Osaka team pulls off cornea cell transplant using human iPS cells

In a world's first, a team of researchers here transplanted cornea cells created from human iPS cells into a patient whose visual acuity has been improved.

The transplant was conducted in July by a team led by Kohji Nishida, a professor of ophthalmology at Osaka University.

The team announced the achievement on Aug. 29 at a news conference at the university's campus in Suita, Osaka Prefecture.

The patient, a woman in her 40s, has made good progress since the operation and was released from the hospital on Aug. 23.

“It’s been just a month, but right now we see the operation as a success,” Nishida said.

The transplant is intended for patients with corneal epithelial stem cell impoverishment syndrome.



The cause of the syndrome is a loss of stem cells that produce a new cornea that can cover the surface of a pupil caused by injury or other reasons. The syndrome leads to poor eyesight and sometimes blindness.

The team transformed iPS cells from a third party into cornea cells. They then turned them into a sheet 0.03 to 0.05 millimeters thick and transplanted them onto the patient’s left eye.

If all goes well, the transplanted cells will enable a lasting production of cornea cells, maintain corneal transparency and help the patient regain lost vision.

“After the operation, her clouded cornea became transparent and her vision has improved considerably. We'll continue to monitor her condition to see if it stays that way," Nishida said.

The team said it has not observed an abnormal increase in the transplanted cornea cells, and the patient has regained vision to the extent that she can go about her daily life.

Following the success, the team expects to perform a second transplant by the end of the year.

Corneas of dead people are currently transplanted into patients with the particular syndrome, but the organs are chronically in short supply.

According to the health ministry, organs from 720 people who were certified brain dead or in cardiac arrest were provided to patients with corneal diseases and 1,155 transplantation surgeries were performed in fiscal 2018.

As of the end of March this year, 1,613 people were on a waiting list for a cornea transplant.

In the team’s estimate, several hundred people in the country each year will become subjects for the cornea transplants using iPS cells.

The operation was the third successful transplant using iPS cells, following the 2014 transplantation of retina cells by the government-affiliated Riken institute and Kyoto University researchers transplanting nerve cells into the brain of a Parkinson’s disease patient in 2018.

Ref: The Asahi PR

Fate Therapeutics doses initial patient in 1st US trial of a iPSC-derived therapeutic

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

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

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