in National Harbor, MD. Dr. John Powderly II of the Carolina BioOncology Institute, Huntersville, NC, presented "Interim Results of an Ongoing Phase 1, Dose Escalation Study of MGA271 (Fc-optimized Humanized Anti-B7-H3 Monoclonal Antibody) in Patients with Refractory B7-H3-Expressing Neoplasms or Neoplasms Whose Vasculature Expresses B7-H3 (Press release, MacroGenics, NOV 7, 2015, View Source [SID:1234508087])."

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This study is being conducted to evaluate the safety of enoblituzumab in patients with advanced cancer that expresses B7-H3 in the tumor and/or tumor-associated vasculature. Additional study objectives are to define the toxicity profile, maximum tolerated dose, pharmacokinetics, immunogenicity and potential anti-tumor activity of enoblituzumab in patients with refractory cancer that expresses B7-H3.

Enoblituzumab has been well tolerated at all dose levels tested in the Phase 1 study (up to 15 mg/kg), with Grade 3/Grade 4 drug-related adverse events (AEs) in only 4% of patients, no severe immune-related adverse events, and no drug-related treatment discontinuations. The most common AEs have been infusion-related reactions and fatigue. Mild-moderate infusion reactions have been readily managed with conventional supportive care, including administration of corticosteroids and a decreased infusion rate.

In this ongoing Phase 1 dose-escalation study of enoblituzumab, monotherapy anti-tumor activity was observed across several tumor types, including patients with prostate and bladder cancer as well as melanoma. Overall, this patient population had been heavily pre-treated (median number of prior therapies = 3), and in the patients with melanoma, all had been treated previously with one or more checkpoint inhibitors (anti-CTLA-4, anti-PD-1 and/or anti-PD-L1 antibodies).

In addition to the presentation of initial safety and activity data, Dr. Powderly presented findings demonstrating increases in T-cell repertoire (TCR) clonality in the peripheral blood of tumor patients following treatment with enoblituzumab, demonstrating that enoblituzumab can modulate T cells in these patients. Collectively, these findings support the ongoing evaluation of enoblituzumab as monotherapy and in combination with other immuno-oncology agents, including pembrolizumab and ipilimumab.

"We are encouraged by the initial single-agent activity of enoblituzumab, including tumor regression in heavily pre-treated patients across several tumor types," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "The ongoing Phase 1 study also shows that enoblituzumab has been well tolerated in patients, suggesting that this anti-B7-H3 antibody also may be readily combinable with other immuno-oncology agents such as checkpoint inhibitors."

MacroGenics plans to present additional clinical data in 2016, as it continues to enroll patients in additional monotherapy expansion cohorts and recently commenced two combination studies of enoblituzumab with either ipilimumab or pembrolizumab.

Dr. Powderly’s slide presentation at SITC (Free SITC Whitepaper) is available for download from the Events & Presentations page on MacroGenics’ website at View Source

Background on Enoblituzumab (MGA271)

Enoblituzumab is a humanized, Fc-optimized monoclonal antibody that targets B7-H3, a member of the B7 family of molecules that are involved in immune regulation. B7-H3 is over-expressed by a wide variety of solid tumor cells as well as cancer stem cells and tumor-associated vasculature. Enoblituzumab is currently undergoing Phase 1 testing both as monotherapy and in combination with checkpoint inhibitors across patients with a wide range of solid tumors. MacroGenics retains worldwide development and commercialization rights to its franchise of B7-H3 directed programs, including enoblituzumab and MGD009, a bi-specific Dual-Affinity Re-Targeting (DART) molecule targeting B7-H3 and CD3.

On November 07, 2015 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical-stage company developing novel anti-cancer stem cell and immuno-oncology therapeutics, reported new preclinical data for anti-DLL4 combined with anti-VEGF and anti-PD1 during the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Conference (Press release, OncoMed, NOV 7, 2015, View Source [SID:1234508091]).

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A series of preclinical experiments compared the impact of anti-DLL4/VEGF bispecific and a triple blockade of DLL4-VEGF-PD1 on anti-tumor immune responses. The combination of anti-DLL4/VEGF and anti-PD1 was found to have more potent anti-tumor and enhanced immuno-oncology activity than either agent alone across a number of measures. The triple blockade of DLL4-VEGF-PD1 significantly inhibited tumor growth with more pronounced tumor regression. The addition of anti-DLL4/VEGF also improved anti-tumor activity of anti-PD1 alone in both PD1 responsive and non-responsive cancers in murine models.

"These data highlight the ability of the anti-DLL4/VEGF bispecific to combine with anti-PD1 and to modulate anti-tumor immune responses," said Austin Gurney, PhD, Senior Vice President of Molecular and Cellular Biology. "In addition to increased anti-tumor efficacy, we note enhanced generation of memory T cell responses and reduced tumor-associated macrophages. These results show that co-targeting of DLL4 and VEGF with PD1 might be an effective and durable anti-cancer therapy in part by promoting anti-tumor immune responses and inhibiting pro-tumor immune responses"

DLL4 is a ligand within the Notch pathway and plays important roles in regulating cancer stem cells, tumor angiogenesis and pro-tumor immune responses. OncoMed has two clinical agents targeting DLL4: demcizumab (anti-DLL4, OMP-21M18), currently in Phase 2 trials for the treatment of pancreatic cancer and non-small cell lung cancer (NSCLC), and anti-DLL4/VEGF bispecific, (OMP-305B83) currently in a Phase 1a trial in advanced solid tumors. The combination of anti-DLL4/VEGF bispecific with anti-PD1 demonstrated a distinct mechanistic profile versus prior observations of the synergistic combination of anti-DLL4 and anti-PD1 presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2015 Annual Meeting, suggesting potential for increased T-cell activation, maintenance and memory T-cell function.

Angie Park, Ph.D., Director of Immunotherapy and Stem Cell Biology of OncoMed presented these data in a poster titled "Co-Targeting of Delta-like ligand 4 (DLL4) and vascular endothelial growth factor A (VEGF) with Programmed Death 1 (PD1) blockade inhibits tumor growth and facilitates anti-tumor immune responses." during the Optimizing Combination Immunotherapy session.

On November 7, 2015 Tokai Pharmaceuticals Inc. (NASDAQ: TKAI), a biopharmaceutical company focused on developing and commercializing innovative therapies for prostate cancer and other hormonally driven diseases, reported the presentation of new data highlighting the anti-tumor activity of galeterone in multiple preclinical tumor models expressing the androgen receptor (AR) splice variant AR-V7 at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Boston (Press release, Tokai Pharmaceuticals, NOV 7, 2015, View Source;p=RssLanding&cat=news&id=2110153 [SID:1234508097]).

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Today’s presentation supports earlier clinical findings of positive results with galeterone in men with treatment-naïve metastatic castration-resistant prostate cancer (mCRPC) whose prostate tumors have C-terminal loss—the loss of the portion of the AR that contains the ligand binding domain. C-terminal loss, generally, and AR-V7, specifically, have been associated with non-response to abiraterone (Zytiga) and enzalutamide (Xtandi) in mCRPC. The AR-V7 splice variant is believed to be the most common form of C-terminal loss.

Tokai is evaluating galeterone in ARMOR3-SV, an ongoing pivotal trial designed to determine whether treatment with galeterone results in a statistically significant increase in radiographic progression-free survival as compared to enzalutamide in approximately 148 treatment-naïve, AR-V7+ mCRPC patients. Topline results from ARMOR3-SV are anticipated by the end of 2016.

(Filing, 10-Q, NewLink Genetics, NOV 6, 2015, View Source [SID:1234508090])

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On November 6, 2015 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported new preclinical data on varlilumab, a fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade (Press release, Celldex Therapeutics, NOV 6, 2015, View Source [SID:1234508066]). Results suggest that cancers may respond to CD27 immune modulation by independent mechanisms, such as immune co-stimulation and regulatory T cell (Treg) depletion. Varlilumab has the unique ability to act through both of these mechanisms. The new data were presented in a poster entitled "The mechanism of anti-tumor immunity induced by varlilumab, a CD27 agonist mAb, is model dependent" at the Society for the Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting.

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"Our data show that CD27 modulation through varlilumab results in immune activation and suppression of Treg activity, either of which can be independently responsible for a therapeutic effect, depending on the cancer model," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "Because individual human cancers are also likely to have different sensitivities to these anti-tumor activities, varlilumab’s ability to act through both mechanisms provides the broadest potential for therapeutic benefit. Our collection of preclinical and clinical results to date support Celldex’s broad clinical development program across tumor types and in combinations with other anti-tumor agents."

To better understand each mechanism separately, scientists engineered varlilumab to possess either strong co-stimulatory activity (varli-mG1) or strong Treg suppression activity (varli-mG2a) and analyzed their efficacy in several preclinical tumor models. The data indicated that potent co-stimulation activity was required for therapeutic activity in a BCL1 lymphoma model, whereas control of Tregs was required for activity in several other models, such as E.G7 thymoma, CT26 colorectal and colon 26. Importantly, varlilumab has a combination of immune co-stimulation and Treg depleting activity and demonstrated potent anti-tumor activity in all the models.

The immune stimulating and Treg depleting effects of varlilumab were also observed in Celldex’s Phase 1, single-agent clinical trial of varlilumab in patients with refractory, advanced cancers. Specifically, varlilumab administration was associated with a rapid and transient induction of pro-inflammatory cytokines, activation of T cells as assessed by increased HLA-DR expression and a significant decrease in circulating Tregs. The study also demonstrated promising clinical activity. Two patients experienced durable objective responses including a complete response in Hodgkin lymphoma (18.9+ months) and a partial response in renal cell carcinoma (13.6+ months). Thirteen patients experienced stable disease (3-36.2+ months). Varlilumab was very well tolerated and demonstrated minimal toxicity, even in elderly patients. There was no indication of immune-mediated adverse events often seen with other immunotherapies.

Varlilumab is currently being studied in multiple ongoing Phase 1/2 clinical trials with several anti-tumor agents, including nivolumab (Opdivo), ipilimumab (Yervoy) and sunitinib (Sutent) in advanced-stage cancers. Efforts are underway for additional Phase 2 studies with varlilumab, including a combination with atezolizumab (Roche’s anti-PDL1 antibody), and the Company will provide updates on these studies as they are initiated.