On April 18, 2018 Tusk Therapeutics, an immuno-oncology company focused on developing immune-modulating therapeutics by targeting immune cells in cancer, presented pre-clinical proof-of-concept data generated in collaboration with Cancer Research UK and University College London (UCL), relating to its anti-CD25 programme at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Tusk Therapeutics presented data on its first-in-class anti-CD25 programme that has entered pre-clinical development. The antibody depletes regulatory T cells (Tregs) while preserving IL-2 binding and signalling on effector T cells (Teffs). Tusk, together with the University College London research group led by Dr. Sergio Quezada, has shown that targeting Tregs with non-IL-2 blocking anti-CD25 antibodies creates highly potent anti-tumour responses in monotherapy and combination therapy. Proof-of-concept has been established in multiple pre-clinical models.

Tregs, a subpopulation of T cells, are key players in the suppressive tumour microenvironment (TME). Tregs in the TME hinder the body’s ability to control the growth of cancerous cells and their presence is correlated with a worse prognosis in multiple cancers. Effective Treg targeting has been a topic in the cancer field for several years and Tusk’s approach demonstrates it is possible to deplete Tregs in solid tumour which leads to tumour control. Tusk’s antibody is specifically selected to preserve signalling of the IL-2 cytokine on effector cells which is a key regulator of immune-activation.

Commenting on the data, Luc Dochez, Chief Executive Officer of Tusk Therapeutics, said: "The data presented at AACR (Free AACR Whitepaper) demonstrate the unique mechanism of action of our anti-CD25 antibody. Unlike existing aCD25 antibodies our antibody has the ability to deplete Tregs without inhibiting effector cell responses. Based on the promising pre-clinical data, we believe that our anti-CD25 candidates will be an ideal combination partner for existing standard of care and immuno-oncology treatments."

​The data was presented as an oral presentation by Dr. Sergio Quezada, Group Leader and Cancer Research UK Senior Research Fellow at The UCL Cancer Institute, and Chairman of Tusk Therapeutics’ Scientific Advisory Board and in two posters, presented by the Tusk and UCL teams. Tusk Therapeutics’ first-in-class anti-CD25 antibody programme was built on novel biology discovered by Tusk Therapeutics in collaboration with Dr. Quezada and his team at UCL. Tusk Therapeutics, Cancer Research UK (via its Commercial Partnerships Team) and UCL announced in 2017, an exclusive licensing and collaboration deal to develop and commercialise antibody-based therapeutics against CD25.

On April 18, 2018 Genocea Biosciences, Inc. (NASDAQ:GNCA), a biopharmaceutical company developing neoantigen cancer vaccines, reported highlights from its scientific presentations at the 2018 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (AACR 2018), taking place April 14-18, 2018 in Chicago, IL (Press release, Genocea Biosciences, APR 18, 2018, View Source [SID1234525509]).

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Jessica Flechtner, Ph.D., Genocea’s chief scientific officer commented on the AACR (Free AACR Whitepaper) presentations: "We continue to generate data that demonstrate the versatility of our ATLAS platform. As the studies presented at AACR (Free AACR Whitepaper) indicate, ATLAS is a differentiator for Genocea – allowing us to do what in silico approaches cannot – to both identify and characterize neoantigens for use in personalized cancer vaccines. We believe that our ability to find stimulatory and inhibitory antigens during the neoantigen selection process combined with our capacity to explore mechanisms of inhibitory antigens in a murine model, may enable us to help cure cancer by pioneering next-generation cancer vaccines."

Summary of AACR (Free AACR Whitepaper) Poster #730, "Empirical neoantigen identification using the ATLAS platform across thousands of mutations and multiple tumor types highlights advantages over algorithmic prediction methods":

ATLAS enables identification of biologically relevant CD4+ and CD8+ T cell neoantigens in subjects in an unbiased manner, by using subjects’ own antigen-presenting cells (APCs) and T cells rather than predictive algorithms to identify and characterize T cell responses to all candidate neoantigens.
Neoantigen screening was performed on 23 individuals across eight tumor types with mutational burden ranging from 9 to 319 unique mutations.
Empiric identification of neoantigens derived from somatic mutations from each patient’s tumor independently of HLA type and without predictions resulted in the following observations:
ATLAS identified stimulatory neoantigens of both CD4+ and CD8+ T cells, which Genocea believes confirms the importance of including antigens of relevance for both T cell subsets in neoantigen vaccines;
There is little overlap between CD4+ and CD8+ T cell neoantigens; fewer than 2% of empirically confirmed neoantigens were shared between T cell subsets;
Prediction algorithms missed up to 69% of ATLAS-identified neoantigens, with only 2% of CD8+ neoantigens and 24% of CD4+ neoantigens accurately predicted;
The major histocompatibility complex (MHC) class I algorithm appeared to better predict CD4+, not CD8+, neoantigens;
ATLAS also identified inhibitory neoantigens of both CD4+ and CD8+ T cells
Inhibitory neoantigens outnumbered stimulatory neoantigens more than three-fold in aggregate in the screened patients;
Inhibitory antigens currently cannot be identified using in silico approaches.
Summary of Poster #5718, "ex vivo ATLASTM identification of neoantigens for personalized cancer immunotherapy in mouse melanoma":

The B16F10 mouse melanoma model was utilized to characterize neoantigens. More than 1,600 tumor-specific mutations (possible neoantigens) were interrogated using the ATLAS technology and CD8+ T cells from tumor-bearing C57BL/6 mice.
Similar to human neoantigen screens, mouse ATLAS (mATLAS) identified both stimulatory and inhibitory neoantigens:
99% of mutations identified using whole exome sequencing were screened;
68 stimulatory (4% of total mutations) and 57 inhibitory (3% of total mutations) neoantigens were identified.
NetMHCPan, a MHC-binding prediction algorithm, failed to identify the majority of mATLAS-identified neoantigens:
Only 2% of B16F10 neoantigens predicted by algorithms were empirically confirmed to be stimulatory antigens;
91% of stimulatory neoantigens empirically identified with mATLAS were not predicted;
6% of algorithm-predicted neoantigens were inhibitory.
These data demonstrate that inhibitory antigens can be identified in mouse models, allowing for future research into the mechanism of ATLAS-identified inhibitory responses and their relationship to stimulatory neoantigens in mediating tumor control.

On April 18, 2018 OBI Pharma, Inc., a Taiwan biopharma company (TPEx: 4174), reported that the U.S. Food and Drug Administration (FDA) has cleared an investigational new drug (IND) application for a Phase I/II study of OBI-3424, a first-in-class DNA alkylating agent that targets cancers that overexpress the aldo-keto reductase 1C3 (AKR1C3) enzyme (Press release, OBI Pharma, APR 18, 2018, View Source [SID1234525525]).

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OBI plans to enroll patients with local solid tumors, including hepatocellular carcinoma (HCC) and castrate-resistant prostate cancer (CRPC). OBI Pharma’s Chief Medical Advisor, Tillman Pearce, M.D., noted, "This clinical trial intends to verify the safety and preliminary activity profile of OBI-3424, a novel first-in-class prodrug of a DNA alkylating cancer therapeutic that is selectively activated by AKR1C3, an enzyme that is overexpressed in a variety of solid and liquid tumors. We are delighted to conduct this first-in-man clinical trial at the University of Texas M.D. Anderson Cancer Center and The James Cancer Hospital and Solove Research Institute of Ohio State University, two of America’s leading academic oncology research institutions".

Amy Huang, General Manager of OBI Pharma, added, "OBI Pharma is proud to further develop our unique targeted cancer pipeline, including targets like the Globo series and AKR1C3. OBI-3424 enhances OBI’s pipeline in solid and liquid tumors for cancer patients who over-express AKR1C3. OBI is taking a first-step towards testing the safety and initial efficacy of a new class of AKR1C3 targeted therapy. We are excited to develop novel targeted therapeutics in the fight against cancers of unmet need."

About OBI-3424

OBI-3424 is a first-in-class novel small-molecule prodrug that selectively targets cancers overexpressing the enzyme aldo-keto reductase 1C3 (AKR1C3), and selectively releases a potent DNA alkylating agent in the presence of the AKR1C3 enzyme. This selective mode of activation distinguishes OBI-3424 from traditional alkylating agents, such as cyclophosphamide and ifosfamide, which are non-selective.

AKR1C3 overexpression has been documented in a number of treatment-resistant and difficult-to-treat cancers including: hepatocellular carcinomas (HCC), castrate-resistant prostate cancer (CRPC), and T-cell acute lymphoblastic leukemia (T-ALL). AKR1C3 is highly expressed in up to 15 solid and liquid tumors.

Furthermore, individualized patient selection by staining for AKR1C3 overexpression by immunohistochemistry can be performed based on tumor biopsies or circulating tumor cells to identify patients with other tumor types most likely to respond to treatment with OBI-3424, and thus offering the possibility for a streamlined clinical development strategy.

OBI Pharma holds worldwide rights for OBI-3424 with the exception of the following countries, whose rights are held by Ascenta Pharma: China, Hong Kong, Macao, Taiwan, Japan, South Korea, Singapore, Malaysia, Thailand, Turkey, and India.

On April 17, 2018 Arcus Biosciences, Inc. (NYSE:RCUS), a clinical-stage biopharmaceutical company focused on creating innovative cancer immunotherapies, reported that it will present data today from its Phase 1 trial for AB928, its dual adenosine receptor antagonist, in healthy volunteers in a poster presentation titled "Clinical Pharmacokinetic-Pharmacodynamic Relationship for AB928, a Dual Antagonist of the A2aR and A2bR Adenosine Receptors," at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, Illinois (Press release, Arcus Biosciences, APR 17, 2018, View Source [SID1234525418]).

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"We are extremely encouraged by the results from our ongoing Phase 1 trial of AB928. The compound has been shown to be safe and well tolerated at all doses evaluated and achieves near complete inhibition of A2aR adenosine receptor activation in blood samples from healthy volunteers," said Terry Rosen, Ph.D., Chief Executive Officer at Arcus. "Importantly, we achieved this level of inhibition under conditions that we believe are representative of the large concentrations of adenosine found in the tumor microenvironment. These results have informed the selection of the starting dose for our clinical trials of AB928 in combination with other anti-cancer agents, and we look forward to starting these trials shortly."

Design of the Phase 1 Trial for AB928 in Healthy Volunteers
The Phase 1 double-blinded, placebo-controlled trial has enrolled 85 healthy volunteers. The trial includes a single-ascending-dose (SAD) portion as well as a multiple-ascending-dose (MAD) portion. In the SAD portion, single doses of 10, 25, 75 and 150 mg and a twice-daily dose of 100 mg have been evaluated. In the MAD portion, doses of 10, 25, 75 and 150 mg QD and 200 mg QD (with food) have been administered to subjects for four consecutive days. In each dosing cohort, 6 subjects received AB928 and 2 subjects received placebo, and dosing in the trial has been completed. Investigators remain blinded regarding subject assignment to the AB928 or placebo arms.
The objective of this trial is to assess the safety, tolerability, pharmacokinetics and pharmacodynamic profile of AB928 and to inform our selection of the starting dose of AB928 for our combination trials in cancer patients.

Summary of the Results Presented
All doses have been safe and well tolerated, and no safety events prevented escalation to higher doses. To assess the pharmacodynamic effects of AB928, blood samples were taken from subjects at different time points following the administration of AB928 or placebo. As of the cut-off date (COD) of March 30, 2018 for the poster presentation, samples from all dosing cohorts, with the exception of the 200 mg QD (with food) MAD cohort, have been evaluated to assess the pharmacodynamic effects of AB928. These samples were treated with NECA (a synthetic analogue of adenosine), which activates A2aR receptors on T cells. The ability of AB928 to block A2aR receptors on T cells was quantified by measuring the levels of pCREB, which is a marker for activation of the A2aR receptor.
When blood samples from the 150 mg MAD cohort were incubated with 5 µM NECA, AB928 achieved complete inhibition of pCREB activation at two hours post-dosing and approximately 90% mean inhibition of pCREB activation at 24 hours post-dosing on day 4. As experiments conducted in vitro by Arcus have demonstrated that NECA is at least 20 times more potent than adenosine at inducing pCREB activation in blood T cells, stimulation with 5 µM NECA should be comparable to stimulation with adenosine concentrations in excess of 100 µM.
The pharmacokinetic profile of AB928 supports once-daily dosing, with a plasma half-life that exceeds 20 hours.
Complete results from this trial, including pharmacodynamic data for the 200 mg BID (with food) dosing cohort, will be released following the unblinding of data in mid-2018.

AB928 Clinical Development Plans
The results from this healthy volunteer trial demonstrate that a safe and well tolerated dose of AB928 can provide near complete inhibition of A2aR receptor activation. Based on these results, Arcus is preparing to initiate clinical trials to evaluate AB928 in combination with three different chemotherapy regimens and in combination with AB122, its PD-1 antibody, in cancer patients. Regulatory submissions to start these trials are underway.
These trials will include a dose-escalation portion to identify the recommended dose of AB928 for each combination regimen. Based on the safety profile of AB928, the initial dose of AB928 for the dose-escalation portion should achieve close to complete inhibition of A2aR receptor activation. Once the recommended dose has been selected, AB928 will be evaluated in 11 expansion cohorts. Each expansion cohort will evaluate the AB928 + chemotherapy combination and/or the AB928 + AB122 combination in one of the following tumor types: non-small cell lung cancer, renal cell carcinoma, gastroesophageal cancer, colorectal cancer, ovarian cancer and triple negative breast cancer. In both the dose escalation portion and expansion cohorts, Arcus will conduct significant biomarker analysis, which will inform patient selection in future trials. Arcus plans to report data from the dose-escalation portion of these trials in the first half of 2019

On April 17, 2018 DelMar Pharmaceuticals, Inc. (NASDAQ: DMPI) ("DelMar" or the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that the Company presented a positive update on its two ongoing clinical trials of VAL-083, a first-in-class small molecule chemotherapeutic, for the treatment of MGMT-unmethylated Glioblastoma Multiforme ("GBM") at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting (Press release, DelMar Pharmaceuticals, APR 17, 2018, View Source [SID1234525438]).

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"We are pleased with the continued progress of our ongoing clinical trials with VAL-083 as a potential treatment for MGMT-unmethylated GBM," said Saiid Zarrabian, interim president and chief executive officer. "These trials are important elements of our clinical development strategy to advance VAL-083 as a potential treatment for GBM patients who have little or no viable alternatives."
DelMar presented the following updates in two poster presentations at the AACR (Free AACR Whitepaper) Annual Meeting.
1. A biomarker-driven, Phase 2 clinical trial of VAL-083 in patients with MGMT-unmethylated bevacizumab (Avastin)-naïve recurrent glioblastoma, currently being conducted in collaboration with the University of Texas MD Anderson Cancer Center.

Up to 48 patients with MGMT-unmethylated, bevacizumab-naïve, recurrent GBM, will be enrolled to determine if treatment with VAL-083 improves overall survival compared to historical reference control.
22 of a planned 48 patients have been enrolled as of March 31, 2018, compared to 15 patients enrolled as of October 31, 2017.

7 of the 22 enrolled patients (32%) have exhibited stable disease as best response.
Similar to prior clinical experience, myelosuppression has been the most common adverse event observed.
2. A Phase 1-2 clinical trial of VAL-083 in combination with radiotherapy in patients with newly diagnosed MGMT-unmethylated GBM, currently being conducted in collaboration with Sun Yat-sen University Cancer Center.
Up to 30 patients with newly diagnosed MGMT-unmethylated GBM will be treated with VAL-083 combined with radiotherapy by 24 weeks of VAL-083 maintenance therapy. The study is being conducted in two parts: (1) Dose-confirmation: VAL-083 in cohorts (20, 30 and 40 mg/m2/day IV) to assess safety and activity when administered concurrently with x-ray telescope ("XRT") to confirm the maximum tolerated dose ("MTD"), and (2) Expansion: VAL-083 will be studied in up to 20 additional patients at the target dose of 40mg/m2 VAL-083 administered concurrently with XRT.

Dose-confirmation studying 20 and 30 mg/m2/day cycles has been completed (4 patients enrolled).
No dose-limiting toxicities have been reported following treatment with multiple cycles of VAL-083.
The next patient enrolled will receive the study target dose of 40 mg/m2/day VAL-083 combined with radiation.
DelMar’s poster presentations can be viewed on the company’s website at:
View Source

About VAL-083
VAL-083 (dianhydrogalactitol) is a "first-in-class," DNA-targeting agent that introduces interstrand DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death. VAL-083 has demonstrated clinical activity against a range of cancers including GBM and ovarian cancer in historical clinical trials sponsored by the U.S. National Cancer Institute ("NCI"). DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by common mechanisms of chemoresistance in vitro. Further details regarding these studies can be found at:
View Source.
VAL-083 has been granted an orphan drug designation by the U.S. FDA Office of Orphan Products for the treatment of glioma, medulloblastoma and ovarian cancer, and in Europe for the treatment of malignant gliomas. VAL-083 has been granted fast-track status for the treatment of recurrent GBM by the US FDA.