On April 18, 2016 Dynavax Technologies Corporation (NASDAQ: DVAX) reported encouraging additional data from Part 1 of a Phase 1/2 study (LYM-01) evaluating the company’s lead immunotherapy product candidate, SD-101, in combination with low-dose radiation in lymphoma patients (Press release, Dynavax Technologies, APR 18, 2016, View Source [SID:1234510995]). The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana.

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Clinical Findings Included:

SD-101 was reported to be well tolerated across all dose cohorts with no dose limiting toxicities.
The combination of direct injection of SD-101 into a tumor and low-dose radiation resulted in changes in the tumor microenvironment that potentially induced a systemic anti-tumor response.
Tumors not directly injected with SD-101 also decreased in volume across all dose groups, and in most patients, remained stable for at least 180 to 360 days.
No evidence of a dose response was observed, although limited numbers of patients were examined.
"This clinical trial design is unique and takes advantage of the fact that lymphoma patients have easily injectable sites of disease. The local injections are conveniently added to low dose radiotherapy, a standard treatment for low grade lymphoma," stated Ronald Levy, M.D., professor and chief of the Division of Oncology at Stanford School of Medicine and the study’s lead clinical investigator. "We are pleased to have already demonstrated a safety profile, pharmacodynamics and preliminary efficacy in this study," he said.

"These additional data bolster the findings that were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) conference in December, demonstrating SD-101’s ability to promote beneficial changes in the tumor microenvironment to induce a systemic antitumor immune response," stated Eddie Gray, chief executive officer for Dynavax.

Two additional presentations relating to SD-101 are being made at the AACR (Free AACR Whitepaper) Conference — abstract 2322 this afternoon and abstract 4985 on Wednesday morning. Both presentations contain preclinical data relating to SD-101, and all three data presentations will be available on Dynavax’s website (www.dynavax.com) at the "Events and Presentations" tab under the "Investors and Media" section of the website.

About LYM-01, a Phase 1/2 Trial of SD-101 in Lymphoma

In the Phase 1/2 non-randomized, open-label, multicenter, dose-escalation and expansion study, patients had untreated low-grade B-cell lymphoma. At least two sites of measurable disease were required for participation — one of which was treated with low dose radiation and was then injected with SD-101 on days 1, 8, 15, 22 and 29. Other lesions received no treatment.

In Part 1– the dose escalation portion of the study — four dose cohorts with three patients each, received SD-101 at either 1 mg, 2 mg, 4 mg, or 8 mg. The Phase 2 expansion portion of the study is ongoing and is currently enrolling two dose cohorts. The primary endpoints of the trial are maximum tolerated dose (MTD) and evaluation of the safety of intratumoral SD-101 in combination with low dose radiotherapy. In addition, the trial is evaluating anti-tumor activity, pharmacodynamics, and duration of response. For more information about trial enrollment, please look for SD-101 at www.clinicaltrials.gov.

About SD-101

SD-101, the subject of AACR (Free AACR Whitepaper) abstracts CT047, 2322 and 4985, is Dynavax’s proprietary, second-generation, CpG-C class oligodeoxynucleotide TLR 9 agonist. SD-101 activates multiple anti-tumor mechanisms of innate immune cells and activates plasmacytoid dendritic cells to stimulate T cells specific for antigens released from dying tumor cells. TLR9 agonists such as SD-101 enhance T and B cell responses and induce high levels of Type I interferons and maturation of plasmacytoid dendritic cells and B cells. SD-101 is being evaluated in several Phase 1/2 oncology studies to assess its preliminary safety and activity.

On April 18, 2016 Biothera Pharmaceuticals, Inc. reported research providing new insights into the ability of the Company’s Phase 2 cancer immunotherapy to coordinate innate and adaptive immune responses and enhance the effectiveness of combination therapies (Press release, Biothera, APR 18, 2016, View Source [SID:1234511022]). The findings were presented today at the AACR (Free AACR Whitepaper) annual meeting, which is taking place in New Orleans, LA, April 16-20, 2016.

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AACR logoThe company is presenting five poster presentations at the AACR (Free AACR Whitepaper) meeting focusing on the unique therapeutic mechanisms of action for Imprime PGG, a Pathogen Associated Molecular Patterning molecule, or PAMP. Imprime PGG acts as an immunological "ignition switch" enlisting the innate immune system to enhance the therapeutic efficacy of tumor targeting, anti-angiogenic, and immune checkpoint inhibitor antibodies.

"These data provide compelling new evidence demonstrating in vivo that Imprime PGG can re-orient the immunosuppressive tumor microenvironment, especially in concert with anti-VEGF or anti-VEGF2 antibodies," said Jeremy Graff, Ph.D., Chief Scientific Officer and Senior Vice President, Research, at Biothera Pharmaceuticals. "Imprime PGG also effectively binds to dendritic cells, enhancing the maturation of these professional antigen presenting cells, which is key to enabling robust T cell-mediated anti-cancer immune responses and to driving therapeutic synergy with immune checkpoint inhibitors."

The Biothera Pharmaceuticals presentations, including three appearing in the late-breaking immunology research poster session, advance understanding of the mechanisms by which Imprime PGG augments immune responses:

Imprime PGG significantly enhances the efficacy of both anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors in preclinical in vivo Fully 83% of mice treated with Imprime PGG and anti-PD-L1 antibody were tumor-free after 29 days, compared with 33% of mice treated with anti-PD-L1 antibody alone. The tumor-free mice were re-injected in the opposite flank with cancer cells and remained tumor-free, indicating the establishment of immunological memory against the tumor.
Imprime PGG also upregulates expression of the critical co-stimulatory marker CD86, as well as PD-L1, on peripheral blood mononuclear cells (PBMCs) isolated from the blood of Imprime PGG-treated colon cancer patients, providing the first evidence from human clinical trials that Imprime elicits the critical immune changes in humans previously recognized in preclinical studies.
Additionally, Imprime PGG has been shown to trigger the direct tumor-killing functions of the innate immune system, dramatically reducing metastatic burden in concert with a tumor-targeting antibody in a model of melanoma metastases to lung.
By promoting myeloid-derived suppressor cell (MDSC) differentiation and repolarization of suppressive M2 macrophages, Imprime PGG re-educates the immune microenvironment and enhances the therapeutic efficacy of anti-angiogenic antibodies.
Further, Imprime PGG enables the activation and maturation of dendritic cells – the body’s professional antigen presenting cells – to facilitate T cell-mediated, antigen-specific immune responses.
The posters will be available on the Biothera Pharmaceuticals website, as they are presented today and tomorrow.

On April 18, 2016 Heat Biologics, Inc. ("Heat") (Nasdaq:HTBX), an immuno-oncology company developing novel therapies that activate a patient’s immune system against cancer, reported that preclinical data from its collaboration with OncoSec Medical Incorporated ("OncoSec") focused on evaluating the combination of immunotherapy platforms were presented yesterday at the American Conference for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (www.aacr.org) (Press release, Heat Biologics, APR 18, 2016, View Source [SID:1234510953]).

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In the poster entitled "In vivo intra-tumoral electroporation of gp96-Ig/Fc-OX40L stimulates CD8+ T cell cross-priming to tumor specific neoantigens" (Abstract #567), researchers concluded that combining Heat’s ComPACT vaccine with OncoSec’s intratumoral DNA electroporation delivery platform stimulated an expansion of neoantigen-specific CD8+ T cells, leading to a regression in both treated and untreated cancer lesions in two mouse studies (melanoma and colorectal cancer). Heat and OncoSec announced their collaboration last year to evaluate the preclinical efficacy of delivering Heat’s immunotherapy vaccines via OncoSec’s ImmunoPulse platform.

"In this first preclinical study demonstrating the feasibility of electroporating ComPACT DNA plasmids, we saw robust neoantigen T cell response and tumor regression in both treated and untreated tumors, indicating a systemic anti-tumor response that could be reflective of what we might see in metastatic lesions," said Taylor Schreiber, M.D., Ph.D., Heat’s Chief Scientific Officer. "We believe that this approach is promising and that further studies are merited, especially as this combination approach has the potential to stimulate shared and private tumor antigens without introducing the complexities associated with personalized therapies."

"We are excited by our collaboration with Heat and by these initial findings. The ability of the tumor’s microenvironment to evade immune recognition and remain non-immunogenic is a significant challenge, which we believe needs to be addressed when designing new immuno-therapies," added Robert H. Pierce, M.D., OncoSec’s Chief Scientific Officer. "The initial feasibility data between our two platforms are encouraging and we are currently exploring the potential synergy between our platforms with both ComPACT and interleukin-12 expressing plasmids."

Copies of the abstract are available and can be viewed online through the AACR (Free AACR Whitepaper) website at www.aacr.org. The poster is available in the Publications section of Heat’s corporate website.

On April 18, 2016 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that new preclinical data on FPA144 were featured today in a poster presentation from 8 AM to 12 PM (CDT) during the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held April 16-20, in New Orleans (Press release, Five Prime Therapeutics, APR 18, 2016, View Source [SID:1234510972]).

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The poster titled "FPA144, a Therapeutic Monoclonal Antibody Targeting the FGFR2b Receptor, Promotes Antibody Dependent Cell-Mediated Cytotoxicity and Stimulates Sensitivity to PD-1 in the 4T1 Breast Tumor Model in Mice" will be made available on the publications page of the Five Prime website.

"The ability of FPA144 to both recruit and drive an innate response with NK cells followed by an adaptive response with T cells is new and striking biology," said Drew Pardoll, M.D., Ph.D., Seraph Professor of Oncology, Medicine, Pathology and Molecular Biology and Genetics at the Johns Hopkins University of Medicine. "Driving this immune cascade in a patient’s tumor could provide a new therapeutic mechanism for treating solid tumors."

FPA144 is an FGFR2b-specific humanized monoclonal antibody designed to treat patients with cancers that overexpress FGFR2b. FPA144 is a targeted immunotherapy that Five Prime engineered to recruit NK cells into the tumor microenvironment and kill cancer cells by antibody-dependent cell-mediated cytotoxicity (ADCC).

"We are excited by the results we’ve seen in this model. Surprisingly, they suggest that FPA144 can drive an anti-tumor response that involves multiple immune cell types. The upregulation of PD-L1 suggests that combination with an anti-PD-1 agent could yield even more activity," said Robert Sikorski, M.D., Ph.D., Senior Vice President of Global Clinical Development at Five Prime. "Based on these results and the preliminary clinical data we reported in January, we are considering opportunities to evaluate FPA144 in immuno-oncology combination therapies and in tumors types beyond gastric cancer, including those with moderate levels of FGFR2b expression."

Five Prime evaluated the immune cell recruitment and anti-tumor effects of FPA144 in the orthotopic 4T1 model of breast cancer. In this model, the FGFR2 gene is not amplified and tumor cells express only moderate levels of FGFR2b. Doses of FPA144 or FPA144 N297Q (a modified antibody lacking Fc effector function) were administered at Day 0 and Day 3 and tumor histology and FACS were conducted at Day 1 and Day 4. The following was observed with FPA144 treatment:

24 Hours Post 1st Dose 24 Hours Post 2nd Dose
NK cell infiltration within the tumor Persistence of NK cells
Increase in PD-L1-positive cells within the tumor Persistence of PD-L1-positive cells
No change in T cells Increase in T cells within the tumor

Furthermore, therapeutic treatment with FPA144 in this model resulted in a reduction in tumor burden (33%, P < 0.001), while FPA144 N297Q neither inhibited tumor growth nor led to the recruitment of NK cells. These data provide further evidence of the ability of FPA144 to increase NK and T cell numbers within a tumor and suggest that its enhanced ADCC activity may play an important mechanistic role in anti-tumor efficacy in cancers with modest FGFR2b expression.

Additionally, the 4T1 model was used to evaluate the anti-tumor effect of FPA144 alone and in combination with an anti-PD-1 antibody (RMP1-14). Following biweekly dosing, tumor volume was assessed at day 19. Although anti-PD-1 treatment alone did not inhibit tumor growth, treatment with anti-PD-1 in combination with FPA144 inhibited tumor growth by 49% (P < 0.001). Collectively, these results suggest that FPA144 alters the immune cell composition of the tumor microenvironment in a way that primes the tumor to respond to anti-PD-1 therapy, and an additive anti-tumor effect is observed when FPA144 is combined with PD-1 blockade.

Dose expansion is ongoing in the Phase 1 monotherapy trial of FPA144 in patients with gastric cancer, a disease in which FGFR2b protein overexpression and FGFR2 gene amplification have been associated with poor prognosis. Preliminary data showing anti-cancer activity during the dose escalation portion of the trial were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium in January 2016. Updated data from the trial have been accepted for oral presentation during the ASCO (Free ASCO Whitepaper) Annual Meeting in June 2016.

About FPA144

FPA144 is an anti-FGF receptor 2b (FGFR2b) humanized monoclonal antibody in clinical development as a targeted immune therapy for tumors that over-express FGFR2b, as determined by a proprietary immunohistochemistry (IHC) diagnostic assay. FPA144 is designed to block tumor growth through two distinct mechanisms. First, it binds specifically to FGFR2b and prevents the binding of certain fibroblast growth factors that promote tumor growth. Second, it has been engineered to drive immune-based killing of tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and the recruitment of natural killer (NK) cells. FGFR2 gene amplification (as identified by FISH) is found in a number of tumors, including in approximately 5% of gastric cancer patients, and is associated with poor prognosis.

On April 18, 2016 Mustang Bio, Inc. ("Mustang"), a Fortress Biotech (NASDAQ: FBIO) Company, reported that two abstracts pertaining to its MB-101 (IL13Rα2-specific CAR-T cells) product candidate in development were selected for presentation at the upcoming American Society of Gene and Cell Therapy 19th Annual Meeting (ASGCT) (Free ASGCT Whitepaper), to be held May 4-7, 2016, at the Marriott Wardman Park Hotel in Washington, DC (Filing, 8-K, Fortress Biotech, APR 18, 2016, View Source [SID:1234510996]).

Pre-clinical Oral Presentation:
· Title: Optimization of IL13Rα2-specific CAR T cells for Clinical Development Using Orthotopic Human Glioblastoma Models in NSG Mice
o Abstract Number: 275
o Session: Oral Abstract Session 243 – Cancer-Immunotherapy, Cancer Vaccines I
o Date and Time: Thursday, May 5, 2016; 4:00 – 5:45 PM ET
o Location: Marriott Wardman Park Hotel, Washington 4
o Presenter: Dr. Christine Brown, Associate Director, T cell Therapeutics Research Laboratory at the City of Hope Medical Center ("COH")

Clinical Oral Presentation:
· Title: Phase I Study of Second Generation Chimeric Antigen Receptor–Engineered T cells Targeting IL13Rα2 for the Treatment of Glioblastoma
o Abstract Number: 247
o Session: Scientific Symposium 201 – Clinical Trials Spotlight
o Date and Time: Thursday, May 5, 2016; 8:00 AM – 10:00 AM ET
o Location: Marriott Wardman Park Hotel, Thurgood Marshall NE
o Presenter: Dr. Benham Badie, Vice Chair and Professor, Department of Surgery, Chief, Division of Neurosurgery, Director, Brain Tumor Program and Neurosurgeon at the City of Hope Medical Center ("COH")

Copies of the above referenced abstracts can be viewed online through the ASGCT (Free ASGCT Whitepaper) meeting website at View Source

About Glioblastoma multiforme (GBM)
Glioblastomas (GBM) are tumors that arise from astrocytes—the star-shaped cells that make up the supportive tissue of the brain. These tumors are usually highly malignant (cancerous) because the cells reproduce quickly and they are supported by a large network of blood vessels. GBM is the most common brain and central nervous system (CNS) malignancy, accounting for 15.1% of all primary brain tumors, and 55.1% of all gliomas. There are an estimated 12,120 new glioblastoma cases predicted in 2016 in the U.S. Malignant brain tumors are the most common cause of cancer-related deaths in adolescents and young adults aged 15-39 and the most common cancer occurring among 15-19 year olds in the U.S. (Brain Tumor Statistics. American Brain Tumor Association. December 2015). While GBM is a rare disease (2-3 cases per 100,000 person life years in the U.S. and E.U.), it is quite lethal with 5-year survival rates historically less than 10%. Chemotherapy with temozolomide and radiation are shown to extend mean survival from ~12 to ~15 months, while surgery remains the standard of care. GBM remains difficult to treat due to the inherent resistance of the tumor to conventional therapies. Treatment is further complicated by the susceptibility of the brain to damage, difficulty of the brain to repair itself and limitation to drugs crossing the blood brain barrier. Immunotherapy approaches targeting brain tumors offer promise over conventional treatments.

About MB-101 (IL13Rα2-specific CAR-T cells)
IL13Rα2 is an attractive target for CAR-T therapy as it has limited expression in normal tissue but is over-expressed on the surface of the majority of GBM. CAR-T cells designed to express a membrane-tethered IL-13 receptor ligand (IL-13) incorporating a single point mutation display high affinity for IL13Rα2 and reduced binding to IL13Rα1 in order to reduce healthy tissue targeting.

We are developing an optimized CAR-T product incorporating enhancements in CAR design and T-cell engineering to improve antitumor potency and T-cell persistence. We include a second generation hinge optimized CAR containing mutations in the IgG4 linker to reduce off target Fc interactions, as well as the 41BB (CD137) co-stimulatory signaling domain for improved survival and maintenance of memory T-cells, and extracellular domain of CD19 as a selection/safety marker. In order to further improve persistence, memory T-cells are enriched and genetically engineered using a manufacturing process that limits ex vivo expansion in order to reduce T-cell exhaustion and maintain a memory T-cell phenotype.

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