On April 2, 2019 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported interim data from the Company’s CD40 agonist program in a late-breaking poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Press release, Celldex Therapeutics, APR 2, 2019, View Source [SID1234534902]). CD40, expressed on dendritic cells and other antigen presenting cells, is an important target for immunotherapy, as it plays a critical role in the activation of innate and adaptive immune responses.CDX-1140 is a fully human agonist anti-CD40 monoclonal antibody that was specifically designed to balance good systemic exposure and safety with potent biological activity, a profile which differentiates CDX-1140 from other CD40-activating antibodies.

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CDX-1140 is currently in a Phase 1 dose escalation study. The study includes both monotherapy and combination cohorts with CDX-301, Celldex’s dendritic cell growth factor, designed to increase the number of dendritic cells which are critical to initiating antitumor immunity and are a key target for CDX-1140.

"Preclinical data support that CD40 activation could play an extremely important role in cancer immunotherapy by activating anti-tumor immunity and overcoming resistance to PD-1 blockade," said Rachel Sanborn, MD, Co-director of the Thoracic Oncology Program and Leader of the Phase 1 Trials Program at Providence Cancer Institute and a lead investigator in this study. "The interim results presented today have demonstrated that CDX-1140 is a potent activator of CD40 and can be safely administered at doses that we believe will support good tissue and tumor penetration. We are now reaching dose levels that have the potential for meaningful clinical benefit, especially in combination with drugs that target other key immune pathways, and look forward to initiating tumor specific expansion cohorts to test potential clinical activity."

CDX-1140 has a unique combination of properties relative to other CD40 agonist antibodies: potent agonist activity resulting in dendritic cell and B cell activation is independent of Fc receptor interaction, contributing to more consistent, controlled immune activation; CD40 ligand (CD154) binding is not blocked, allowing potential synergy with the natural CD40 activation pathway; and the antibody promotes strong immune activation without significant adverse events in preclinical toxicology studies.

Presentation Highlights:

Abstract #: LB-194: First in human Phase 1 study of the CD40 agonist monoclonal antibody (mAb) CDX-1140 alone and in combination with CDX-301 (rhFLT3L) in patients with advanced cancers: interim results (Sanborn, et. al)

Overview: 30 patients were enrolled in the study at the time of data analysis (n=22 monotherapy; n=8 combination. Six monotherapy dosing cohorts in both solid tumors and non-Hodgkin lymphoma (NHL) (0.01, 0.03, 0.09, 0.18, 0.36 and 0.72 mg/kg) have been completed. The seventh monotherapy cohort at 1.5 mg/kg is currently being enrolled. Two combination cohorts in solid tumors (0.09 and 0.18 mg/kg) with CDX-301 have been completed and the third cohort at 0.36 mg/kg is currently being enrolled. In general, patients have advanced disease and are heavily pretreated (median number of prior therapies: 4 monotherapy arm; 3.5 combination arm).

Safety: CDX-1140 has been generally well tolerated. A maximum tolerated dose (MTD) has not been reached to date and only three patients have experienced serious treatment related adverse events (pneumonitis and hypoxia; possible cytokine release, fatigue and fever; and, fatigue and nausea). High grade, drug-related (Grade 3 and above) changes in liver function tests or platelet count have not been observed to date, including at CDX-1140 dose levels which exceed the MTDs reported with other CD40 agonists. The addition of CDX-301 has not affected the tolerability of CDX-1140 at dose levels tested to date in the combination cohorts.

Systemic Dosing and Biomarker Analysis: Higher dose levels have achieved circulating antibody concentrations in the range of 20 to 30 micrograms CDX-1140 per milliliter. Transient dose-dependent pharmacodynamic effects have been observed including activation of dendritic cells and B cells, along with increases in pro-inflammatory cytokines and chemokines in the blood, all of which are consistent with CD40-mediated immune activation and the hypothesis that CDX-1140 is achieving dose levels optimal for systemic exposure. The addition of CDX-301 has further enhanced cytokine responses.

Early Clinical Activity: While not anticipated at these lower CDX-1140 dose levels, stable disease has been observed in this heavily pretreated population who have received, at a minimum, all standard of care therapies for their tumor type. Recently enrolled dose levels are still under evaluation.

Future development: Additional patient enrollment (backfill) has been initiated at the 0.72 mg/kg CDX-1140 dose level to characterize the effects of CDX-1140 in the tumor microenvironment and tumor specific expansion cohorts are planned. Future combination opportunities are being considered, including with PD-1 or PD-L1 inhibitors, radiation therapy and Celldex’s potent CD27 agonist monoclonal antibody varlilumab. Several B cell lymphomas (subtypes of NHL) express both CD40 and CD27 and varlilumab has been shown to synergize with CDX-1140 in NHL models.

On April 2, 2019 Heat Biologics, Inc. (NASDAQ: HTBX), a biopharmaceutical company developing immunotherapies designed to activate a patient’s immune system against cancer, reported that it delivered a poster presentation yesterday, April 1, 2019, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Heat Biologics, APR 2, 2019, View Source [SID1234534901]). The Company’s presentation, entitled, ”Generation of a novel, allogeneic cell-based, Gp96-Ig/OX40L cancer vaccine, improves anti-tumor immunity and long-term memory T-cell generation,” is available online here.

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The poster presentation featured the Company’s next generation cellular vaccine platform, ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), which incorporates a tumor antigen chaperone (gp96-Ig) with T-cell costimulation (OX40L-Ig), simulating a single tumor cell line source that secretes both products. The presentation modeled how the addition of human HS-130, which secretes OX40L-Ig, to HS-110 may ImPACT anti-tumor immune responses. This combination generated a three-fold increase in CD8+ T-cell expansion, increased numbers of long-lived tumor-specific T-cells, and potent short-lived killer T-cells required for tumor growth control.

Matt Seavey, Ph.D., Heat’s Senior Director of Research, commented, ”We are highly encouraged by these preliminary results in a mouse model, which demonstrate that the combination of HS-110 with OX40L co-stimulation has the potential to dramatically enhance anti-tumor immune responses. Moreover, this study further informed our selection of the ideal ratio of gp96 to OX40L, which will be helpful as we prepare to file an IND for our HS-130 ComPACT trial later this quarter.”

About AACR (Free AACR Whitepaper) Annual Meeting 2019

The AACR (Free AACR Whitepaper) Annual Meeting program covers the latest discoveries across the spectrum of cancer research – from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy – and highlights the work of the best minds in research and medicine from institutions all over the world.

On April 2, 2019 Alder BioPharmaceuticals, Inc. (NASDAQ:ALDR), a biopharmaceutical company focused on developing novel therapeutic antibodies for the treatment of migraine, reported that members of the management team will provide a business overview and update at the 18th Annual Needham Healthcare Conference at 10:40 am ET on Tuesday, April 9, 2019 in New York, NY (Press release, Alder Biopharmaceuticals, APR 2, 2019, View Source [SID1234534900]).

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The presentation will be webcast live on the Events & Presentations page of the Investors section of Alder’s website at View Source, or by following the link below in your web browser. An archived replay of the webcast will be available on Alder’s website for at least 30 days after the live event concludes.

On April 2, 2019 Odonate Therapeutics, Inc. (NASDAQ: ODT), a pharmaceutical company dedicated to the development of best-in-class therapeutics that improve and extend the lives of patients with cancer, reported its results of preclinical studies of tesetaxel, Odonate’s investigational, orally administered taxane, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Press release, Odonate Therapeutics, APR 2, 2019, View Source [SID1234534899]). The presentation is entitled, "Tesetaxel, a novel, oral taxane, crosses intact blood-brain barrier (BBB) at therapeutically relevant concentrations" (Poster Board #12; Abstract 3087).

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These preclinical results indicate that, following oral administration, tesetaxel achieves brain concentrations that exceed concentrations required for tumor killing for a sustained period of time. This is in contrast to paclitaxel and docetaxel, the most commonly prescribed taxanes, which do not substantially cross the BBB.

"The development of effective treatment options for patients with brain metastases remains an enormous unmet medical need", said Nancy Lin, M.D., Associate Chief of Breast Oncology, Susan F. Smith Center for Women’s Cancers, and Director of the EMBRACE Metastatic Breast Cancer Program, Dana-Farber Cancer Institute. "Taxanes are one of the most active and widely used classes of chemotherapy agents for the treatment of both early stage and metastatic breast cancer, but conventional taxanes do not cross the blood-brain barrier. The preclinical results showing tesetaxel penetration across an intact blood-brain barrier are compelling and raise the potential for both treatment and prevention of brain metastases. We look forward to investigating the possible translation of this finding into clinical outcomes in CONTESSA, CONTESSA 2 and CONTESSA TRIO, each of which allows enrollment of patients with brain metastases."

About Tesetaxel

Tesetaxel is an investigational, orally administered chemotherapy agent that belongs to a class of drugs known as taxanes, which are widely used in the treatment of cancer. Tesetaxel has several pharmacologic properties that make it unique among taxanes, including: oral administration with a low pill burden; a long (~8-day) terminal plasma half-life in humans, enabling the maintenance of adequate drug levels with relatively infrequent dosing; no history of hypersensitivity (allergic) reactions; and significant activity against chemotherapy-resistant tumors. In patients with metastatic breast cancer, tesetaxel was shown to have significant, single-agent antitumor activity in two multicenter, Phase 2 studies.

About CONTESSA

CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel, an investigational, orally administered taxane, in patients with locally advanced or metastatic breast cancer (LA/MBC). CONTESSA is comparing tesetaxel dosed orally at 27 mg/m2 on the first day of each 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m2/day dosed orally for 14 days of each 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day dosed orally for 14 days of each 21-day cycle) in approximately 600 patients randomized 1:1 with human epidermal growth factor receptor 2 (HER2) negative, hormone receptor (HR) positive LA/MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in LA/MBC. Where indicated, patients must have received endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. The primary endpoint is progression-free survival (PFS) as assessed by an Independent Radiologic Review Committee (IRC). CONTESSA’s secondary efficacy endpoints are overall survival (OS), objective response rate (ORR) as assessed by the IRC and disease control rate (DCR) as assessed by the IRC. To learn more, please visit www.contessastudy.com.

About CONTESSA 2

CONTESSA 2 is a multinational, multicenter, Phase 2 study of tesetaxel, an investigational, orally administered taxane, in patients with locally advanced or metastatic breast cancer (LA/MBC). CONTESSA 2 is investigating tesetaxel dosed orally at 27 mg/m2 on the first day of each 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m2/day dosed orally for 14 days of each 21-day cycle) in approximately 125 patients with human epidermal growth factor receptor 2 (HER2) negative, hormone receptor (HR) positive LA/MBC not previously treated with a taxane. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in LA/MBC. Where indicated, patients must have received endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. The primary endpoint is objective response rate (ORR) as assessed by an Independent Radiologic Review Committee (IRC). The secondary efficacy endpoints are duration of response (DoR) as assessed by the IRC, progression-free survival (PFS) as assessed by the IRC, disease control rate (DCR) as assessed by the IRC and overall survival (OS).

About CONTESSA TRIO

CONTESSA TRIO is a multi-cohort, multicenter, Phase 2 study of tesetaxel, an investigational, orally administered taxane, in patients with locally advanced or metastatic breast cancer (LA/MBC). In Cohort 1, approximately 90 patients (with potential expansion to up to 150 patients) with locally advanced or metastatic triple-negative breast cancer (TNBC) who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive tesetaxel dosed orally at 27 mg/m2 on the first day of each 21-day cycle plus either: (1) nivolumab at 360 mg by intravenous infusion on the first day of each 21-day cycle; (2) pembrolizumab at 200 mg by intravenous infusion on the first day of each 21-day cycle; or (3) atezolizumab at 1,200 mg by intravenous infusion on the first day of each 21-day cycle. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are immuno-oncology (IO) agents approved for the treatment of multiple types of cancer. One of these agents, atezolizumab, in combination with the intravenously delivered taxane, nab-paclitaxel, was recently approved by the U.S. Food and Drug Administration (FDA) as a first-line treatment for patients with metastatic TNBC. The dual primary endpoints for Cohort 1 are objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the three PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the three approved PD-L1 diagnostic assays. In Cohort 2, approximately 40 elderly patients (with potential expansion to up to 60 patients) with human epidermal growth factor receptor 2 (HER2) negative MBC will receive tesetaxel monotherapy dosed orally at 27 mg/m2 on the first day of each 21-day cycle. The primary endpoint for Cohort 2 is ORR. Secondary endpoints include PFS, DoR and OS. Patients with central nervous system metastases are eligible for both cohorts.

On April 2, 2019 OncoSec Medical Incorporated (OncoSec) (NASDAQ: ONCS), a company developing novel cancer immunotherapies, reported its pre-clinical data highlighting its novel anti-tumor product candidate, SPARK, and its improved electroporation generator, "APOLLO," during a poster presentation at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Atlanta, Georgia (Press release, OncoSec Medical, APR 2, 2019, View Source [SID1234534898]).

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The poster, entitled, "Intratumoral electroporation of plasmid IL-12 and CXCL9 with membrane-bound anti-CD3 elicits robust anti-tumor immunity," provides new preclinical data demonstrating robust anti-tumor responses driven by significant enhancements made to OncoSec’s proprietary cancer immunotherapy platform.

"The data presented at AACR (Free AACR Whitepaper) highlight OncoSec’s potentially game-changing approach to drug development. With this data, we show the ability to not only identify the right genes to have anti-cancer effect, but, importantly, that we can deliver those genes directly into tumor cells. We are able to do this with any gene that is identified as having an anti-cancer effect, without having to expose the patient to a systemic therapy, in an expeditious and cost-effective manner. In doing so, these cells convert immunologically cold tumors into inflamed immunogenic lesions, which is fundamental to generating objective responses in both treated and untreated distant tumors," said Daniel J. O’Connor, President and CEO of OncoSec. "Many immunotherapies are stalled for serious toxicity issues associated with treatment, including cytokine release syndrome. In contrast, our clinical studies, in more than 180 patients with several different tumor types, have demonstrated that TAVO has broad clinical activity without the toxicity commonly associated with IL-12. The foundation of our DNA-based immunotherapy relies on electroporation, which bypasses the pitfalls associated with viral vectors or systemic cytokines."

The Company’s research laboratory discovered complimentary anti-tumor immunological pathways related to IL-12 derived from samples of previously treated TAVO patients. These discoveries resulted in the selection of two new genes, CXCL9 and aCD3 (expressing membrane-bound anti-CD3), to further drive a now enhanced version of IL-12, utilizing P2A in place IRES (TAVOPLUS). In parallel, OncoSec’s researchers reengineered the Company’s existing electroporation generator. The new generator, APOLLO, greatly increases DNA-plasmid cellular transfection rates in order to deliver more anti-cancer fighting genes directly into tumor cells. These independent evolutions of both components of OncoSec’s proprietary cancer immunotherapy platform converged in the design of its new product candidate, SPARK.

Highlights of the data presented at AACR (Free AACR Whitepaper) regarding SPARK and APOLLO demonstrate that:

APOLLO, using lower voltage and a longer pulse width, greatly increased DNA-plasmid cellular transfection rates to deliver more anti-cancer fighting genes directory into tumor cells;
TAVOPLUS, OncoSec’s new proprietary IL-12 enhanced DNA-plasmid, which expresses full-length IL-12 via bicistronic expression of both the p35 and p40 subunits, coupled with APOLLO, meaningfully improves anti-cancer responses;
SPARK, OncoSec’s new proprietary product candidate, drives strong anti-tumor immune responses by combining two novel anti-cancer genes, CXCL9 and aCD3, with TAVOPLUS
CXCL9 with TAVOPLUS
Productively modulates immune/tumor microenvironment
Significantly increases antigen-specific CD8+ CTL
Augments abscopal response of TAVOPLUS
aCD3, expressing membrane bound anti-CD3, with TAVOPLUS
Drives polyclonal T cell expansion and antigen-specific killing in vivo
Augments abscopal response when combined with TAVOPLUS
aCD3 complements CXC by strongly increasing cytotoxic anti-cancer tumor inflammation; and
SPARK, when delivered via APOLLO, significantly improves regression of untreated (distant) tumors in a difficult to treat preclinical melanoma model
"The encouraging data presented at AACR (Free AACR Whitepaper) demonstrate the potential of SPARK to integrate three key immunotherapeutic elements, IL-12, CXCL9 and anti-CD3 complimentary, into a single novel, multi-gene expression platform that we believe will have broad applicability across numerous tumor types," said Christopher G. Twitty, Chief Scientific Officer of OncoSec. "Importantly, SPARK builds upon our plasmid-based cancer immunotherapy platform by amplifying the power of intratumoral IL-12 through the sequenced addition of both CXCL9, a critical T cell chemokine and anti-CD3, a membrane-bound strong pan T cell stimulator. We look forward to filing an Investigational New Drug (IND) application for SPARK."