On February 9, 2016 Adaptimmune Therapeutics plc (Nasdaq: ADAP), a leader in the use of TCR engineered T-cell therapy to treat cancer, reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for the company’s affinity enhanced T-cell therapy targeting NY-ESO in synovial sarcoma for HLA-A*201, HLAA*205 or HLA-A*206 allele-positive patients with inoperable or metastatic synovial sarcoma who have received prior chemotherapy and whose tumor expresses the NY-ESO-1 tumor antigen (Press release, Adaptimmune, FEB 9, 2016, View Source [SID:1234509015]).

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"We are committed to investigating the potential of our NY-ESO-1-T cell therapy across a variety of cancers. We are pleased that the FDA has granted Breakthrough Therapy designation for our T-cell therapy in synovial sarcoma, recognizing both the unmet need for patients suffering from this disease as well as the promise of these early data," said Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. "We look forward to working closely with the FDA to expedite the clinical development of this therapeutic candidate."

The Breakthrough Therapy designation was based on the results of a phase I/II trial in patients with unresectable, metastatic or recurrent synovial sarcoma who have received prior chemotherapy. Patients were treated with lymphodepleting chemotherapy followed by immunotherapy with T-cells engineered to recognize an HLA-A2 restricted NY-ESO-1 peptide.

Data from this study were most recently presented at the 2015 Annual Meeting of the Society of Immunotherapy for Cancer (SITC) (Free SITC Whitepaper) in November 2015. In the primary efficacy analysis, 60 percent of the 10 patients receiving the target dose of cells responded, and there was a 50 percent overall response rate in the 12 patients receiving any dose of cells. 90 percent (9/10) of those patients who received the target dose and 75 percent (9/12) of all patients were alive and on long term follow-up. The most common adverse events included nausea, anemia, pyrexia, lymphophenia and neutropenia. Cytokine release syndrome (CRS) was seen in four of twelve subjects, with grade 3 CRS observed in two subjects; no grade 4 CRS events were observed.

Adaptimmune recently announced that it will aim to initiate pivotal studies with its affinity enhanced Tcell therapy targeting NY-ESO in synovial sarcoma around year end 2016, and that it will also explore development in myxoid round cell liposarcoma. Studies with this therapy are also under way in myeloma, melanoma, ovarian cancer and non-small cell lung cancer.

About Breakthrough Therapy Designation
The breakthrough therapy designation was enacted as part of the Food and Drug Administration Safety and Innovation Act of 2012 and is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for breakthrough therapy designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. According to the FDA, breakthrough therapy designation conveys all of the fast track program features, more intensive FDA guidance on an efficient drug development program, an organizational commitment involving senior managers, and eligibility for rolling review and priority review of the company’s Biologic License Application when submitted.

About Soft Tissue Sarcoma
Soft tissue sarcomas can develop from soft tissues like fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues. There are approximately 50 types of soft tissue sarcomas, including synovial sarcoma, a cancer of the connective tissue around joints. Soft tissue sarcomas can develop at almost any anatomic site, such as the extremities, trunk or thorax, abdomen and retroperitoneum, pelvis and the head and neck region. The more common soft tissue sarcomas originate from muscle, nerve tissue, fat or deep skin tissue. For a number of sarcomas, such as synovial sarcoma, the tissue origin is not well characterized. Surgical resection is the standard therapy for localized disease and radiation therapy (preoperative or postoperative) is added in selected cases. The American Cancer Society estimates 11,930 new soft tissue sarcoma diagnoses (6,610 cases in males and 5,320 cases in females) in the United States in 2015, representing approximately 2 percent of all cancers, and approximately 4,870 Americans (2,600 males and 2,270 females) are expected to die of soft tissue sarcomas.

On February 09, 2016 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, reported positive topline data from three ongoing Phase 1 oncology studies that support continued development of its two primary in vivo immuno-oncology product candidates, CMB305 and G100 (Press release, Immune Design, FEB 9, 2016, View Source [SID:1234509012]).

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CMB305: First-in-class Prime-boost Immunotherapy Targeting NY-ESO-1 Tumors

Data from a completed first-in-human dose-escalation study and an early subset of patients from an expansion study of CMB305 as a single agent in patients with cancers expressing the NY-ESO-1 tumor antigen revealed:

CMB305 was safe, without dose-limiting toxicities, as reviewed by an independent data safety monitoring board (DSMB);
A significant subset of CMB305-treated patients had NY-ESO-1-specific CD8 T cell responses that were generated or increased after therapy;
Patients who did respond immunologically had a greater degree of antigen-specific T cell response than that previously reported in a Phase 1 study of LV305 alone, which is consistent with the intent of the prime-boost approach; and
Preliminary clinical benefit in the form of progression-free rate (PFR) was observed in patients with soft tissue sarcoma.
LV305: Novel Vector Delivering NY-ESO-1 RNA Specifically to Dendritic Cells in vivo Maintains Safety and Immunogenicity with Improved Clinical Benefit Profile

Data from the expansion study following the previously-reported dose escalation study of LV305 in patients with tumors expressing NY-ESO-1 revealed:

A consistently favorable safety profile, as reviewed by an independent DSMB;
A consistent immune response rate; and
An improved clinical benefit profile.
G100: Intratumoral Administration of aTLR4 Agonist Significantly Modifies the Tumor Microenvironment (TME) and Maintains Clinical Benefit

New data from the completed pilot trial of G100 with local radiation in patients with Merkel cell carcinoma revealed:

Safety was consistent with that originally reported, demonstrating an acceptable profile alone or in combination with local radiation;
G100 significantly altered the TME, causing inflammation and transforming tumors to a "hot" state in G100 responding patients; and
Clinical benefit remained constant with the full patient set.
Abstracts for each of these three Phase 1 studies have been submitted for presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (June 3-7, 2016). If afforded the opportunity to present, it is the company’s intent to work with the Principal Investigator for each product candidate to present a more complete data set at the Conference.

"The accumulating data, including this new set, clearly supports proceeding with the clinical development of our two first products, CMB305 and G100, each activating the anti-tumor immune response by targeting a predefined tumor antigen or neo-antigens, respectively," said Carlos Paya, M.D., Ph.D, President and Chief Executive Officer of Immune Design. "The initiation of randomized studies in which we are combining our two products with inhibitors of the PD-1/L1 axis through our collaborations with Genentech and Merck will provide the evidence as to how novel products that activate the immune system and aim to make tumors "hot" add or synergize with check-point inhibitors."

Additional Information on Immune Design’s Distinct Immuno-oncology Approaches

About CMB305

CMB305 is an immuno-oncology product candidate that involves the sequential dosing of two active agents, LV305 and G305. LV305 is a hybrid vector from the ZVex discovery platform that specifically targets dendritic cells (DCs) in vivo and delivers the RNA for NY-ESO-1, enabling the DCs to express the entire tumor antigen and potentially induce a diverse set of CTLs targeting NY-ESO-1 in tumors. G305, in contrast, is designed to boost the CTL response via the induction of antigen-specific CD4 "helper" T cells. G305 consists of recombinant NY-ESO-1 protein formulated with a proprietary synthetic small molecule called glucopyranosyl lipid A (GLA), the novel TLR4 agonist at the core of the GLAAS platform. CMB305 is intended to be an "off-the shelf" therapy that does not require patient-specific manufacturing or ex vivo manipulation of patient samples. Immune Design has conducted prior studies to establish the safety and individual immunologic activity of LV305 and G305. CMB305 is currently being evaluated in a Phase 1B trial in patients with locally advanced, relapsed or metastatic solid cancers whose tumors express NY-ESO-1 and a randomized Phase 2 trial of CMB305 combined with Genentech’s investigational cancer immunotherapy, atezolizumab (anti-PD-L1), in patients with soft tissue sarcoma, pursuant to a collaboration with Genentech.

About G100

G100 is Immune Design’s intratumoral Immune Activation approach to treating cancer and is expected to directly activate dendritic and other antigen presenting cells near the tumor, which may enhance the function of pre-existing cytotoxic T lymphocytes (CTLs) and create both a local and systemic immune response against neo-antigens. G100 is a product of the company’s GLAAS platform and recently completed a Phase 1 study in patients with Merkel cell carcinoma. G100 also has potential therapeutic utility in any accessible tumor and will be investigated in combination with local radiation and Merck’s anti-PD-1 agent, KEYTRUDA, in a randomized study in patients with follicular Non-Hodgkin lymphoma, pursuant to a collaboration with Merck.

On February 09, 2016 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company focused on new cancer immunotherapies, reported that the first patient has been enrolled in a Phase 1 clinical study of its second generation non-viral CD19-specific chimeric antigen receptor (CAR) modified T-cell therapy in patients with advance lymphoid malignancies (Press release, Ziopharm, FEB 9, 2016, View Source [SID:1234509011]). The CD19-specific T cells were modified using the Sleeping Beauty system to stably express the CAR in T cells.

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The Sleeping Beauty transposon-transposase is a unique non-viral system for introducing genes encoding CARs and T-cell receptors (TCRs) into lymphocytes and is exclusively licensed by Intrexon Corporation (NYSE:XON) through The University of Texas MD Anderson Cancer Center and accessed as part of ZIOPHARM’s collaboration. This non-viral approach may play an important role in immunotherapy and has several potential advantages over viral delivery systems, including:

Lower cost of generating genetically modified T cells
Generate T cells with minimal ex vivo processing
Conduit to targeting solid tumor neo-antigens using TCRs
Pathway to overcome regulatory hurdles

"The survival benefit seen in early clinical results with our first generation CD19-specific CAR+ T cells were highly encouraging, and preclinical results to date suggest that our next generation CAR structure may improve upon these outcomes," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM. "These studies continue to strengthen our understanding of the application and benefit of the Sleeping Beauty platform, the only efficient non-viral gene transfer system in clinical application. Sleeping Beauty offers the potential to significantly reduce the expense and simplify the implementation of genetically modified T cells, both of which are critical to the personalization and broad application of immunotherapies based on CARs and TCRs."

In two prior trials the first generation CD19-specific CAR+ T cells, patient-derived (autologous) or donor-derived (allogeneic) T cells were administered to recipients with advanced CD19-expressing leukemias and lymphomas after hematopoietic stem-cell transplantation (HSCT). Results demonstrated an apparent doubling of survivals compared to historical controls.

The second-generation Sleeping Beauty CAR+ T cells employ a revised CAR construct designed to improve persistence and anti-tumor response over the first generation therapy. Additionally, this investigational treatment is independent of HSCT. This trial is being conducted at MD Anderson.