On December 9, 2017 Fate Therapeutics, Inc. (NASDAQ:FATE), a biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported the generation of chimeric antigen receptor (CAR)-targeted CD8αβ+ T cells from a clonal engineered master pluripotent cell line (MPCL) (Press release, Fate Therapeutics, DEC 9, 2017, View Source [SID1234522462]). The clonal engineered MPCL was created from an induced pluripotent stem cell (iPSC), which was modified in a one-time engineering event using CRISPR/Cas9 to both insert a CAR into the T-cell receptor α constant (TRAC) locus and eliminate T-cell receptor (TCR) expression. The groundbreaking development enables the renewable production of CAR-targeted, TCR-null CD8αβ+ T cells that are not restricted to an individual patient for off-the-shelf administration.

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The breakthrough was reported today at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition by scientists from the laboratories of Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering, Memorial Sloan Kettering Cancer Center and Fate Therapeutics. In September 2016, Fate Therapeutics and Memorial Sloan Kettering Cancer Center launched a multi-year partnership led by Dr. Sadelain to develop off-the-shelf T-cell product candidates using clonal engineered MPCLs. The collaborators are currently conducting preclinical studies and finalizing current good manufacturing practice protocols for the development of CAR-targeted, TCR-null T-cell immunotherapies. A first-in-human clinical trial of FT819, a CAR19 T-cell product candidate derived from a clonal engineered MPCL with complete elimination of TCR expression and TRAC-regulated CAR expression, is being planned.

"The use of a clonal engineered master pluripotent cell line enables cost-effective manufacture, timely availability and reliable off-the-shelf delivery of targeted T-cell cancer immunotherapy without patient restriction," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "Additionally, unlike conventional allogeneic CAR T-cell approaches that involve billions of heterogeneous engineering events to modify the genomic function of primary T cells, an engineered iPSC clone is defined by a single uniform engineering event. As a result, a T-cell product generated from a clonal engineered master pluripotent cell line is homogeneous with respect to genomic modification and cell product composition. This revolutionary approach has the potential to mediate safer, more effective pharmacologic activity, including in combination with cycles of other cancer treatments."

In February 2017, Dr. Sadelain and colleagues published a set of preclinical studies in the journal Nature using primary T cells demonstrating that directing a CD19-specific CAR to the TRAC locus with CRISPR/Cas9 resulted in uniform CAR expression and enhanced T-cell potency as compared to conventional CAR T cells. Scientists from the laboratories of Sadelain and Fate Therapeutics advanced the observation by instead engineering iPSCs and generating CD8αβ+ T cells from a clonal engineered MPCL with a CD19-targeted CAR inserted into the TRAC locus and complete elimination of TCR expression. The collaborators demonstrated that the CAR-targeted, TCR-null CD8αβ+ T cells display antigen-specific anti-tumor potency, including cytokine release and targeted cellular cytotoxicity.

Fate Therapeutics has built an extensive intellectual property portfolio broadly covering the genomic engineering of iPSCs and off-the-shelf engineered T- and NK cell cancer immunotherapies. Its proprietary portfolio includes compositions and methods for editing iPSCs to modify their biological properties using CRISPR and other nucleases, including the use of CRIPSR to insert a CAR in the TRAC locus for endogenous transcriptional control, and for manufacturing cells of all hematopoietic lineages from iPSCs including T cells. In addition, the Company has an exclusive license from Memorial Sloan Kettering covering iPSC-derived T cells expressing chimeric antigen receptors for human therapeutic use, and maintains an option to exclusively license intellectual property arising from all research and development activities under the collaboration.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables large-scale generation of off-the-shelf, engineered, homogeneous cell products that can be administered in repeat doses to mediate more effective pharmacologic activity. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event, and selecting a single iPSC for maintenance as a clonal master pluripotent cell line (MPCL). Similar to master cell lines used for the manufacture of monoclonal antibodies, clonal MPCLs can serve as a renewable cell source for the consistent and repeated manufacture of homogeneous cell products with the potential to treat many different diseases and many thousands of patients in an off-the-shelf manner. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 90 issued patents and 100 pending patent applications.

On December 9, 2017 Amphivena Therapeutics Inc., a privately held biotechnology company developing AMV564, a CD33/CD3 T cell redirector for the treatment of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS), reported that it will present in an oral presentation at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) preclinical data that demonstrate that treatment with AMV564 selectively depletes myeloid-derived suppressor cells (MDSCs) in bone marrow cells from patients with MDS with resultant reactivation of T lymphocytes (Press release, Amphivena Therapeutics, DEC 9, 2017, View Source [SID1234522520]). AMV564-induced restoration of immune homeostasis was accompanied by a significant improvement in hematopoiesis. AMV564 is a CD33/CD3 bivalent bispecific antibody that binds both CD33 and CD3 with strong avidity and results in T-cell directed lysis of CD33-expressing myeloid cells.

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"These preclinical data provide a strong rationale for clinical investigation of this innovative approach in patients with MDS, who have limited treatment options today. The data also underscore an opportunity to develop AMV564 for patients with other malignancies where MDSCs have been shown to contribute to the immunosuppressive tumor microenvironment," said Eric J. Feldman, M.D., Amphivena’s Senior Vice President, Clinical Development.

Alan List, M.D., President and CEO of Moffitt Cancer Center, who presented on behalf of the investigators, said, "AMV564 eliminated CD33+ MDSCs in a dose-dependent manner and restored critical aspects of immune homeostasis. In addition, proliferation of CD4+ and CD8+ T cells more than doubled with AMV564 treatment as compared to baseline; IFN-γ production, as measured by gene expression, markedly increased in AMV564-treated cells. AMV564-directed elimination of MDSCs was associated with decreased DNA damage in CD34+ stem cells and improved colony-forming capacity. Finally, the presentation concluded, AMV564 and anti-PD-1 treatment are synergistic for T-cell activation."

Amphivena plans to launch a Phase 1 clinical study in patients with MDS in early 2018. Currently, the company is conducting a Phase 1 clinical study of AMV564 in relapsed or refractory AML and is also exploring the utility of AMV564 in solid tumors.

On December 9, 2017 H3 Biomedicine Inc., a clinical stage biopharmaceutical company specializing in the discovery and development of precision medicines for oncology and a member of Eisai’s global Oncology Business Group, reported that data from the company’s academic collaborations in RNA splicing biology will be presented over the next three days at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in Atlanta, GA (Press release, H3 Biomedicine, DEC 9, 2017, View Source [SID1234522463]). The presentations are part of three academic research collaborations and will detail pre-clinical studies evaluating the role of RNA splicing in cancer biology and potential approaches for therapeutic intervention.

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Participating in these studies with H3 Biomedicine are Memorial Sloan Kettering Cancer Center, Cold Spring Harbor Laboratory, the University of Manchester, Institute Gustave Roussy, Université Paris-Saclay, the University of Texas, Dana Farber Cancer Institute, University of California, Center for Molecular Medicine of the Austrian Academy of Sciences, MD Anderson Cancer Center, Broad Institute, Beckman Research Institute and Harvard Medical School.

"We are grateful to the academic centers that have become a key aspect of our research efforts, and we are pleased to continue these ongoing relationships," said Markus Warmuth, M.D., Chief Executive Officer and President of H3 Biomedicine. "We look forward to exploring the potential of our RNA splicing platform and expand our insights on how best to target the spliceosome, in order to help H3 enhance its mission to develop important new cancer drugs."

The details of the presentations are as follows:

Title 1: Splicing Modulation Perturbs Key Survival Pathways and Sensitizes Chronic Lymphocytic Leukemia to Venetoclax Treatment
Program: Oral and Poster Abstracts
Type: Oral
Session: 641. CLL: Biology and Pathophysiology, excluding Therapy: Therapeutic Resistance in CLL
Date/Time: Saturday, December 9, 2017: 5:15 PM. Building C, Level 1, Room C101
Location: Auditorium of the Georgia World Congress Center

Title 2: Spliceosomal Dysfunction Is a Critical Mediator of IDH2 Mutant Leukemogenesis
Program: Oral and Poster Abstracts
Type: Oral
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis I
Date/Time: Sunday, December 10, 2017: 5:30 PM
Location: Building C, Level 2, C202-C204 of the Georgia World Congress Center

Title 3: 289 Dynamic BH3 Profiling to Assess the Effects of Novel Agents on Anti-Apoptotic Protein Dependence of CLL Cells
Program: Oral and Poster Abstracts
Session: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster III
Date/Time: Monday, December 11, 2017, 6:00-8:00 p.m.
Location: Building A, Level 1, Hall A2 of the Georgia World Congress Center

"H3 is exploring the potential of targeting the spliceosome, which has become an integral part of our research and development efforts," said Pete Smith, Ph.D., Chief Scientific Officer for H3 Biomedicine. "A critical component of our research and translational work is undertaken in strong collaboration with leading investigators and academic centers. This work will be exemplified through the presentations at the ASH (Free ASH Whitepaper) meeting."

On December 9, 2017 Magenta Therapeutics, a biotechnology company developing therapeutics to improve and extend the use of curative bone marrow transplant for more patients, reported the presentation of preclinical data from its CD117 antibody-drug conjugate (ADC) conditioning program (Press release, , DEC 9, 2017, View Source [SID1234522521]). These data were presented at the 59th annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta, Ga.

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Magenta is developing a portfolio of ADC-based conditioning agents that specifically deplete target cells using an approach that may be less toxic than the current chemotherapy-based conditioning regimens for bone marrow transplant. One of Magenta’s programs, CD117-ADC, is a conditioning agent that selectively binds to host hematopoietic stem and progenitor cells (HSPCs). CD117 (also known as C-KIT) is highly expressed on HSPCs and an ideal target for conditioning across broad sets of diseases, including hematological malignancies and hemoglobinopathies, with potential applicability in both bone marrow transplant and stem cell gene therapy. CD117 is also frequently overexpressed on tumor cells in patients with acute myelogenous leukemia (AML). The CD117-ADC-based transplant conditioning approach has the potential to limit systemic toxicity for transplant patients and additionally reduce tumor burden in transplant patients with AML.

"For patients undergoing bone marrow transplant, the toxicity and mortality associated with current conditioning protocols remain significant challenges and prevent more patients from benefitting from this life-saving and potentially curative procedure. Current conditioning regimens use highly toxic and non-specific chemotherapy drugs or irradiation that can result in infections, organ failure, infertility and even death," said Michael Cooke, Ph.D., chief scientific officer, Magenta Therapeutics. "Given the significant unmet need for new conditioning options for bone marrow transplant, we are pleased to see that CD117-ADC was capable of selective depletion of human hematopoietic stem cells in the bone marrow of humanized mice and showed anti-leukemia effects in vivo. This conditioning regimen has the potential to increase the number of patients eligible for transplant for both malignant and non-malignant diseases by reducing the toxicity of the procedure."

Non-Genotoxic Conditioning for Hematopoietic Stem Cell Transplant Using a Human Antibody Drug Conjugate Targeting C-KIT (Abstract #1894)
Overview and results, presented by Adam Hartigan, Ph.D., Magenta Therapeutics, include:

Magenta Therapeutics developed CD117-ADC, a fully human ADC targeting CD117 (also known as C-KIT) capable of depleting both proliferating and quiescent cells.
Humanized NSG mice treated with a single dose of CD117-ADC had greater than 90% depletion of human hematopoietic stem and progenitor cells in the bone marrow after a single administration of the ADC.
Magenta scientists demonstrated the specificity of CD117-ADC for hematopoietic stem and progenitor cells in humanized animal studies.
CD117-ADC demonstrated greater than 90% killing of the human leukemia cell line Kasumi-1, and was equally effective at killing primary human CD34+ bone marrow cells during in vitro culture.
Preliminary data suggest that a single dose of CD117-ADC is also effective at reducing tumor burden and conferring survival benefits in mice challenged with C-KIT-expressing AML cells.
About Bone Marrow Transplant

Healthy bone marrow stem cells and the blood cells they form are crucial for survival, but certain diseases can affect the bone marrow, interfering with its ability to function properly. A bone marrow transplant is a process to replace unhealthy bone marrow with healthy bone marrow stem cells. Bone marrow transplant can save the lives of patients with blood cancers and genetic diseases and is a potential cure for patients with severe, refractory autoimmune diseases. However, the high risks, toxic side effects and complexity of the procedure currently prevent many patients from being able to benefit.

On December 9, 2017 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that new data from the Company’s ongoing Phase 1 study of IMGN779, a next-generation CD33-targeting ADC, in patients with relapsed or refractory adult acute myeloid leukemia (AML) were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta (Press release, ImmunoGen, DEC 9, 2017, View Source [SID1234522464]). Poster presentations on preclinical data for IMGN779 in combination with cytarabine and CD123-targeting IMGN632 in acute lymphoblastic leukemia (ALL) are also being presented at the meeting.

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The Phase 1 data presented at ASH (Free ASH Whitepaper) demonstrate that IMGN779 was well-tolerated with no dose-limiting toxicities (DLTs) observed in patients with relapsed or refractory AML across nine dose levels administered once every two weeks (Q2W) and one dose level administered once a week (QW). In addition, anti-leukemia activity was seen at doses ≥0.39 mg/kg in both schedules in patients with poor prognostic features. The maximum tolerated dose has not been reached and dose escalation continues. Data across the first seven dose levels on the Q2W schedule were presented in June at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper).

"The data at ASH (Free ASH Whitepaper) build on the initial safety and anti-leukemia data presented earlier this year at EHA (Free EHA Whitepaper), and further support continued dose escalation of IMGN779, a novel, next-generation treatment for AML," said Anna Berkenblit, M.D., vice president and chief medical officer of ImmunoGen. "Given investigator enthusiasm and high unmet need, the dosing cohorts have been rapidly enrolling and we are very encouraged by the initial findings with IMGN779. We are continuing to dose escalate on the every two week schedule and, to evaluate the potential of continuous exposure, we have opened a weekly dosing schedule in parallel. We look forward to establishing the optimal dose and schedule, and quickly moving this compound into later stages of development."

Phase 1 Data on IMGN779 in AML

Key findings presented from the Phase 1 study of IMGN779 at ASH (Free ASH Whitepaper) (Abstract #1312) include the following:

IMGN779 displays a tolerable safety profile.
No DLTs were observed on either administration schedule at doses examined – up to 0.91 mg/kg Q2W and 0.39 mg/kg QW.
No increase in the nature, frequency, or severity of any treatment-emergent adverse event was observed with increasing dose.
This profile has enabled repeat dosing, with one patient showing a 93% reduction in bone marrow blasts with extended treatment and who remains on therapy through Cycle 14.
Pharmacokinetic (PK) exposures and pharmacodynamic (PD) CD33 saturation continue to increase with dose, and support further escalation and exploration of both the QW and Q2W schedules.
Anti-leukemia activity was seen at doses ≥0.39 mg/kg in both schedules with:
16 of 17 patients showing a decrease in peripheral blasts within 10 days after first dose with a median maximal decrease of 71%; and
Seven of 17 patients showing a 48%-96% reduction in bone marrow blasts. These seven patients had poor prognostic features (e.g., prior intense therapy, primary refractory disease, RAS/TP53/FLT3/IDH mutations).
This ongoing Phase 1 trial is designed to establish the maximum tolerated dose and determine the recommended Phase 2 dose for IMGN779 administered as monotherapy. The trial is also intended to evaluate safety and tolerability, and characterize PK, PD, and preliminary anti-leukemia activity in relapsed or refractory AML.

Preclinical Presentations on IMGN779 in Combination with Cytarabine and IMGN632 in ALL

Supporting data evaluating the mechanism, anti-leukemia efficacy, and tolerability of repeated dosing of IMGN779 in combination with cytarabine using in vitro and in vivo human AML preclinical models were also presented. Key findings from the poster presentation (Abstract #1357) include:

The combination of IMGN779 and cytarabine increased DNA damage response, cell cycle arrest, and apoptosis in vitro when compared to single agent treatment.
The combination of IMGN779 and cytarabine lead to increased survival and greater numbers of complete responses in in vivo preclinical AML models.
Use of cytarabine increased cell surface CD33 levels on AML cells, suggesting a novel mechanism for potentiating IMGN779 uptake.
Preclinical data (Abstract #2718) on IMGN632 reporting the prevalence of CD123 expression in acute lymphoblastic leukemia (ALL), and assessing the anti-leukemia activity of IMGN632 on ALL cells will also be presented. Among the findings:

CD123 expression is prevalent across ALL subtypes including 90% of B-cell ALL (B-ALL) and nearly half of T-cell ALL patient samples.
IMGN632 demonstrates promising activity against B-ALL cell lines and patient samples in vitro, including the elimination of more than 90% of B-ALL blasts in 6 out of 8 patient samples. Normal cells were not affected by IMGN632 at 100-fold higher concentrations.
More information can be found at www.hematology.org, including abstracts.

Poster Session Schedule and Details

Title (Abstract #1312): "IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate (ADC) Demonstrates Initial Antileukemia Activity in Patients with Relapsed or Refractory Acute Myeloid Leukemia"
Poster session #613: Saturday, December 9, 5:30 – 7:30 PM ET.
Title (Abstract #1357): "IMGN779, a Next Generation CD33-Targeting ADC, Combines Effectively With Cytarabine in Acute Myeloid Leukemia (AML) Preclinical Models, Resulting in Increased DNA Damage Response, Cell Cycle Arrest and Apoptosis In Vitro, and Prolonged Survival In Vivo"
Poster session #616: Saturday, December 9, 5:30 – 7:30 PM ET.
Title (Abstract #2718): "CD123 Expression Patterns and Potential of IMGN632, a CD123-Targeted Antibody Drug Conjugate, in Acute Lymphoblastic Leukemia"
Poster session #618: Sunday, December 10, 6:00 – 8:00 PM ET.
About IMGN779
IMGN779 is a novel ADC that combines a high-affinity, humanized anti-CD33 antibody, a cleavable disulfide linker, and one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent preclinical anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.1,2 IMGN779 is in Phase 1 clinical testing for the treatment of AML.

About IMGN632
IMGN632 is a humanized anti-CD123 antibody-drug conjugate that is a potential treatment for AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN), myelodysplastic syndrome, B-cell acute lymphocytic leukemia, and other CD123-positive malignancies. IMGN632 uses a novel IGN payload, linker and antibody technology and in AML xenograft models has demonstrated a large therapeutic index.3 ImmunoGen has filed an investigational new drug (IND) application for IMGN632 and expects to open a Phase I study before year end.

About IGNs
Indolino-benzodiazepine cancer-killing agents, or IGNs, are a new class of cancer-killing agent developed by ImmunoGen for use in ADCs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.4,5 IMGN779, a CD33-targeting ADC in Phase 1 testing for AML, was the first IGN ADC to enter clinical testing. IMGN632, a CD123-targeting ADC entering Phase 1 testing for AML and BPDCN, deploys a novel IGN payload.

About Acute Myeloid Leukemia (AML)
AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems and anemia.

It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients will die from the disease.6