Fate Therapeutics Announces First Patient Treated with iPSC-derived NK Cell Cancer Immunotherapy FT500 Successfully Completes Initial Safety Assessment
No Dose-Limiting Toxicities or Serious Adverse Events Reported following Three Once Weekly Doses of Universal, Off-the-Shelf NK Cell Product Candidate
Fate Therapeutics Announces FDA Clearance of IND Application for World’s First Cell Therapy Derived from an Engineered Pluripotent Stem Cell
No Dose-Limiting Toxicities or Serious Adverse Events Reported following Three Once Weekly Doses of Universal, Off-the-Shelf NK Cell Product Candidate
New Preclinical Data of Universal, Off-the-shelf, iPSC-derived NK Cell Product Candidates FT516 and FT596 Highlighted at 2019 AACR Annual Meeting
Fate Therapeutics, Inc., a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, today announced that the first patient treated with FT500 successfully completed an initial safety assessment. The patient received three once weekly doses of FT500, and the treatment cycle was well-tolerated with no dose-limiting toxicities or serious adverse events reported during the initial 28-day observation period. The universal, off-the-shelf natural killer (NK) cell product candidate is the first-ever cell therapy derived from an induced pluripotent stem cell (iPSC) administered to a patient in the U.S.
“The ability to effectively and efficiently deliver multiple doses of a cellular immunotherapy ‘on demand’ brings us closer to our goal of transforming the treatment of cancer for more patients. This initial observation of tolerability from the first-ever cancer patient to receive multiple doses of a universal, off-the-shelf cell product derived from a clonal master iPSC line provides early clinical validation of our proprietary iPSC product platform for off-the-shelf cancer immunotherapy,” said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. “In addition to our clinical progress with FT500, our engineered iPSC-derived NK cell product candidates continue to exhibit a highly-differentiated therapeutic profile in preclinical models and we look forward to generating initial clinical data with FT516 and FT596 in 2019.”
Two additional patients have also been treated with FT500 as a monotherapy in the first dose cohort of 1x108 cells per dose and are currently within the initial 28-day observation period. The FT500 clinical trial is a two-arm study in up to 64 patients for the treatment of advanced solid tumors. The study is designed to assess the safety and activity of three once weekly doses of FT500 as a monotherapy and in combination with one of three FDA-approved checkpoint inhibitor therapies – nivolumab, pembrolizumab or atezolizumab – in patients that have failed or have confirmed disease progression on checkpoint inhibitor therapy. Patients that are clinically stable following the initial 28-day observation period are eligible to receive a second treatment cycle.
FT516 Novel CD16 Receptor Promotes High-Affinity Engagement with Monoclonal Antibody Therapy
Today the Company presented preclinical data for FT516, its universal, off-the-shelf NK cell product candidate derived from a clonal master iPSC line engineered to express a novel CD16 Fc (hnCD16) receptor, at the 2019 American Association for Cancer Research (AACR) in Atlanta, Georgia. FT516 is the first-ever cell therapy derived from a genetically engineered pluripotent stem cell cleared for clinical testing in the world, and the Company is preparing to initiate clinical investigation of FT516 in the U.S. in patients with certain relapsed/refractory hematologic malignancies, including acute myelogenous leukemia as a monotherapy, non-Hodgkin's lymphoma in combination with rituximab, and multiple myeloma in combination with elotuzumab.
While CD16 is naturally expressed on NK cells and mediates antibody-dependent cellular cytotoxicity, numerous clinical studies with FDA-approved tumor-targeting antibodies have demonstrated that patients with CD16 high-affinity variant 158V have improved clinical outcomes. However, only about 15% of humans are homozygous for 158V. Additionally, the expression of CD16 on NK cells in cancer patients can undergo considerable down-regulation, which significantly inhibits the cell’s anti-tumor activity. The novel CD16 Fc receptor expressed by FT516 has been designed to overcome these inherent deficiencies: it is comprised of the high-affinity 158V variant and is resistant to down-regulation.
In preclinical studies using a B-cell lymphoma line, the Company showed that approximately 70% of peripheral blood NK cells down-regulated CD16 expression upon co-culture with rituximab, while CD16 expression on FT516 remained resistant to down-regulation. These differences resulted in a significant anti-tumor benefit in vivo where, in a human lymphoma cancer model, mice treated with peripheral blood NK cells and rituximab had a median survival time of 39 days as compared to mice treated with FT516 and rituximab, where the median survival time was not yet reached at 100 days.
FT596 CAR and CD16 Modalities Exert Synergistic Anti-Tumor Activity
The Company also presented today at AACR new preclinical data for FT596, the Company’s first iPSC-derived chimeric antigen receptor (CAR) NK cell product candidate that is designed to concurrently target multiple tumor-associated antigens. FT596 is derived from a clonal master iPSC line engineered to express a proprietary CAR targeting CD19, a hnCD16 Fc receptor, and a novel IL-15 receptor fusion.
In a mixed co-culture assay, the Company showed that the concurrent activation of the CAR and hnCD16 targeting modalities of FT596 exert synergistic anti-tumor activity. Increased degranulation (CD107a) and cytokine release (interferon-gamma and TNF-alfa) were observed upon concurrent activation of both the CAR and CD16 receptors in CD19+CD20+ Raji cancer cells with rituximab as compared to activation of each receptor alone, suggestive that dual antigen engagement may elicit a deeper and more durable response. Additionally, in a cellular cytotoxicity assay designed to model CD19 antigen escape, FT596 combined with rituximab was able to effectively eliminate leukemia and lymphoma cancer cells that were positive for CD19 antigen expression as well as those that were null for CD19 antigen expression.
About FT500
FT500 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line. FT500 is being investigated in an open-label, repeat-dose Phase 1 clinical trial for the treatment of advanced solid tumors in up to 64 patients, both as a monotherapy and in combination with FDA-approved checkpoint inhibitor therapy. Despite the favorable response rates observed with checkpoint inhibitor therapy, the majority of patients do not respond and many responders relapse. One common mechanism of resistance to checkpoint inhibitor therapy is associated with loss-of-function mutations in genes critical for antigen presentation. A potential strategy to overcome resistance is through the administration of allogeneic NK cells, which have the inherent capability to recognize and directly kill tumor cells with these mutations.
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.
Source: Fate PR
Refs: Clinical Trial
UC San Diego trial site news
Fate Therapeutics Announces FDA Clearance of IND Application for World’s First Cell Therapy Derived from an Engineered Pluripotent Stem Cell
FT516 Off-the-Shelf NK Cell Cancer Immunotherapy Cleared for Clinical Investigation by FDA
Product Candidate Derived from Clonal Master iPSC Line Engineered with Novel CD16 Fc Receptor
Clinical Trial to Evaluate Multi-dose Cycles of FT516 for Treatment of Hematologic Malignancies, including in Combination with Targeted Antibody Therapy
Fate Therapeutics, Inc., a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, announced today that the U.S. Food and Drug Administration (FDA) has allowed its Investigational New Drug (IND) application for FT516, the Company’s off-the-shelf natural killer (NK) cell product candidate derived from a clonal master induced pluripotent stem cell (iPSC) line engineered to express a novel CD16 Fc receptor. FT516 is the first-ever cell therapy derived from a genetically engineered pluripotent stem cell cleared for clinical testing in the world, and is the Company’s second off-the-shelf, iPSC-derived NK cell product candidate cleared for clinical investigation by the FDA within the past two months. The Company intends to initiate clinical testing of FT516 in patients with certain relapsed/refractory hematologic malignancies, including acute myelogenous leukemia (AML) as a monotherapy, non-Hodgkin's lymphoma (NHL) in combination with rituximab, and multiple myeloma (MM) in combination with elotuzumab.
“This allowance by the FDA of our FT516 IND application is a watershed event in the clinical development of engineered cell therapies. Our industry-leading iPSC product platform enables the manufacture of engineered cell products that can be extensively characterized, cryopreserved and delivered ‘on demand’ to reach more patients,” said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. “FT516 is a first-of-kind cell product in that it originates from a single genetically engineered pluripotent stem cell, which serves as a clonal master cell line that can be repeatedly used to mass-produce large quantities of homogeneous cell product in a cost-effective manner. This innovative approach uniquely supports a new treatment paradigm with engineered cell therapies, where multiple doses of cell product are readily available for administration with the goal of driving deeper and more durable responses. We look forward to treating patients with multiple doses of FT516, including in combination with FDA-approved monoclonal antibody therapy, across multiple treatment cycles in this first clinical study.”
CD16 is naturally expressed on NK cells and mediates antibody-dependent cellular cytotoxicity (ADCC), a potent immune mechanism through which NK cells can recognize, bind and kill antibody-coated cancer cells. ADCC is an underlying mechanism associated with the clinical efficacy of many monoclonal antibodies that are approved for the treatment of various cancers, including hematologic malignancies and solid tumors. The expression of CD16 on NK cells can undergo considerable down-regulation in cancer patients, which significantly inhibits the immune system’s anti-tumor response. FT516 incorporates a novel CD16 Fc receptor, which has been modified to prevent its down-regulation and to augment its binding to tumor-targeting antibodies, for enhanced ADCC.
The initial clinical study of FT516 is intended to assess the safety and tolerability of three weekly doses for the treatment of certain relapsed/refractory hematologic malignancies. The study includes three independent, dose-escalating treatment arms: monotherapy for AML; combination with rituximab for NHL; and combination with elotuzumab, plus pomalidomide and dexamethasone, for MM. All subjects will receive low-dose conditioning chemotherapy consisting of cyclophosphamide and fludarabine (Cy/Flu) and cytokine support with IL-2. Subjects are eligible to receive a second treatment cycle following an initial 28-day safety assessment.
FT516 is the second off-the-shelf, iPSC-derived NK cell product candidate cleared for clinical investigation by the FDA from the Company’s proprietary iPSC product platform. In November 2018, the FDA cleared the Company’s IND application for FT500, an off-the-shelf, iPSC-derived NK cell product candidate for use in combination with checkpoint blockade therapy for the treatment of solid tumors.
Cheers!
Source: Fate PR here
Fate Therapeutics Announces FDA Clearance of Landmark IND for FT500 iPSC-derived, Off-the-Shelf NK Cell Cancer Immunotherapy
Company to Initiate First-ever U.S. Clinical Investigation of iPSC-derived Cell Product
Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, announced today that the U.S. Food and Drug Administration (FDA) has allowed its Investigational New Drug (IND) Application for FT500, the Company’s universal, off-the-shelf natural killer (NK) cell product candidate derived from a clonal master induced pluripotent stem cell (iPSC) line. The clinical trial of FT500 is expected to be the first-ever clinical investigation in the U.S. of an iPSC-derived cell product.
“The clearance by the FDA of our FT500 IND is a significant milestone and marks the beginning of an exciting new era for the clinical development of cell products,” said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. “Clonal master iPSC lines are a renewable cell source that can uniquely produce cell products which are uniformly engineered and well characterized, can be mass produced in a cost-effective manner, and can be delivered off-the-shelf to treat many patients. This revolutionary paradigm overcomes significant challenges that limit both patient- and donor-derived cell therapy, where heterogeneous populations of primary cells are repeatedly sourced, engineered, expanded and characterized on a batch-by-batch basis resulting in cell therapies with substantial variability in quality, consistency and potency.”
The Company plans to initiate first-in-human clinical testing of FT500 in combination with checkpoint inhibitor therapy for the treatment of advanced solid tumors. This study is expected to evaluate the safety and tolerability of multiple doses of FT500, in multiple dosing cycles with nivolumab, pembrolizumab or atezolizumab, in subjects that have progressed or failed on checkpoint inhibitor therapy.
Cheers!
Press Release here
Also recent news from Fate on their partnership with Japan for CAR-T Cell Cancer Immunotherapies based on Fate's iPSC technology here.
Further, Fate licenses new route to master iPS cell lines:
Fate PR announcement here
Fate Therapeutics is a clinical-stage biopharmaceutical company dedicated to the development of next-generation cellular immunotherapies for cancer and immune disorders. Its first-in-class cell therapy products undergoing clinical development today utilize healthy donor cells, which we modify ex vivo using pharmacologic modulators, such as small molecules, to improve the cells’ biological properties and therapeutic function. They're also pioneering a revolutionary approach to cell therapy – we use renewable master induced pluripotent stem cell (iPSC) lines generated from our proprietary iPSC product platform to derive cell therapy products that can be delivered off-the-shelf for the treatment of a large number of patients.
Fate's cells of interest are the cells of the immune system. They're cell therapy product pipeline is comprised of immuno-oncology programs, including off-the-shelf NK- and T-cell products derived from master iPSC lines, and immuno-regulatory programs, including products to prevent life-threatening complications in patients undergoing hematopoietic cell transplantation and to promote immune tolerance in patients with autoimmune disease.
Fate's cell therapy product pipeline is comprised of first-in-class cellular immunotherapies for cancer and immune disorders. Their programs reflect our dedication and commitment to pioneering ground breaking science to address severe, life-threatening diseases where the unmet need is significant and the treatment options are limited. Source & for further info: www.fatetherapeutics.com
iPSC Platform: Platform for Induction and Maintenance of Transgene-free hiPSCs Resembling Ground State Pluripotent Stem Cells
NK cancer paper: Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity
To provide an overview of the work Fate is undertaking, I've added below an interview with one of the leading scientists behind Fate's push forward using iPSC derived NK cells for cancer.
Natural killer cells as effective as, less toxic than T cells
Natural killer cells engineered with chimeric antigen receptors demonstrated comparable efficacy as T cells but appeared less toxic, according to study results.
The findings could be significant, given the advantages that natural killer cells offer.
For example, engineered natural killer cells could be delivered safely in an off-the-shelf manner, and research so far suggests natural killer cells do not trigger the same potentially severe toxicities — such as organ damage, neurotoxicity or death — that have been associated with use of re-engineered T-cells.
The results — obtained from studies in mice — have laid the groundwork for a planned trial in humans.
“One of the main challenges of immunotherapy has been the clinical manufacture of modified cells,” Dan S. Kaufman, MD, PhD, professor of medicine in the division of regenerative medicine and director of cell therapy at UC San Diego School of Medicine, as well as a HemOnc Today Editorial Board Member, said in a press release. “We have shown that we can engineer [human-induced pluripotent stem cells] and create chimeric antigen receptor-expressing natural killer cells to better target refractory cancers that have resisted other treatments.”
HemOnc Today spoke with Kaufman about the research his team has conducted into re-engineering natural killer cells with chimeric antigen receptors, the advantages to using natural killer cells instead of T cells, the potential implications if this approach is proven effective and safe, the malignancies for which this approach may offer the greatest benefit, and the next steps in research.
Question: Can you explain the rationale for this approach?
Answer: Natural killer cells are a population of lymphocyte immune cells that are separate from T cells. They are known to be a part of the immune system and are known to kill tumor cells and virally infected cells. Clinical studies with natural killer cells have been conducted for more than 15 years, and they have shown that allogeneic natural killer cells have been effective for treating certain cancer types — primarily leukemia, and specifically acute myeloid leukemia.
For the full interview from HemOnc Today please link here
