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

Refs: Clinical Trial 

         UC San Diego trial site news

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!

IND Press Release here

See Fate's dedicated Blog page 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

The N Factor

The mere mention of a possible stop-gap option to the grave medical realities of those that suffer, let alone a lifeline to a solution, is enough to get most patients and their families/friends talking. Clinical trials however are relatively few and far between for specific diseases and those that are available are currently akin to drawing the lottery where circumstances such as referral, timing, scale, proximity and onerous inclusion criteria set a very high bar to entry.

The vast majority of patients don’t have any options.

I’ll relay a representative case in point - a friend of mine was diagnosed recently with Stage 4 Melanoma, an advanced skin Cancer which is all but fatal in relatively short order. His doctors gave him the ticking clock and little hope. However, given his wish to live and determination to see his young son grow up he studied, turned over every rock and reached out. He landed a very rare spot as a tag along to a new immunotherapy trial. He was lucky, most are not, given he didn’t meet the strict criteria for official entry. The trial treatment saved his life.

T-Cells in Action

Hope is a cruel bedfellow with its constant draw of energy and resources from the very reservoir it seeks to fill. Yet without that flicker of a flame gasping for oxygen the very medical system built upon empirical data derived from clinical trials designed to advance knowledge wouldn’t exist.

The system needs patients and patients need the system - both rely on the other and as such require inclusive practices to further the agenda of progress towards real solutions.

Emily Whitehead

N is a strong and decisive letter in our everyday language but in investigative medicine it’s a defining research statement which confers status and validity where quantitative analysis imbues significance and wields judgement on meaningfulness. For those not on the in, the N is translational science parlance for the number of patients treated and their data sets. The lower the N the more likely there will be variability in the eventual safety and benefit outcomes when applied to the patient population at large. While the larger the N the more significant the potential correlation in delivering a safe option and potentially treating the targeted disease indication. 

As fundamental as the N is to applying the scientific method to proving the safety and potential for wide scale application, it cannot be suggested to be devoid of meaning at any level, especially considering the human impact and nascent development of promising new therapeutic modalities for treating previously unmet medical needs.

The mere fact that we will all suffer in one form or another from the debilitating conditions of age is enough to warrant more attention to the secondary benefits in N data given the lack of achieved endpoints of trialed drug interventions to-date. Combine the natural degenerative conditions of the aged with a population rife with chronic and acute medical issues that continue to overburden the system, leaving a significant population of those in need without a solution, and you have the argument for considered change.

Breakthroughs in medical science indeed offer a real opportunity to effect change and the more that can be done to allow for inclusion and support for that transformative process to occur the more representative the N will be that correlates to real tangible wellbeing data logged for the betterment of the science as well as the patient. 

Cheers

Ref: Related Cancer Blog on Emily Whitehead

The Hemangioblast Progeny - Ocata's Blood, Immune & Cancer Programs

When we speak of the various programs Ocata has in development, apart from the Eye, they are referred to as "other" and are separated into boxes so the general targets become clearer - Blood, Immune & Cancer.

However, it important to understand that all these "others," and their various derivative relations, are based off of the Hemangioblast cell state precursor... i.e. eImmune Modulation using MSCs, eCancer Targeting using Dendritic/NK cells & eBlood Repair using Platelets, all via Ocata's Non-Destructive hESC Platform source or from any of the alternative Pluripotent Platform technologies (i.e. iPS, Parthenogenesis, SCNT).

Tissue engineering (organs) isn't yet in the preclinical phase at Ocata but could of course be a focus of research and product development/IP licensing if the company opts to push forward in that direction down the line with Pluripotent cells, most likely with Autologous reprogrammed cells using iPS, Parthenogenesis or SCNT Pluripotent sources.

For now it's the Allogeneic Hemangioblast offspring and as such all discussions in Blood, MSC/Immune, Cancer should be considered in relation to this when reviewing what the opportunity is for product development.

A program for engineered eDendritic cells targeting a pathogenic or virus strain can be separated from an engineered eDendritic cell deal for a Cancer indication - both derived from a Patented Pluripotent eDendritic cell IP rights chain that goes back three Patent layers to source. However, on top of those source IP rights is the engineered cell product itself (synthetic Product Claim) which will be the Exclusive Product License.

Is it more beneficial to break-up IP than outright License it wholesale per cell type? Will this occur When and If unique synthetic versions can be developed to optimize & uniquely address target market indications? For example why License the entire Cancer market to one partner when there are multiple potential partners in the space? Granted a potential Partner may address a cross-section of the space but one Partner may only be interested in or dominate in a few disease areas while others may be active in unrelated diseases and so forth... Each can have a tailored product using exclusive IP from cell origin to intermediate cell states to final proprietary formulation...

This is the strategic design for securing multiple partnerships to Ocata's underlying Platform & Program IP.

It is the unique or synthetic nature of the final product for distinct targets that will exponentially and dramatically expand the scope of collaborative understanding with Industry players.

The explosion in awareness and movement in cellular targeting via synthetic biology is the beginning of the paradigm shift in medicine.

        

CAR-T has been a research focus for a couple of years ago now - which was a welcome adjunct to an on-again off-again research effort on immunity, genetics & gene editing technologies. The nature of beating disease by way of empowering & harnessing the immune/blood system is fundamental to next generation therapies. Emily was one such proof many had been hoping for. Not that pure cells themselves or synthetic editing aren't invaluable in their own right to fight disease, but that complex modified biological cell constructs are possible as future effective treatments.

As with all cell treatments the ability to manufacture an inexhaustible supply of a replicable standard as an off-the-shelf product is what will separate the mass market offering from the targeted niche. The cell progeny differentiated to a terminal state and used in therapeutics worldwide is akin to a small molecule drug produced on an assembly line.

Autologous treatments against Cancer may be required when specific and unique disease states & expression patterns apply and will therefore require bespoke cellular targeting. However, in the broader market a product with replicable standards, cost & scale will be vital and sought after by way of Allogeneic product methodologies. 

Some Allo programs already exist based on adult cell sources however when the inherent expression benefits of Pluripotent derived cell factories are combined with synthetic multi-target gene edits and/or pathway modifications the final product becomes naturally more effective and valuable, in addition to the replicable conformity & economies of scale benefits. 

Allogeneic product isn't by itself the definition of a complete solution purely because it's from an immortal source & is replicable to a standard but it is when combined with the inherently more potent properties of early cell state gene expression and enhanced synthetic action/targeting... 

Product is the goal and when next gen product is available early prototypes, niche offerings & more costly general alternatives will be mooted.

Profitability models favor a wider adoption formula for acute, unmet and orphan diseases where there is no effective standard of care. Pricing will vary depending on volumes.

Repeat treatment requirements are yet to be determined in many cases for cellular therapies and may factor in to longer term chronic care maintenance, more in line with existing treatment options.  

The science is on the cusp of having a solid fighting chance against disease, trauma & degeneration. That is perhaps something I wouldn't have said only a few years ago. However, doubt is gone in my mind and only time is left to answer what will be the optimal mechanism to defeat each target. Knowledge is expanding exponentially and as a result I imagine within a relatively short period of time the majority of our molecular pathways and stepwise complexities of action and reaction within our cellular communities will be known.

There is a race on that has only one possible ending - the complete and total banking of knowledge of the biological process map of our physical selves.

Just as The Human Genome Project opened the doors to a world of new discoveries, the uncovered realities of cellular based mechanisms are paving the way for fundamental changes in our societies that will impact the very nature of how we live our lives. Once disease is tamed our planet will turn to sustainability to maximize the efforts of our new longevity. The full cycle may take a generation or two to occur but it is inevitable and beginning now.

Ocata is one of the many at the forefront of this new dawn, contributing with knowledge & potential. Their unique understanding, developmental expertise, early cell state technology, IP positioning and mission is what sets them apart as a sector leader and underscores what the opportunity represents as a whole.

Cheers