On April 19, 2016 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 inhibitor drugs to improve immune cell trafficking and increase the ability for T-cells to track and destroy cancer, reported the presentation of preclinical data for X4P-001, its lead drug candidate in development for the treatment of clear cell renal cell carcinoma (ccRCC) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, held April 16-20 in New Orleans . The data demonstrated synergistic anti-tumor effects of CXCR4 inhibition in combination with axitinib, a tyrosine kinase inhibitor(Press release, X4 Pharmaceuticals, APR 19, 2016, View Source [SID:1234511098]) approved for use as a targeted therapy for renal cell carcinoma (RCC), in animal models of RCC. The data also showed that X4P-001 suppressed the increased MDSC tumor infiltration caused by axitinib treatment.

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"We are excited to share these early findings with clinicians who know the challenges of treating patients with RCC," said James W. Mier, M.D., Associate Professor of Medicine at the Beth Israel Deaconess Medical Center and senior author of the poster presentation. "We believe there are opportunities to improve outcomes beyond the available targeted therapies, such as kinase inhibitors, which can be hindered by resistance. By inhibiting CXCR4, X4P-001 offers an approach to target a key mechanism of resistance and address unmet needs for cancer patients."

Acquired resistance of tumors to certain anti-cancer therapies has been associated with increased trafficking of key immune cells, such as T-regulatory cells and myeloid derived suppressor cells (MDSCs), in and around the tumor. Trafficking of these cells is controlled by chemokines such as CXCL-12 and its receptor, CXCR4. CXCR4 inhibition blocks the infiltration of these cells and neutralizes the immunosuppressive microenvironment, enabling the cancer-fighting T-cells to reach the tumor.

"These data confirm our belief that CXCR4 inhibition can play an important therapeutic role in immune cell trafficking with the potential to improve treatment outcomes for patients," said Robert Arbeit, M.D., Sr. Vice President of Clinical Development and Translational Research for X4 Pharmaceuticals and an author of the poster presentation. "The data also provide a strong rationale for our upcoming clinical study evaluating the combination of X4P-001 and axitinib in patients with advanced ccRCC."

The poster entitled "Regulation of MDSC trafficking and function in RCC by CXCR4 in the presence of a VEGF-R antagonist" will be presented on Tuesday, April 19th (Abstract number: 4155; 1-5pm). The reported findings include:

X4P-001 in combination with axitinib demonstrated synergistic anti-tumor activity in two renal xenograft models; tumor regression was observed
X4P-001 suppressed the increased MDSC tumor infiltration caused by axitinib treatment
About X4P-001

X4P-001 is an oral, small molecule inhibitor of CXCR4, or C-X-C receptor type 4, the receptor for the chemokine CXCL12 (also known as stromal derived factor-1, or SDF-1). Recent studies demonstrate that CXCR4/CXCL12 is a primary receptor-ligand pair that cancer cells and surrounding stromal cells use to block normal immune function and promote angiogenesis through the trafficking of T-effector and T-regulatory cells, as well as myeloid derived suppressor cells (MDSCs), in the tumor microenvironment.1, 2 Pre-clinical studies have demonstrated X4P-001 activity alone and in combination with approved cancer therapies including tyrosine kinase inhibitors and checkpoint inhibitors resulting in an increased tumor-specific immune response and significant delays in tumor growth. X4P-001 was previously tested in over 70 subjects in four prior clinical trials in healthy volunteers and HIV-infected patients and was shown to be safe and well tolerated.

About Renal Cell Carcinoma

Kidney cancer is among the ten most common cancers in both men and women with more than 60,000 new diagnoses each year in the United States.3 Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, and advanced ccRCC accounts for approximately 20% of the patient population. Therapies for advanced ccRCC include immunotherapies, mammalian target of rapaymcin (mTOR) kinase inhibitors, and angiogenesis inhibitors, such as vascular endothelial growth factor (VEGF) inhibitors.4 There continue to be unmet medical needs with advanced ccRCC because durable responses remain a serious clinical challenge for patients with advanced disease.

On April 19, 2016 Euclises Pharmaceuticals, Inc., a biopharmaceutical company focused on the discovery and development of novel COX-2 inhibitors for the treatment of cancer, reported that its Late-Breaking Abstract has been accepted for presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans on April 19, 2016 (Press release, Euclises, APR 19, 2016, View Source [SID:1234511093]).

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Entitled, "Anti-tumor effects of ECP-1014 in combination with erlotinib in HT-29 xenograft murine colon carcinoma model," the presentation will report the results of key preclinical experiments using Euclises’ COX-2 inhibitor candidate, ECP-1014. The study, conducted in collaboration with Guangzhou Institute of BioMedicine and Health, builds upon recent research demonstrating a role for overactive COX-2 in maintaining an immunosuppressive microenvironment for a variety of tumors, including colorectal and non-small cell lung cancers.

"The epidermal growth factor (EGFR) inhibitor erlotinib is the current standard of care for advanced colorectal cancer," said Dr. Bobby W. Sandage, Jr., Ph.D., CEO of Euclises. "In this preclinical study, we demonstrate a substantial additional benefit in tumor suppression from combining erlotinib with our third-generation COX-2 inhibitor."

"The research to be presented at AACR (Free AACR Whitepaper) strongly validates Euclises’ approach," added Rick Ryan, Ph.D., chairman of Euclises’ board. "These results comprise an important step towards the clinical translation and commercialization of effective COX-2 inhibitors for colorectal cancer patients."

Dr. Sandage will present the research on Tuesday morning, April 19, in Section 11 of the Late-Breaking Research: Experimental and Molecular Therapeutics 3 poster session.

On April 19, 2016 Cerulean Pharma Inc. (NASDAQ:CERU), a clinical-stage company developing nanoparticle-drug conjugates (NDCs), reported the presentation of clinical data in a late-breaker at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. Adrian Senderowicz, M.D., Senior Vice President and Chief Medical Officer of Cerulean will present results from the first 18 patients enrolled in an investigator-sponsored trial (Press release, Cerulean Pharma, APR 19, 2016, View Source [SID:1234511092]).

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The trial studies CRLX101 in combination with Avastin in patients with platinum-resistant ovarian cancer. The trial employs a Simon Two-Stage Design and has met the stage gate criteria for advancement into Stage 2. In order to advance to Stage 2, more than two events of progression-free survival at six months (PFS6) were needed. Eighteen patients were treated in Stage 1, and 25 patients will be enrolled in Stage 2. The study is sponsored by Massachusetts General Hospital. Cerulean and Genentech provide the trial with CRLX101 and Avastin, respectively.

"This arm of the study is designed to assess whether combining Avastin with CRLX101 improves the antitumor activity observed with CRLX101 in the monotherapy arm of the study," said Carolyn N. Krasner, M.D., principal investigator of the trial. "VEGF inhibitors such as Avastin starve tumors of oxygen, resulting in tumor shrinkage, but they may exacerbate the hypoxic conditions present in solid tumors, which would increase HIF-1α. CRLX101 inhibits HIF-1α and mitigates HIF-associated resistance to VEGF inhibitors. The Stage 1 results show that CRLX101 plus Avastin appears to provide a greater benefit than CRLX101 alone. I am pleased that the study has advanced into Stage 2."

"The increased tumor activity observed by combining CRLX101 with Avastin is encouraging," said Dr. Senderowicz. "We also are evaluating the combination of CRLX101 and Avastin in our randomized Phase 2 study in 3rd and 4th line renal cell carcinoma, and there are many other opportunities to combine our HIF-inhibitor with Avastin or other therapies, including TKIs, chemotherapy or radiation therapy."

Results from Stage 1 Arm of Phase 2 Trial of CRLX101 in Combination with Avastin in Platinum-Resistant Ovarian Cancer

In this open-label study, patients were dosed in two arms: a CRLX101 monotherapy arm (Group A) and a combination arm of CRLX101 with Avastin (Group B). Group A patients received CRLX101 at 15 mg/m2 every other week (presented at ASCO (Free ASCO Whitepaper) 2014) and Group B patients received CRLX101 at 15 mg/m2 with Avastin 10 mg/kg every other week. The primary endpoint for both groups was the rate of PFS6 using RECIST 1.1 criteria. Secondary endpoints were objective response rate (ORR), PFS, ≥50% reduction of CA125 over baseline, and safety. Adverse events (AEs) were assessed by CTCAE v4.0. Pre- and post-treatment tumor biopsies were collected from a cohort of patients on CRLX101 as monotherapy to evaluate relevant progressive disease endpoints.

In Stage 1 of Group B, a total of 18 platinum-resistant ovarian cancer patients were evaluated. PFS6 (defined as patients that are free of progression at six months) was demonstrated in 56% of patients (10 out of 18). The overall response rate was 17% (3 out of 18 patients). The overall stable disease rate was 78% (14 out of 18 patients). The clinical benefit rate (defined as patients that either achieved a partial response or stable disease) was 94% (17 out of 18). Median PFS (defined as time from first dose to discontinuation of treatment) is 6.2 months so far, and 2 of 18 patients have been on treatment after 11 months. A ≥ 50% decline in CA125 was demonstrated in 44% patients (8 out of 18). Thus far, Group B showed increased antitumor activity relative to Group A on all of the aforementioned dimensions.

AEs most commonly observed with the combination were anemia (10 patients, 56%); nausea (10 patients, 56%); fatigue (6 patients, 33%); and proteinuria (5 patients, 28%). The majority of AEs were Grade 1. There were four drug-related AEs that were Grade 3 or 4: Grade 3 anemia, elevated alanine transaminase levels, and non-infective cystitis, and Grade 4 febrile neutropenia.

Details of the AACR (Free AACR Whitepaper) late-breaking poster presentation are as follows:

Title:
Phase 2 trial of the NDC CRLX101 in combination with Avastin in patients with Platinum-Resistant OvarianCancer (PROC)
Date and Time:
Tuesday, April 19 – 8:00 am to 12:00 pm
Abstract number:
CT090
Location:
Section 13
Poster board number:
18

A copy of the poster will be available upon request following AACR (Free AACR Whitepaper) by emailing [email protected].

About CRLX101

CRLX101 is a nanoparticle-drug conjugate (NDC) designed to concentrate in tumors and slowly release its anti-cancer payload, camptothecin, inside tumor cells. CRLX101 inhibits topoisomerase 1 (topo 1), which is involved in cellular replication, and also inhibits hypoxia-inducible factor-1α (HIF-1α), which research suggests is a master regulator of cancer cell survival mechanisms. CRLX101 has shown activity in four different tumor types, both as monotherapy and in combination with other cancer treatments. CRLX101 is in Phase 2 clinical development and has been dosed in more than 350 patients. The U.S. FDA has granted CRLX101 Orphan Drug designation for the treatment of ovarian cancer and Fast Track designation in combination with Avastin in metastatic renal cell carcinoma.

On April 19 2016 Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immune-oncology company focusing on the development of T cell immuno-therapies for the treatment of cancer, reported that clinical data of a dendritic cell (DC) vaccine trial for the treatment of prostate cancer were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA, USA (Press release, MediGene, APR 19, 2016, View Source [SID:1234511089]).

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The clinical data were collected, utilising Medigene’s DC vaccine technology in part, in an ongoing clinical phase I/II study on dendritic cell (DC) vaccines for the treatment of prostate cancer at the Department of Cellular Therapy at the Oslo University Hospital, Norway, under the responsibility of Prof. Gunnar Kvalheim. The poster presented was entitled "Clinical results of a Phase I/II trial of adjuvant therapeutic vaccination in high risk resected prostate cancer patients using autologous dendritic cells loaded with mRNA from primary prostate cancer tissue, hTERT and survivin".

More than 50% of high risk prostate cancer patients will develop an early biochemical relapse, with no curative therapy presently available. Therefore, Prof. Gunnar Kvalheim and his team have chosen this patient population for their ongoing Phase I/II dendritic cell (DC) vaccine study. Dendritic cells from each of the 20 enrolled patients were differentiated from enriched monocytes and matured with one of two different maturation cocktails. The DCs were then transfected with mRNA from primary prostate cancer tissue, hTERT and Survivin and then frozen and stored until use. Based on encouraging clinical results with a new type of DCs in patients with different types of tumours treated in a compassionate use[1] programme, the DC vaccine protocol was changed to the use of new generation DCs. The last five of 20 treated patients received DCs that were matured with a new TLR7/8-agonist maturation cocktail developed by Medigene. Three of 15 patients given DC vaccines derived with the old (standard) maturation cocktail have experienced a biochemical relapse (raised levels of prostate-specific antigen, PSA) during the vaccination period of 3 years. None of the patients given the new type of DC vaccines has so far experienced a rise in PSA levels.

Prof. Gunnar Kvalheim, Head of Department of Cellular Therapy, Oslo University Hospital concluded on the results: "To our knowledge this is the first adjuvant DC vaccine study in high risk prostate cancer and we conclude that the study is feasible, safe and utmost promising."

Prof. Dolores J. Schendel, CEO/CSO of Medigene AG added: "We feel very encouraged by these preliminary data. The advanced method of making DC vaccines is identical with the method Medigene is also using in its own ongoing DC vaccine study in acute myeloid leukaemia."

More detailed information on the presented data can be found under the following link: View Source;sKey=ac456e79-efd5-416e-a7de-67382c67723a&cKey=2ab5cd11-b3d8-40a8-8087-b0c57f2e8034&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267

The Oslo University Hospital has an agreement with Medigene for use of Medigene`s new generation DC vaccines for their ongoing academic clinical studies.

About Medigene’s DC vaccines: The platform for the development of antigen-tailored DC vaccines is the most advanced platform of the highly innovative and complementary immunotherapy platforms of Medigene Immunotherapies. Currently, Medigene evaluates its DC vaccines in a company-sponsored phase I/II clinical trial in acute myeloid leukaemia (AML). Further studies utilising Medigene’s DC vaccine technology include two ongoing clinical investigator-initiated trials (IITs): a clinical phase I/II trial for treating acute myeloid leukaemia (AML) at Ludwig Maximilians University Hospital Grosshadern, Munich, and a clinical phase II trial of a treatment for prostate cancer at Oslo University Hospital. Moreover, compassionate use patients are treated with DC vaccines at the Department of Cellular Therapy at Oslo University Hospital.

Dendritic cells (DCs) are the most potent antigen presenting cells of our immune system. Their task is to take up, process and present antigens on their cell surface, which enables them to activate antigen-specific T cells for maturation and proliferation. This way T cells can recognise and eliminate antigen-bearing tumour cells. Dendritic cells can also induce natural killer cells (NK cells) to attack tumour cells. The team of Medigene Immunotherapies GmbH’s scientists has developed new, fast and efficient methods for generating dendritic cells ex-vivo, which have relevant characteristics to activate both T cells and NK cells. The DC vaccines are developed from autologous (patient-derived) precursor cells, isolated from the patient’s blood, and can be loaded with tumour-specific antigens to treat different types of cancer. Medigene’s DC vaccines are in development for the treatment of minimal residual disease or use in combination therapies.

On April 19, 2016 Innate Pharma and OREGA Biotech today presented preclinical data on IPH52, a new CD39 checkpoint inhibitor program, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana, USA (Press release, Innate Pharma, APR 19, 2016, View Source [SID:1234511088]).

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Poster #3222 presents IPH52, Innate’s humanized anti-CD39 blocking antibody. This novel antibody exhibits high affinity and specificity for CD39 and potently inhibits ATPase activity in in vitro assays and ex vivo models with patient biopsies. In a murine tumor model, treatment with anti-CD39 antibody results in a significant decrease in tumor volume, and improved survival.

Poster #3218 presents for the first time the impact of CD39 disruption on the efficacy of other cancer therapeutics by comparing their effects in wildtype versus CD39 knock-out mice. The results revealed that CD39 deficiency sensitized to anti-PD1 treatment in animals that failed to respond to anti-PD-1 treatment. The antitumor efficacy of CD39 disruption is further improved when combined with an immunogenic chemotherapy. In animals bearing PD-1 insensitive tumors, combination of immunogenic chemotherapy, anti-PD1 antibody and CD39 disruption led to complete tumor eradication and long term protection (specific anti-tumor immunity) in most animals. The efficacy of an ADCC-inducing cytotoxic antibody was also improved in CD39 knock-out mice compared to wildtype.

Nicolai Wagtmann, CSO of Innate Pharma, said: "Taken together, the data presented by Innate and our partner OREGA Biotech form a very promising body of evidence supporting the development of this new, first-in-class checkpoint inhibitor antibody. The results presented today raise exciting perspectives for the development of IPH52, both as single-agent and in combination with other checkpoint inhibitors, and we are eager to now take this first-in-class candidate forward into the preclinical development phases".

Jeremy Bastid, COO of OREGA Biotech, further commented: "CD39 mediates immunosuppression through a different mechanism than other immune checkpoints and may broadly impede the efficacy of cancer therapies. The exciting data released today using both antibody blockade and genetic CD39 deficiency shed light on the capacity of CD39 disruption to drive antitumor immune responses, either alone or in combination with PD-1 checkpoint blockers, ADCC antibodies and immunogenic chemotherapy, suggesting broad development potential".