On November 11, 2016 Idera Pharmaceuticals, Inc. (NASDAQ:IDRA), a clinical-stage biopharmaceutical company developing toll-like receptor and RNA therapeutics for patients with cancer and rare diseases, is reporting translational data supporting the mechanism of action of intratumoral IMO-2125, a Toll-like receptor (TLR) 9 agonist from the ongoing Phase 1 dose escalating clinical trial (Press release, Idera Pharmaceuticals, NOV 11, 2016, View Source;p=RssLanding&cat=news&id=2221857 [SID1234516527]). In this trial, IMO-2125 is being evaluated in combination with ipilimumab for treatment of patients with metastatic melanoma with disease that is refractory to anti-PD-1 inhibitors, and have minimal options and low expectation of clinical response with ipilimumab treatment alone. Taken together, the previously reported early clinical responses and the supporting mechanism of action translational data being presented today, indicate that intratumoral IMO-2125 is a potent agent for the stimulation of the tumor microenvironment.

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In the oral presentation at the 2016 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (SITC) (Free SITC Whitepaper), entitled "Reactivating the anti-tumor immune response by targeting innate and adaptive immunity in a phase I/II study of intratumoral IMO-2125 in combination with systemic ipilimumab in patients with anti-PD-1 refractory metastatic melanoma," Cara Haymaker, Ph.D., from the University of Texas, MD Anderson Cancer Center, presented an overview of the modulation of the tumor microenvironment through the unique mechanism of action of intratumoral IMO-2125 and provided an update on the initial findings of the translational data through the first cohorts of the trial. Immunological analysis of the biopsy taken from the lesion injected with IMO-2125 showed rapid dendritic cell maturation which is a critical first step in the induction of the immune cascade within the tumor microenvironment. During the treatment period, T-cell expansion and activation and importantly, immune infiltration was observed in the biopsied distant lesions of the responding patients, demonstrating the abscopal effect.

From a clinical perspective, through all dosing cohorts tested to date, no dose-limiting toxicity has been seen. Preliminary clinical activity is also encouraging in this population with disease that is refractory to PD-1 inhibitors as 3 responses (including one CR) have already been recorded. The trial continues to dose escalate and enrollment into the planned anti-PD-1 inhibitor combination arm has also commenced.

"We hypothesized that the intratumoral injection of IMO-2125 into a single tumor lesion would stimulate dendritic cells to produce interferon and the downstream immune cascade in the tumor microenvironment, resulting in the recruitment and activation of tumor-killing T-cells in both the injected and non-injected tumors," said Joanna Horobin, M.B., Ch.B., Idera’s Chief Medical Officer. "When combined with a systemic checkpoint inhibitor, this change in the tumor microenvironment was expected to affect tumor responses in both injected and distant tumors. Today Dr. Haymaker presented analyses of serial biopsies from the tumors of patients with anti-PD-1 refractory melanoma in our ongoing phase 1 dose escalation trial of intratumoral IMO-2125 which clearly demonstrated these beneficial changes in the tumor microenvironment, essentially turning "cold" tumors "hot" in responding patients. We are thrilled to see what we believe to be, the clear translation of our hypothesis in patients. Moreover, in three patients the investigator has reported substantial tumor shrinkage with 2 partial and one complete response."

A copy of the slides from today’s presentation as well as a copy of a related poster presentation are currently available on Idera’s corporate website at View Source

These early results are from the phase 1 portion of study IMO-2125-204 (NCT02644967) in which cohorts of patients with metastatic melanoma unresponsive to PD-1 inhibitor therapy are being administered escalating doses of IMO-2125 ranging from 4 mg/kg through 32 mg/kg. IMO-2125 is injected intra-tumorally into a designated tumor lesion together with a standard dosing regimen of ipilimumab. The trial has recently been amended to also study the combination of IMO-2125 and pembrolizumab given intravenously. Following determination of the recommended phase 2 doses (RP2D) additional patients will be treated in an expansion phase 2 portion of the study. The primary objective of the phase 1 portion of the trial is to characterize the safety and determine a RP2D of IMO-2125 when administered intra-tumorally in combination with ipilimumab or pembrolizumab. The primary objective of the phase 2 portion is to assess the clinical activity of IMO-2125 in each combination at the respective RP2Ds. Assessment will be based on the immune-related response criteria (irRC) and additionally the traditional RECIST criteria. Serial biopsies are being taken of selected injected and non-injected tumor lesions to assess immune changes and correlate with clinical response assessments. The trial will enroll approximately 60 patients. The study is being conducted at MD Anderson and is being led by Adi Diab, MD, Assistant Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, MD Anderson as part of a strategic research alliance announced by Idera and MD Anderson in 2015.

Additionally at SITC (Free SITC Whitepaper), on November 9th, Idera’s Oncology Lead, Mark Cornfeld, M.D., M.P.H., presented an overview of IMO-2125’s unique mechanism of action in an oral presentation, entitled "IMO-2125, An Investigational Intratumoral Toll-Like Receptor 9 Agonist, Modulates the Tumor Microenvironment to Enhance Anti-Tumor Immunity" during a session focused on New Clinical Agents in Development. A copy of the slides from this presentation is currently available on Idera’s corporate website at View Source

About Toll-like Receptors and Idera’s Immuno-Oncology Research Program

Toll-like receptors (TLRs) play a central role in the innate immune system, the body’s first line of defense against invading pathogens, as well as damaged or dysfunctional cells including cancer cells. The innate immune system is also involved in activating the adaptive immune system, which marshals highly specific immune responses to target pathogens or tissue. Cancer cells may exploit regulatory checkpoint pathways to avoid being recognized by the immune system, thereby shielding the tumor from immune attack. Checkpoint inhibitors such as agents targeting CTLA4 or programmed cell death protein 1 (PD1) are designed to enable the immune system to recognize tumor cells. In this setting, intra-tumoral TLR9 agonist administration may increase the tumor-infiltrating lymphocytes (TILs), and thereby potentiate anti-cancer activity of checkpoint inhibitors in the injected tumor as well as systemically.

Idera’s TLR9 agonists, IMO-2125 and IMO-2055, have been created using the company’s proprietary chemistry-based discovery platform. IMO-2125 has been shown in various scientific presentations and publications to activate dendritic cells and induce interferon. Idera selected IMO-2125 to advance into clinical development in combination with checkpoint inhibitors based on this immunological profile. In previously completed clinical trials, subcutaneous administration of IMO-2125 was generally well tolerated in about 80 patients with hepatitis C. Idera has conducted further preclinical research evaluating the potential of IMO-2125 to enhance the anti-tumor activity of other checkpoint inhibitors in cancer immunotherapy with data being presented at several medical conferences during the past twelve months. The posters from these presentations can be found at View Source

About Metastatic Melanoma
Melanoma is a type of skin cancer that begins in a type of skin cell called melanocytes. As is the case in many forms of cancer, melanoma becomes more difficult to treat once the disease has spread beyond the skin to other parts of the body such as by through the lymphatic system (metastatic disease). Melanoma accounts for only one percent of skin cancer cases, but causes a large majority of skin cancer deaths. The American Cancer Society estimates that in 2016, there will be 76,380 new cases of melanoma in the U.S., and about 10,130 will die of this disease.

On November 11, 2016 Delcath Systems, Inc. (NASDAQ: DCTH), an interventional oncology company focused on the treatment of primary and metastatic liver cancers, reported financial results for the three and nine months ended September 30, 2016 (Press release, Delcath Systems, NOV 11, 2016, View Source;p=RssLanding&cat=news&id=2221745 [SID1234516515]).

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Highlights for the third quarter of 2016 and recent weeks include:

Raised $1,275,000 through an underwritten public offering of common stock and warrants;
Expanded the FOCUS Phase 3 Trial in hepatic dominant ocular melanoma to include 10 new research centers in the U.S. and Europe;
Presented data from two single-institution studies conducted in Germany on the use of the Delcath Hepatic CHEMOSAT Delivery System to treat patients with liver metastases in scientific posters at the Cardiovascular and Interventional Radiology Society of Europe (CIRSE) annual meeting;
Announced acceptance for publication of a retrospective review study, "Chemosaturation Percutaneous Hepatic Perfusion: A Systemic Review," by Dr. Arndt Vogel, et al, in the prestigious journal Advances in Therapy; and
Sponsored the Ocular Melanoma Foundation Eye Am Not Alone patient education retreat.
"Throughout the third quarter we continued to make steady progress in our clinical development program for Melphalan/HDS and in our efforts to advance CHEMOSAT as a commercially viable treatment option for primary and metastatic liver cancers in Europe," said Jennifer K. Simpson, Ph.D., MSN, CRNP, President and Chief Executive Officer of Delcath. "We also recently secured an additional $1.275 million in financing via a small fundraise in October, which will bridge us to receipt of the first cash release from the committed financing we announced in June 2016. Assuming all conditions are satisfied, we expect the anticipated quarterly releases throughout 2017 will fund our clinical development plan through the end of 2017, while also supporting our commercial activities in Europe.

"The presentation and publication of data supportive of CHEMOSAT continued during our third quarter. This includes a retrospective review study conducted by a team led by Dr. Arndt Vogel of the University of Hanover in Germany, which was accepted for publication by the prestigious peer-reviewed journal, Advances in Therapy. This study originated as a white paper produced by our Experts Panel in 2015, and we are pleased that the potential for CHEMOSAT to treat primary and metastatic liver cancers as identified by our experts will now reach a wider audience. Also during the quarter investigators from Asklepios Barmbek Clinic and Hanover Medical School in Germany, and Southampton University Hospital in the United Kingdom, presented compelling data from their single-institution investigations. These data provide us with considerable confidence that similar results may be formally validated by the trials that comprise our Clinical Development Plan, and we look forward to additional presentations and publications of data in support of CHEMOSAT throughout the remainder of the year and beyond.

"Negotiations by hospitals in Germany to determine reimbursement levels for CHEMOSAT under the ZE national system are expected to conclude during our fourth quarter. We believe that favorable reimbursement levels defined through this process will support growth in procedure volumes in Germany and provide important validation for reimbursement appeals in other markets in Europe.

"The advances we made in 2016 have positioned us to achieve important clinical inflection points in our FOCUS trial and our global Phase 2 program in HCC and ICC, as we work to expand global access to CHEMOSAT for the benefit of patients suffering with primary and metastatic liver cancers," concluded Dr. Simpson.

Third Quarter Financial Results

Total revenues for the third quarter of 2016 and 2015 were $0.4 million. Selling, general and administrative expenses for the third quarter of 2016 were $2.4 million, compared with $2.3 million for the same period in 2015, primarily attributable to a slight increase in facility and professional expenses. Research and development expenses increased to $2.7 million for the 2016 third quarter from $1.7 million for the same period in 2015, primarily due to increased investment in clinical development initiatives, specifically the global Phase 3 FOCUS clinical trial.

Total operating expenses for the third quarter of 2016 increased to $5.0 million from $4.0 million for the same period in 2015. This reflects an increase in clinical development initiatives.

The Company recorded a net loss for the three months ended September 30, 2016 of $1.0 million, or $0.66 per share, a decrease of $1.4 million from a net loss of $2.4 million, or $1.96 per share, for the same period in 2015. This was primarily driven by amortization of debt discounts related to the convertible note issued in June 2016 and a change in the fair value of the warrant liability, a non-cash item.

Nine Month Financial Results

Total revenues for the first nine months of 2016 and 2015 were $1.3 million. Selling, general and administrative expenses for the first nine months of 2016 were $7.0 million, an improvement of $0.8 million or 11% from $7.8 million reported for the same period in 2015, primarily attributable to a reduction in facility expenses related to the lease restructurings. Research and development expenses during the first nine months of 2016 increased to $6.0 million compared with $4.1 million for the same period in 2015, primarily due to increased investment in clinical development initiatives.

Total operating expenses for the first nine months of 2016 were $13.0 million compared with $12.0 million for the same period in 2015.

The Company recorded a net loss for the nine months ended September 30, 2016 of $9.5 million, or $6.39 per share, a decrease of $0.1 million from a net loss of $9.6 million, or $10.75 per share, for the nine months ended September 30, 2015. This was primarily driven by amortization of debt discounts related to the convertible note issued in June 2016 and a change in the fair value of the warrant liability, a non-cash item.

Balance Sheet Highlights

As of September 30, 2016, Delcath had cash and cash equivalents of $3.7 million, compared with $12.6 million as of December 31, 2015. During the first nine months of 2016, the Company used $10.6 million in cash to fund its operating activities. In June 2016, Delcath issued $35.0 million of senior convertible notes and related common stock purchase warrants and in October 2016, the Company raised $1,275,000 through an underwritten public offering of common stock and warrants. As a result, Delcath believes it has sufficient capital to fund its operating activities through the end of 2017.

On November 11, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported an oral presentation with updated data on its study of NY‑ESO SPEAR (Specific Peptide Enhanced Affinity Receptor) T‑cells in the ongoing synovial sarcoma trial at the 2016 Connective Tissue Oncology Society (CTOS) annual meeting presented by Dr. Sandra P. D’Angelo of the Memorial Sloan Kettering Cancer Center (Press release, Adaptimmune, NOV 11, 2016, View Source;p=RssLanding&cat=news&id=2221814 [SID1234516498]). This presentation included an update to Cohort 1 median survival data. The meeting is being held at the Corinthia Hotel in Lisbon, Portugal from November 9 through 12, 2016.

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In an oral presentation entitled, "Open Label Non-Randomized Multi-Cohort Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO SPEAR T-cells in HLA-A*02+ Patients with Synovial Sarcoma," Dr. Sandra P. D’Angelo of the Memorial Sloan Kettering Cancer Center described that median survival for Cohort 1 is now calculated to be ~18 months (80 weeks), compared to ~13 months (56 weeks) as previously reported. The updated median survival calculation is based on analyses of additional patient follow-up data (cutoff of September 30, 2016). Other updates indicate that there continue to be additional partial responses among low NY-ESO expressors in Cohort 2, which is ongoing.

On November 11, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported the presentation of data at the 2016 Society for Immunotherapy for Cancer (SITC) (Free SITC Whitepaper) annual meeting (Press release, Adaptimmune, NOV 11, 2016, View Source;p=RssLanding&cat=news&id=2221778 [SID1234516497]). The posters summarize: (1) preclinical data from Adaptimmune’s wholly-owned MAGE-A4 SPEAR (Specific Peptide Enhanced Affinity Receptor) T‑cells; (2) preclinical data from the Company’s second generation SPEAR T-cell, which is engineered to overcome immunosuppression in the tumor microenvironment by blocking the effects of transforming growth factor Beta (TGF-Beta); and (3) a single-patient case study from the Company’s ongoing synovial sarcoma study. The 2016 SITC (Free SITC Whitepaper) annual meeting is being held at the Gaylord National Hotel & Convention Center in National Harbor, Maryland on November 9 through 13, 2016.

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"We are pleased to present the preclinical data that underpins the decision to progress our next SPEAR T‑cell candidate, MAGE-A4, into clinical trials and we plan to file an IND in early 2017," said Gwendolyn Binder-Scholl, PhD Adaptimmune’s Chief Technology Officer. "MAGE–A4 is an attractive target which is broadly expressed in multiple solid tumors. Our MAGE-A4 SPEAR T-cell candidate has shown promising activity without any major safety concerns identified by our extensive preclinical testing. In addition, we are presenting initial data from a second generation NY-ESO SPEAR T-cell to overcome TGF‑Beta immunosuppression in the tumor microenvironment, as well as translational results from a case study of a patient with synovial sarcoma treated with NY-ESO SPEAR T‑cells. We believe that this type of data underscores our leadership in the field, and helps us to improve the function of SPEAR T-cells and inform future clinical study design."

Preclinical Testing of Wholly-owned MAGE-A4 SPEAR T-cells
In a poster presentation entitled, "Preclinical evaluation of an optimal-affinity MAGE-A4 T-cell receptor for adoptive T-cell therapy," Daniel Williams, Ph.D. of Adaptimmune, presented data examining MAGE-A4 expression in tumor and non-tumor tissues, and generation of an optimal affinity-enhanced MAGE-A4 SPEAR T‑cell.

MAGE-A4 is a cancer‑testis antigen, one of a number of genes with expression in adult tissues restricted to the testes, but also known to be expressed in several tumor types;
Target validation data indicates that MAGE-A4 is a very attractive target due to widespread and frequent expression in multiple tumor types including non‑small cell lung cancer, bladder, melanoma, head and neck, ovarian, esophageal, and gastric cancers with no detectable expression in non-tumor, non-germline tissues;
No major safety concerns were identified for MAGE-A4 SPEAR T-cells using Adaptimmune’s extensive in vitro preclinical testing platform;
MAGE-A4 SPEAR T-cells displayed strong cytotoxicity towards MAGE-A4+ melanoma and NSCLC cell lines, and;
These data will support filing of an IND, with submission planned for early 2017.
Second Generation SPEAR T-cell Engineered to Overcome TGF-Beta Tumor-mediated Immunosuppression
In a poster presentation entitled, "Engineering 2nd generation SPEAR T-cells to overcome TGF-Beta-mediated immunosuppression for adoptive cell therapy," Andrew Gerry, Ph.D. of Adaptimmune presented preclinical data regarding the development of this second generation SPEAR T-cell.

NY-ESO SPEAR T-cells have shown promising activity in clinical trials for both solid and liquid tumors. However, the depth and durability of response may potentially be affected by inhibitory factors in the tumor microenvironment;
One such factor is an inhibitory cytokine known as TGF-Beta that inhibits many T‑cell functions including proliferation, cytotoxicity, and cytokine production. Truncation of the intracellular signaling domain of the TGF-Beta receptor produces a dominant negative form of this receptor (dnTGFBetaRII), and data from the literature indicate that expression of this dominant negative receptor negates the inhibitory effects of TGF-Beta;
Adaptimmune engineered a second generation NY-ESO SPEAR T-cell co-expressing dnTGFBetaRII to produce resistance to TGF-Beta immunosuppression, and;
Data indicate that these second generation NY-ESO SPEAR T-cells co-expressing dnTGFBetaRII are resistant to inhibition by TGF-Beta in vitro.
Case Study Demonstrating Long-term SPEAR T-cell Persistence and Maintenance of Tumoricidal Activity
In a poster presentation entitled, "Case Report: Specific Peptide Enhanced Affinity Receptor T-Cells (SPEAR T-cells) demonstrate long-term persistence and both in vivo and ex vivo tumoricidal activity," Samik Basu M.D. and Gareth Betts Ph.D., both of Adaptimmune, presented translational data from a single patient who was treated in October 2013 in Cohort 1 of the ongoing study of NY-ESO SPEAR T-cell in synovial sarcoma. This patient was included in analyses that have been previously presented.

Data indicate that NY-ESO SPEAR T-cells have long-term persistence as they were readily detectable in the patient’s peripheral blood at 28 months post-infusion;
These cells exhibited markers of long‑term, self-renewing memory T-cells with minimal expression of phenotypic markers of exhaustion;
NY-ESO SPEAR T-cells retained tumoricidal activity when they were evaluated ex vivo against tumor targets exhibiting substantial killing of NY-ESO-1+ cells without additional re-stimulation, and;
Mechanisms underlying tumor progression remain under investigation and broadly appear to be related to T-cell exclusion by tumor, supporting consideration of rational combination study designs.

On November 11, 2016 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that a poster featuring preclinical data related to its tetravalent anti-GITR agonist antibody, FPA154, was presented today at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in National Harbor, Maryland (Press release, Five Prime Therapeutics, NOV 11, 2016, View Source [SID1234516495]). Poster #175 titled, "Novel tetravalent anti-GITR antibody is a potent anti-tumor agent in vivo," is available at View Source

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"With our lead anti-GITR candidate, FPA154, now in pre-IND enabling studies, we are pleased to highlight our first preclinical data supporting the development and differentiation of this novel, tetravalent antibody," said Luis Borges, Ph.D., Senior Vice President of Research, at Five Prime. "In vitro data demonstrates that our tetravalent antibody has agonistic activity in the absence of Fc-mediated crosslinking. In vivo, the antibody has potent anti-tumor activity in various murine tumor models and it confers long-term anti-tumor immunity. It alters the ratio of Tregs to effector T cells, creating a favorable environment for an effective anti-tumor immune response. These findings suggest the potential for FPA154 to activate T cell immunity against various tumors and we are working to move this program rapidly toward clinical development."

FPA154 has been designed using single-domain antibodies in a tetravalent format, inducing effector T cell stimulation in vitro that is superior to a conventional bivalent antibody format and conferring agonistic activity even in the absence of Fc-mediated crosslinking. The poster features preclinical data provided by a mouse-reactive surrogate molecule that demonstrate potent inhibition of tumor growth in mouse tumor models:

Potent anti-tumor activity following a single dose: A single dose of tetravalent anti-GITR significantly inhibited tumor growth in multiple models including CT26 and MC38. Treatment was capable of inducing complete tumor rejection, and activity was observed at doses as low as 0.08 mg/kg in both models.

Fc-independent activity: Tetravalent anti-GITR antibody retained partial tumor growth inhibition activity even in the absence of Fc-mediated crosslinking or effector function, whereas a conventional bivalent antibody (DTA-1) required Fc function.
Pharmacodynamic responses: Tetravalent anti-GITR antibody treatment reduced the number of T cells in the peripheral blood 3 days post-treatment. In the tumor, Treg and conventional CD4 T cells decreased, but CD8 T cell numbers were maintained. This resulted in a ratio of CD4 and CD8 effector T cells to Treg that created a favorable environment for an effective anti-tumor immune response.

Induction of long-term immunity: Mice that eliminated CT26 tumors in response to tetravalent anti-GITR were resistant to tumor regrowth upon re-challenge with the same tumor, but not to an antigenically-unrelated tumor.