On April 1, 2019 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported promising data from the Company’s growing bispecific and TAM (Tyro3, Axl, MerTK) receptor programs during poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Press release, Celldex Therapeutics, APR 1, 2019, View Source [SID1234534839]).

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"Our research and discovery efforts have yielded multiple promising candidates that address important needs in cancer immunotherapy and complement our pipeline," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "CDX-527 joins two powerful pathways in the immune system, PD-1 blockade and CD27 costimulation. The data we presented at AACR (Free AACR Whitepaper) demonstrate that this bispecific antibody candidate has greater activity than the combination of the two individual antibodies and support advancing the program into IND-enabling studies. In addition, we also presented data on our lead candidate antibodies targeting the TAM receptors, which act as checkpoints on myeloid cells. We have uncovered a unique mechanism for antibody-mediated activation of dendritic cells and macrophages and demonstrated that a surrogate MerTK mAb promotes anti-tumor immunity alone and enhances the activity of PD-1 blockade. We look forward to continuing to progress both CDX-527 and our TAM program over the course of the year," concluded Keler.

Presentation Highlights:

Poster #2392: CDX-527: A novel bispecific immune-modulating antibody targeting CD27 and PD-L1 (Vitale, et. al)

The use of bispecific antibodies provides opportunities to engage two independent pathways involved in controlling immune responses to tumors. Preclinical and clinical studies support the safety and benefit of combining PD-1 blockade with a CD27 agonist.
The bispecific CDX-527 combines a novel and potent PD-L1 antibody for blocking the PD-1 checkpoint pathway with the binding domains of a CD27 agonist antibody for CD27-mediated costimulation of T cells.
CDX-527 demonstrated potent inhibition of PD-1 signaling and T cell activation using in vitro models with reporter cell lines and human primary cell cultures.
Anti-tumor activity was tested with a surrogate bispecific molecule that binds mouse PD-L1 and human CD27 in human CD27-expressing transgenic mice. The bispecific demonstrated potent anti-tumor activity in a BCL1 lymphoma model and was significantly more effective than the combination of the CD27 and PD-L1 monoclonal antibodies (mAbs).
A pilot study in non-human primates suggests that CDX-527 demonstrates good pharmacokinetic properties and no toxicities were observed.
Based on the promising data observed to date and the PK/PD profiles, Celldex has initiated manufacturing activities and investigational new drug (IND) enabling studies to support clinical studies of CDX-527.
Poster #1555: Monoclonal antibodies targeting the TAM family of receptor tyrosine kinases (Alvarado, et al)

TAM receptors (Tyro3, Axl, MerTK) are receptor tyrosine kinases (RTKs) expressed in innate immune cells. These receptors have been gaining importance in the immunotherapy field due to their role as checkpoint molecules on macrophages, dendritic cells, and other immune cells, where they can negatively regulate anti-tumor immunity.
Celldex presented data showing that lead candidate mAbs targeting MerTK, Axl or Tyro-3 activate myeloid cells, including monocytes, macrophages and dendritic cells, enhancing pro-inflammatory cytokine release, increasing expression of costimulatory molecules and enhancing T cell activation in mixed lymphocyte reaction (MLR) assays.
Celldex demonstrated that the potent activity of the TAM-specific antibodies are dependent on a unique coupling of the TAM receptors with Fc receptors.
Celldex’s most advanced program targets MerTK, where the Company has demonstrated that antibody targeting of MerTK in mice elicits an inflammatory cytokine response similar to that observed in the human cells and in MerTK deficient mice and has anti-tumor activity when dosed alone or in combination with a PD-1 inhibitor in a colon cancer model.
These data support development of anti-TAM mAbs as therapies to activate innate immune responses with a potential for systemic dosing. The Company intends to advance potential candidates into development activities this year.

On April 1, 2019 AVEO Oncology (NASDAQ:AVEO) and Biodesix, Inc. reported results from an investigator-sponsored Phase Ib expansion cohort of ficlatuzumab, AVEO’s potent hepatocyte growth factor (HGF) inhibitory antibody product candidate, in combination with cytarabine in patients with relapsed and refractory acute myeloid leukemia (AML) (Press release, AVEO, APR 1, 2019, View Source [SID1234534855]). The results were presented in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2019 Annual Meeting. The presentation, titled, "CyFi: Results from a phase Ib expansion cohort of ficlatuzumab (Fi) combined with high-dose cytarabine (Cy) in patients with high risk relapsed or refractory acute myeloid leukemia (AML)" (abstract CT078/2) is available in the Publications & Presentations section of AVEO’s website.

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Elevated serum HGF level is an adverse prognostic factor associated with worse survival in AML and other cancers. Pre-clinical models have shown that myeloid blasts produce HGF and that blocking the HGF/c-Met pathway sensitizes blasts to cell death. The Phase Ib trial, which was funded by Gateway for Cancer Research and is being conducted at the UCSF Medical Center under the direction of Charalambos Andreadis, M.D., Associate Professor of Clinical Medicine, Director, Clinical Research Support Office, UCSF Helen Diller Family Comprehensive Cancer Center, was designed to assess the safety, tolerability and preliminary efficacy of ficlatuzumab with cytarabine in AML patients who are refractory to first line therapy (7+3) or have relapsed within one year of induction, a population known to have poor outcomes.

The maximally tolerated dose was 20 mg/kg of ficlatuzumab on day 1 followed by 2 g/m2 cytarabine daily on days 2-7. Of 12 patients who received ficlatuzumab and cytarabine at the maximally tolerated dose, one of whom was non-evaluable, 6 achieved a complete response (CR). Of 18 patients enrolled in the study, 17 were evaluable and 9 achieved a CR. The most frequent grade 3/4 treatment emergent adverse events observed were febrile neutropenia, LFT abnormalities, and electrolyte disturbance. There was one death from sepsis and multi-organ failure that was determined to be disease related, and one patient withdrew from the study due to grade 4 gastrointestinal bleed, determined to be likely ficlatuzumab related. scRNA sequencing identified a TNF alpha and IFN gamma inflammatory signature that correlated with response to ficlatuzumab at count recovery.

"Patients with AML who are refractory to induction therapy or relapse within one year have poor outcomes," said Dr. Andreadis. "Elevated serum HGF level is an adverse prognostic factor, and these results demonstrate that the anti-HGF antibody ficlatuzumab combined with cytarabine holds potential to affect outcomes in patients with relapsed or refractory AML. We look forward to potentially evaluating ficlatuzumab in larger outcome studies in AML."

"In addition to an attractive tolerability profile observed to date, we also see the potential to identify biomarkers of response using RNA sequencing. In light of these data, we believe that further evaluation in this patient population is warranted, and we look forward to considering additional studies with our partners at Biodesix as a potential next step for the program," said Michael Bailey, president and chief executive officer of AVEO.

"We look forward to supporting ficlatuzumab’s biomarker development initiatives with a broad set of diagnostic technologies," said Paul Beresford, chief business officer of Biodesix.

About Ficlatuzumab

Ficlatuzumab (formerly known as AV-299) is a potent hepatocyte growth factor (HGF) inhibitory antibody that binds to the HGF ligand with high affinity and specificity to inhibit HGF/c-Met biological activities. AVEO and Biodesix, Inc. have a worldwide agreement to develop and commercialize ficlatuzumab. Ficlatuzumab is currently being evaluated in investigator-sponsored trials in squamous cell carcinoma of the head and neck (HNSCC), metastatic pancreatic ductal cancer (PDAC), and acute myeloid leukemia (AML).

On April 1, 2019 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leading off-the-shelf, allogeneic T-cell immunotherapy company developing novel treatments for patients with cancer, autoimmune and viral diseases, reported off-the-shelf, allogeneic CAR T platform preclinical proof-of-concept results at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 in Atlanta, Georgia (Press release, Atara Biotherapeutics, APR 1, 2019, View Source [SID1234534875]).

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"Atara is building a leading next-generation CAR T pipeline," said Christopher Haqq, M.D., Ph.D., Executive Vice President and Chief Scientific Officer of Atara Biotherapeutics. "Preclinical results presented today demonstrate that our EBV-specific T cell platform has the potential to be efficiently engineered to generate off-the-shelf, allogeneic CAR T immunotherapies with favorable characteristics. We look forward to advancing this technology using novel co-stimulatory domains and intrinsic checkpoint inhibition, leveraging Atara’s research expertise and world-class T cell manufacturing capabilities."

Atara engineered EBV-specific T cells to express second-generation CD19 CARs (EBV.CD19.CAR T), utilizing CD28 or 4-1BB co-stimulatory domains, resulting in high expression of both the CD19 CAR and EBV T cell receptor (TCR). EBV.CD19.CAR T cells exerted potent and specific cytotoxicity against CD19 or EBV-positive cells and had limited activity against CD19-negative cells, while also depleting alloreactive activity. EBV.CD19.CAR T cells also demonstrated a central memory phenotype that balances expansion with effector function and is associated with persistence.

"EBV.CD19.CAR T cells exhibited optimal CAR T characteristics and in vivo function," said Blake T. Aftab, Ph.D., Vice President, Head of Preclinical and Translational Science for Atara Biotherapeutics. "These data also demonstrate that Atara’s off-the-shelf, allogeneic CAR T process effectively eliminated in vitro alloreactivity. Our findings establish feasibility for combining EBV-specific T cells with novel CAR technologies and support our further development of next-generation off-the-shelf, allogeneic CAR T clinical candidates."

EBV.CD19.CAR T anti-tumor activity was evaluated in vivo in a mouse model of aggressive lymphoma. Following a period of tumor establishment, a single injection of EBV.CD19.CAR T cells significantly inhibited tumor growth.

Additionally, yesterday at the AACR (Free AACR Whitepaper) Annual Meeting 2019, Atara’s collaborators at Memorial Sloan Kettering Cancer Center (MSK), Prasad S. Adusumilli, M.D., and Michel Sadelain, M.D., Ph.D., presented Phase 1 clinical results for a mesothelin-target CAR T immunotherapy that included safety data, anti-tumor responses, and combination data with a PD-1 checkpoint inhibitor. The results further support Atara’s planned development of a next-generation, mesothelin-targeted CAR T immunotherapy using MSK’s novel 1XX CAR signaling domain and PD-1 dominant negative receptor (DNR) checkpoint inhibition technologies for patients with mesothelin-associated solid tumors.

Abstract 2310: Functional demonstration of CD19 chimeric antigen receptor (CAR) engineered Epstein-Barr virus (EBV) specific T cells: An off-the-shelf, allogeneic CAR T-cell immunotherapy platform
Session Category: Immunology
Session Title: Adoptive Cell Therapy 2
Poster Presentation Date and Time: Monday, April 1, 2019, from 1:00 p.m. – 5:00 p.m. EDT
Location: Georgia World Congress Center, Exhibit Hall B
Authors: Blake T. Aftab, Rhine R. Shen, Christina D. Pham, Michelle Wu, Daniel J. Munson
Affiliations: Atara Biotherapeutics

On April 1, 2019 MaxCyte presented the corporate presentation (Press release, MaxCyte, APR 1, 2019, View Source [SID1234537621]).

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On April 1, 2019 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported late-breaking preclinical data highlighting the Company’s unmatched ability to mass produce uniformly engineered chimeric antigen receptor (CAR) T cells for off-the-shelf cancer immunotherapy at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 in Atlanta, Georgia (LB-073/18: Generation of Novel Single Cell-derived Engineered Master Pluripotent Cell Line as a Renewable Source for Off-the-shelf TCR-less CAR T Cells in support of First-of-kind Clinical Trial) (Press release, Fate Therapeutics, APR 1, 2019, View Source [SID1234534823]).

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The Company’s proprietary approach to CAR T-cell therapy utilizes a one-time genetic modification event followed by high-throughput selection of a single gene-edited induced pluripotent stem cell (iPSC). In contrast to repeatedly engineering large populations of patient- or donor-derived T cells which results in batch-to-batch and cell-to-cell variability, the Company has shown that a single gene-edited iPSC can be maintained as a clonal master engineered iPSC line which can be repeatedly used for production of uniformly engineered CAR T cells.

"The efficiency, accuracy, and uniformity of genetic modifications have the potential to impact the safety and efficacy of CAR T-cell therapy. We know that, when engineering a population of T cells, current gene-editing technologies create genomic heterogeneity and result in undesired byproducts, such as DNA mutagenesis and translocations. The selection of a single gene-edited cell for the derivation of a clonal master engineered iPSC line ensures that the effects of gene editing can be fully characterized and that only engineered T cells meeting rigorous quality standards are administered to patients," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics.

New preclinical data presented today at AACR (Free AACR Whitepaper) for FT819, the Company’s universal, off-the-shelf CAR19 T-cell product candidate being developed under a collaboration with Memorial Sloan Kettering Cancer Center (MSK) led by Michel Sadelain, M.D., Ph.D., demonstrate the production of clonal master engineered iPSC lines having complete elimination of T-cell receptor (TCR) expression and insertion of a novel 1XX CAR signaling domain into the T-cell receptor alpha (TRAC) locus. These synthetic features are intended to mitigate the risk of graft-versus-host disease, a severe life-threatening condition that occurs when donor T cells attack a patient’s healthy tissue, and to regulate CAR expression to enhance the therapeutic profile of CAR T cells.

Scientists from the Company and MSK are using clonal master engineered iPSC lines under the collaboration to overcome the complexity, heterogeneity, and substantial costs associated with engineering T cells from a patient or a donor. As proof-of-principle for the therapeutic advantages arising from selecting a single gene-edited cell for the production of CAR T-cell therapy, the scientists engineered a population of 545 cells using CRISPR-directed gene editing and found that only about 5% of cells contained both bi-allelic disruption of the TCR and insertion of the CAR into the TRAC locus. Upon further characterization for off-target genomic modifications and functional performance, only about 2% of the cell population were determined to meet the Company’s standards for genomic integrity and overall quality.

Previously published work by Dr. Sadelain in the journal Nature has shown that directing a CD19-specific CAR to the TRAC locus enhances T-cell potency, and that TRAC-targeted CAR T cells vastly outperform conventionally-generated CAR T cells in a mouse model of acute lymphoblastic leukemia (View Source). Additionally, Dr. Sadelain has shown in published work described in the journal Nature Medicine that the third-generation 1XX CAR signaling domain balances T-cell effector and memory programs, resulting in CAR T cells with potent activity and longer durability (View Source).

Fate Therapeutics has exclusively licensed from MSK foundational intellectual property covering the production and composition of iPSC-derived T cells for human therapeutic use. Additionally, in May 2018, the Company expanded its existing license agreement with MSK to include certain patents and patent applications relating to a novel 1XX CAR construct and off-the-shelf CAR T cells, including the use of CRISPR and other innovative technologies for their production. In addition, Fate Therapeutics owns an extensive intellectual property portfolio that broadly covers compositions and methods for the genome editing of iPSCs using CRISPR and other nucleases, including the use of CRISPR to insert a CAR in the TRAC locus for endogenous transcriptional control.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered in repeat doses to mediate more effective pharmacologic activity, including in combination with cycles of other cancer treatments. 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 iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf to treat many patients. As a result, the Company’s platform is uniquely capable of addressing the limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is fraught with batch-to-batch and cell-to-cell variability that can affect safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 100 issued patents and 100 pending patent applications.