On December 7, 2015 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, reported the presentation of data on G100 demonstrating both direct and abscopal (indirect) tumor regression, as well as tumor-specific, long-term immune protection (Press release, Immune Design, DEC 7, 2015, View Source [SID:1234508477]). G100 is Immune Design’s intratumoral TLR4 agonist-based product candidate and is currently in clinical trials. Results were highlighted during an oral presentation at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida.

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The research, authored by Ronald Levy and Idit Sagiv-Barfi of Stanford University and Hailing Lu, Jessica Hewitt, Frank Hsu and Jan ter Meulen of Immune Design, investigated the therapeutic impact and immune response of intratumoral administration of G100 in a preclinical model of lymphoma. Results demonstrated:

tumor regression in 60-100 percent across the animal models;

tumor growth inhibition reported in both injected tumors as well as uninjected tumors (abscopal effects);

responders remained tumor-free at least three months post G100 treatment and were resistant to secondary challenge with the same tumor type;

tumor-specific, systemic CD8 T cell responses were induced and shown to mediate anti-tumor protection;

combination with immune checkpoint modulation led to enhanced tumor protection and improved survival; and
G100 had an impact on the tumor microenvironment, changing it from a non-inflammatory state ("cold" tumor microenvironment) to an inflamed state ("hot" tumor microenvironment).

"These data demonstrate the ability of G100 to alter the tumor microenvironment and generate a systemic T-cell based anti-tumor response that is both specific and long-lasting," said Dr. Ronald Levy, Professor and Chief, Division of Oncology, Stanford University School of Medicine. "G100, either alone or in combination with immune checkpoint modulators, according to this model may hold potential as a treatment for lymphoma patients."

"These findings build on the strong set of preclinical and clinical data that support the ability of Immune Design’s G100 product candidate to have an impact on the immunotherapy landscape, including in combination with other immuno-oncology approaches," said Jan ter Meulen, MD, PhD, Chief Scientific Officer at Immune Design. "These data provide support for our planned clinical trial in patients with follicular non-Hodgkin’s lymphoma receiving local radiation, with or without the anti-PD-1 therapy, Keytruda, pursuant to our collaboration with Merck."

About G100

G100 is a product candidate generated from the company’s GLAASTM discovery platform, and includes a specific formulation of Glucopyranosyl Lipid A (GLA), a synthetic, toll-like receptor-4 (TLR-4) agonist. G100 is part of Immune Design’s intratumoral immune activation, or ‘Endogenous Antigen’ approach to treating cancer, which leverages the activation of dendritic and other immune cells in the tumor microenvironment to potentially create a robust immune response against the tumor’s preexisting diverse set of antigens. Preclinical and clinical data have demonstrated the ability of G100 to activate dendritic cells in tumors and to increase antigen-dependent systemic humoral and cellular Th1 immune responses.

G100 Study in Patients with Merkel Cell Carcinoma

A Phase 1 study of G100 in patients with Merkel cell carcinoma (MCC) recently completed enrollment, and Immune Design presented data at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. In the first eight patients of the MCC study, G100 had an acceptable safety profile and resulted in an objective response rate (ORR) of 50% per protocol.

G100 Study in Patients with Follicular Non-Hodgkin’s Lymphoma

A Phase 1 study evaluating intratumoral G100 in patients with follicular non-Hodgkin’s lymphoma is currently enrolling patients (NCT: 02501473). The study is being updated to examine intratumoral administration of G100 with intravenous administration of KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in patients with follicular non-Hodgkin’s lymphoma receiving local radiation. In addition to an evaluation of the safety of the combination, the study will assess the response in both injected and non-injected lesions.

On December 7, 2015 Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM), a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, reported preclinical data from studies of its CIDeCAR CAR T-cell technology, including product candidate BPX-401, in an oral presentation at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting today (Press release, Bellicum Pharmaceuticals, DEC 7, 2015, View Source;p=RssLanding&cat=news&id=2120758 [SID:1234508476]). The preclinical in vivo data show that tumors can be eliminated quickly and safely with the Company’s CIDeCAR novel costimulatory domain and safety switch.

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In the oral presentation, "Expression of MyD88/CD40 Drives In Vivo Activation and Proliferation of Chimeric Antigen Receptor Modified T Cells That Can Be Effectively Regulated by Inducible Caspase-9," Bellicum scientists compared CIDeCARs targeting CD19 or other tumor antigens to CAR constructs based on 4-1BB and CD28. CIDeCAR combines Bellicum’s novel costimulatory domain MC (MyD88/CD40) and the CaspaCIDe safety switch. Bellicum’s small molecule rimiducid was used to activate the CaspaCIDe safety switch. The CaspaCIDe safety switch was also employed as a "dimmer switch," titrating the number of CIDeCAR cells in order to remain within a therapeutic window that maximizes both safety and efficacy, for improved clinical benefit.

Study Highlights

Activation:

The addition of the MC costimulatory domain led to a significant increase in in vivo activation and persistence of the CIDeCAR CAR T cells when compared to CARs constructed with conventional costimulatory domains CD28 and 4-1BB.
Studies also showed that CAR T cells with the MC costimulatory domain eliminated cancer cells faster in animal models than CARs using CD28 or 4-1BB.
Safety:

In CD19 and HER2 animal models, the majority of CAR T cells can be eliminated if needed, leading to rapid recovery from cytokine release-like syndrome, without tumor relapse.
Experiments also demonstrate that the CaspaCIDe safety switch can be titrated. Lower concentrations of small molecule activator rimiducid led to elimination of only a portion of circulating CAR T cells, including possibly the most active cells, without losing the antitumor effect of treatment.
GoCAR-T and GoTCR Poster Presentations

Two additional poster presentations1,2 at ASH (Free ASH Whitepaper) featured the Company’s GoCAR-T and GoTCR technologies. GoCAR-T technology uses rimiducid to control persistence of CAR-T cells in vivo for therapeutic effect. In animal experiments targeting CD19 and Prostate Stem Cell Antigen (PSCA), Bellicum scientists demonstrated that a single IV injection of GoCAR-T cells containing the proprietary iMC (inducible MyD88/CD40) activation switch could eliminate large, established solid tumors and lymphomas. Administration of rimiducid stimulated the survival and proliferation of GoCAR-T cells, which may allow more effective therapy of solid tumors in patients.

In an additional poster session, Bellicum scientists used the same iMC activation switch to complement HLA-A2/Preferentially Expressed Antigen in Melanoma (PRAME)-specific TCR-modified T cells to create "GoTCR"s that also could be activated by rimiducid, similar to the GoCAR-T platform. PRAME-targeted GoTCRs were active against PRAME-expressing tumors in vitro and in vivo. Activation with weekly administration of rimiducid led to more effective tumor control. In this application of the CID technology, toxicity is controlled by the cessation of rimiducid administration, acting like "lifting one’s foot off of a gas pedal," without the loss of tumor control.

"These preclinical data support the advancement of our product candidates BPX-401 and BPX-601 into clinical trials. We are also excited about the potential of our GoTCR platform to address the limitations of TCR therapy by enabling control over the cells’ proliferation and persistence," commented Tom Farrell, Bellicum’s President and CEO.

1 Foster A, Mahendravada A, Shinners N, et al. "Inducible MyD88/CD40 allows rimiducid-dependent activation to control proliferation and survival of chimeric antigen receptor-modified T cells." 2015 Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), Orlando, FL

2 Hoang T, Foster A, Lu A, et al. "Inducible MyD88/CD40 enhances proliferation and survival of PRAME-specific TCR-engineered T cells and increases anti-tumor effects in myeloma 2015." Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), Orlando, FL

On December 07, 2015 TG Therapeutics, Inc. (Nasdaq:TGTX), reported the presentation of updated clinical results from its ongoing Phase I single agent study of TGR-1202, the Company’s next generation PI3K delta inhibitor, as well as its Phase II combination study of TG-1101 (ublituximab), the Company’s novel, glycoengineered monoclonal antibody plus ibrutinib, the oral BTK inhibitor (Press release, TG Therapeutics, DEC 7, 2015, View Source [SID:1234508474]). Data from these studies are being presented today, Monday December 7, 2015 at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held at the Orange County Convention Center in Orlando, FL.

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Michael S. Weiss, the Company’s Executive Chairman and Interim CEO commented on the data, "We are extremely pleased that the activity and safety profile of TGR-1202 continues to exhibit best in class attributes. As a once daily PI3K delta inhibitor, we believe the added convenience along with a low occurrence of hepatic toxicity, will make TGR-1202 a very appealing treatment option for physicians. More importantly, with over 80 patients having been exposed to TGR-1202 for over 6 months and another 42 on drug for more than a year, we believe the data supports that colitis associated with other PI3K deltas is not likely to be a major concern for TGR-1202. We are also excited about the final data from our 1101 plus ibrutinib study in patients with advanced Mantle Cell Lymphoma. More and more, physicians are recognizing the need to deepen ibrutinib responses to avoid relapse and the data demonstrating a doubling of CRs in patients with MCL compared to historical data of single agent ibrutinib seems very encouraging, although in a small number of patients. The deepening of responses in MCL, primarily a nodal disease, is further confirmation of the ability of TG-1101 to penetrate the nodes and improve responses. This is consistent with the deepening of responses seen with the combination in CLL, where we reported 25% CR and/or MRD negativity in rel/ref CLL, which compares favorably to the ibrutinib label. We believe this is further confirmation of the benefit we expect to see in our GENUINE Phase 3 trial."

Dr. Owen A. O’Connor, Professor of Medicine and the Director of the Center for Lymphoid Malignancies, at the Columbia University Medical Center and lead author for the TGR-1202 single agent poster presentation stated, "With many patients on daily TGR-1202 now for well over a year, and upwards of 2.5 years, we are very impressed with the continued tolerability and long term safety profile of TGR-1202, which we believe is truly differentiated from other PI3K delta inhibitors. Discontinuations due to adverse events have been particularly rare, translating into prolonged progression-free survival in relapsed and refractory CLL and indolent NHL patients of two years or more. We are excited at the potential to bring forward this important and needed treatment option for patients with advanced hematologic malignancies."

The following summarizes the posters presented today:

TGR-1202, a Novel Once Daily PI3K-Delta Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile in Patients with CLL and B-Cell Lymphoma (Abstract Number 4154)

This poster presentation includes data from patients with relapsed and refractory Chronic Lymphocytic Leukemia (CLL) and B-Cell lymphoma (NHL and Hodgkin’s) treated with TGR-1202 as a single agent. Eighty-one patients were evaluable for safety, and 63 patients evaluable for efficacy, which includes patients treated with 800 mg of the initial formulation or higher, and any micronized dose level. Patients in this study were heavily pretreated with 57% of patients having seen ≥ 3 prior therapies, and 49% of patients being refractory to their prior therapy.

Highlights from this poster include:

94% (16 of 17) of CLL patients achieved a nodal PR, with the remaining patient still on study pending further evaluation

59% (10 of 17) of these CLL patients achieved a response per the iwCLL (Hallek 2008) criteria

Median progression free survival (PFS) in the CLL cohort was approximately 24 months

75% (12 of 16) of follicular lymphoma patients demonstrated tumor reductions, with a preliminary ORR of 38% (6 of 16), with 2 additional patients achieving 49% reductions in tumor burden, each continuing on study pending further efficacy assessments
Median PFS for the indolent NHL cohort was 27.3 months

TGR-1202 continues to demonstrate a favorable safety profile, differentiated from the other PI3K deltas inhibitors, with only 7% of patients discontinuing due to an adverse event

Limited grade 3/4 adverse events were reported with anemia and neutropenia (each 9%) being the only grade 3/4 adverse events reported in greater than 5% of patients

Long-term safety has been well characterized with 47% (38 of 81) of patients on study more than 6 months, 27% (22 of 81) of patients on study more than 12 months, and the longest exposed to drug for more than 2.5 years

No events of colitis have been reported, and grade 3/4 AST/ALT elevations have been seen in 2% of patients (4% all grades)
Safety and efficacy profile supports combination therapy with other novel targeted agents

Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination With Ibrutinib is Highly Active in Patients with Relapsed and/or Refractory Mantle Cell Lymphoma; Results of a Phase II Trial (Abstract Number 3980)

This poster presentation includes data from 15 patients with previously treated mantle cell lymphoma (MCL) treated with 900mg of TG-1101, in combination with ibrutinib at an oral daily dose of 560mg. There was no limit on prior type or number of therapies and patients previously treated with prior with a BTK inhibitor and/or a PI3K delta inhibitor were permitted. The combination appeared well tolerated in all patients treated, with neutropenia being the only reported grade 3/4 adverse event occurring in greater than 7% of patients and no infusion related reactions being reported for TG-1101.

Highlights from this poster include:

87% (13 of 15) investigator assessed ORR, including a 33% Complete Response rate which compares favorably to historical single agent ibrutinib data (66% investigator assessed ORR and 17% CR)
93% (14 of 15) of patients achieved some reduction in tumor burden on study, with the remaining patient having been refractory to prior anti-CD20 therapy and refractory to prior ibrutinib therapy progressing in Cycle 3
Greater depth of response was achieved over time, with a 62% median reduction in tumor burden at week 8 which increased to a 76% median reduction by week 20
No dose reductions were needed for TG-1101, however 20% (3 of 15) of patients had their ibrutinib dose reduced.

POSTER PRESENTATION DETAILS

A copy of the poster presentations are available on the Company’s website at www.tgtherapeutics.com, located on the Publications Page, within the Pipeline section.

On December 07, 2015 TG Therapeutics, Inc. (Nasdaq:TGTX), reported the presentation of pre-clinical data describing the synergy of the Company’s next generation PI3K-delta inhibitor, TGR-1202, with proteasome inhibitors in various hematologic cell lines and patient donor cells (Press release, TG Therapeutics, DEC 7, 2015, View Source [SID:1234508473]). The oral presentation was delivered by Changchun Deng, MD, PhD, Assistant Professor, Center of Lymphoid Malignancies, Columbia University Medical Center at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held at the Orange County Convention Center in Orlando, FL.

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Combination data was generated using TGR-1202, the PI3k-delta inhibitor idelalisib, and the proteasome inhibitors carfilzomib and bortezomib. Data revealed that the combination of TGR-1202 and carfilzomib was uniquely synergistic as compared to any other combination of a PI3K-delta inhibitor and proteasome inhibitor, including the combination of idelalisib and cafilzomib and idelalisib and bortezomib. These data were generated as part of a large pre-clinical research collaboration with the Center for Lymphoid Malignancies, whereby the activity and mechanism of action of TGR-1202 is being studied in a variety of in-vitro and in-vivo models.

Presently there are no agents approved that specifically target c-Myc, an oncogene often found constitutively active in a variety of cancers, including Diffuse Large B-Cell Lymphoma, and has recently been the target of a class of drugs knows as BET (bromodomain and extraterminal domain family) inhibitors. The combination of TGR-1202 and carfilzomib was found to potently inhibit cap dependent translation of c-Myc in all cell lines tested, including DLBCL, mantle cell lymphoma, multiple myeloma, T-cell lymphoma, and CLL cells. In these cell lines, inhibition of c-Myc expression resulted in increased caspase 3/7 activity and complete cleavage of PARP, both mechanisms of apoptosis. Importantly, the combination was not found to be cytotoxic when evaluated on healthy patient lymphocytes indicating the specificity towards malignant cells. As a result of these data, the combination of TGR-1202 and carfilzomib is intended to be studied in a Phase I/II clinical trial to be led by investigators at Columbia University Medical Center.

Commenting on the data, Owen A. O’Connor, MD, PhD, Professor of Medicine and Experimental Therapeutics, and Director of the Center for Lymphoid Malignancies at Columbia University Medical Center stated, "The development of agents that have the ability to inhibit the expression or activity of c-Myc, a key driver in a large variety of hematologic and solid-tumor malignancies, has long been an area of focused research which to date has yielded modest results. The potential for this unique combination is far reaching, and begins to explain the differentiated pharmacologic profile demonstrated by TGR-1202 in patients. We look forward to continuing to elucidate the mechanisms for TGR-1202’s unique tolerability and efficacy, as well as evaluating this combination in patients in our upcoming Phase I/II study."

Michael S. Weiss, the Company’s Executive Chairman and Interim CEO stated, "TGR-1202 has demonstrated strong activity with a differentiated safety and tolerability profile in patients across a variety of clinical trials, and we are eager to explore and understand the mechanisms that contribute to TGR-1202’s potential best-in-class attributes. We thank the investigators at Columbia University, especially Dr. Deng and Dr. O’Connor, for all their efforts on this important research program."

PRESENTATION DETAILS

A copy of the slides used for the oral presentation is available on the Company’s website at www.tgtherapeutics.com, located on the Publications Page, within the Pipeline section.

On December 7, 2015 Stemline Therapeutics, Inc. (Nasdaq:STML) reported the presentation of positive clinical data, including high response rates, from the lead-in and ongoing expansion stage of its SL-401 pivotal trial in blastic plasmacytoid dendritic cell neoplasm (BPDCN) at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Stemline Therapeutics, DEC 7, 2015, View Source [SID:1234508472]). The poster (no. 3795) detailing these data will be available for viewing 10am-6pm ET today and presented this evening, 6pm-8pm ET, at the conference.

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The data being presented demonstrate that multiple consecutive cycles of SL-401 produced an 86% (12/14) overall response rate (ORR) in BPDCN, with a 100% (9/9) ORR in first-line BPDCN and a 60% (3/5) ORR in relapsed/refractory BPDCN. There were four complete responses (CR) and four clinical complete responses (CRc) defined as a CR in all non-skin affected organ systems (e.g., bone marrow, lymph nodes, and/or viscera/organs) with marked clearance of gross skin lesions and residual microscopic disease detected by skin biopsy. While response duration data are maturing, of nine evaluable BPDCN responders treated at 12 ug/kg/day, five patients (including two relapsed/refractory patients) remain in remission receiving SL-401 therapy and two additional patients were successfully bridged to stem cell transplant (SCT). Patients continue to be followed for progression free survival (PFS) and overall survival (OS) and median PFS and OS have not been reached. Dosing and safety parameters were developed during the lead-in stage of the study to minimize the risk of severe capillary leak syndrome. Since implementation of these measures, SL-401 at doses of 12 ug/kg/day or below have yielded a manageable safety and tolerability profile as well as high levels of clinical activity. Also, multiple consecutive cycles of SL-401 at 12 ug/kg/day or below was not associated with cumulative side effects. The tables below summarize efficacy and safety observed in the lead-in and initial expansion stage of the ongoing pivotal trial in BPDCN. Patients continue to enroll and additional data will be available throughout 2016.

Naveen Pemmaraju, M.D., Assistant Professor, Department of Leukemia at the University of Texas MD Anderson Cancer Center (Houston, TX), an investigator on the study, commented, "We are seeing remarkable activity to date with SL-401 in BPDCN, which in most cases is a fatal disease of unmet medical need. Importantly, we have also been able to successfully bridge some patients to transplant which, for the most part, has not been possible with existing therapies." Dr. Pemmaraju continued, "Based on the number of patients enrolled in the lead-in and expansion stage thus far, and those being referred to us now on a regular basis, we are learning that BPDCN may be a much more prevalent disease than previously thought. We look forward to advancing the study forward in relapsed/refractory patients, and believe the drug will play a key role in the upfront setting as well."

Andrew A. Lane, M.D., Ph.D., Assistant Professor, Medical Oncology at the Dana-Farber Cancer Institute (Boston, MA), an investigator on the study, commented, "The clinical data observed thus far with SL-401 in BPDCN, and reported today at ASH (Free ASH Whitepaper), are exciting and offer a potential new therapeutic approach for patients with this devastating disease for which there are few effective treatment options." Dr. Lane continued, "We are very pleased to be ongoing contributors to this study, and look forward to helping advance this active and promising agent in BPDCN and potentially other diseases as well."

Ivan Bergstein, M.D., Stemline’s Chief Executive Officer, stated, "We view today’s clinical data update as a key milestone for our SL-401 program. We are consistently observing high levels of single agent activity in a serious malignancy of unmet medical need." Dr. Bergstein continued, "We are dedicated to aggressively advancing this promising agent toward potential registration in BPDCN. Additionally, we are actively working to expand SL-401’s clinical potential across a range of additional malignancies."

Table 1. Overview of SL-401 Clinical Activity in BPDCN

Major objective responses

86% (12/14) ORR in BPDCN (all lines)
100% (9/9) ORR in first-line BPDCN
60% (3/5) ORR in relapsed/refractory (r/r) BPDCN
57% (8/14) CR+CRc rate in BPDCN (all lines); 4 CRs, 4 CRcs
Response duration data maturing

Of 9 evaluable BPDCN responders treated at 12 ug/kg/day:
5 patients, including 2 r/r patients, in remission on SL-401 therapy (ongoing)
2 patients bridged to successful stem cell transplant (SCT)