Industry Updates From the Field of Stem Cell Research and Regenerative Medicine in August 2022

Abstract

Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from non-academic institutions in August 2022.

Tweetable abstract

Regenerative medicine industry news digest, August 2022.

Keywords::

• industry
• regenerative medicine
• stem cells

Business development

Collaboration agreement: Poseida & Roche

Poseida Therapeutics (CA, USA; https://poseida.com), a clinical-stage biopharmaceutical company utilizing proprietary genetic engineering platform technologies to create cell and gene therapeutics with the capacity to cure, has entered into a broad strategic collaboration and license agreement with Roche (Switzerland; www.roche.com), focused on developing allogeneic chimeric antigen receptor (CAR) T-cell therapies directed to hematologic malignancies [1]. The global collaboration covers the research and development of multiple existing and novel ‘off-the-shelf’ cell therapies against targets in multiple myeloma, B-cell lymphomas and other hematologic indications. Under the agreement, Roche will receive from Poseida either exclusive rights or options to develop and commercialize a number of allogeneic CAR-T programs in Poseida’s portfolio that are directed to hematologic malignancies, including P-BCMA-ALLO1, an allogeneic CAR-T for the treatment of multiple myeloma and for which a phase I study is underway and P-CD19CD20-ALLO1, an allogeneic dual CAR-T for the treatment of B-cell malignancies with an investigational new drug expected in 2023. Building on complementary expertise and capabilities, the parties will also collaborate in a research program to create and develop next-generation features and improvements for allogeneic CAR-T therapies, from which they would jointly develop additional allogeneic CAR-T product candidates directed to existing and new hematologic targets. For a subset of both the Poseida portfolio programs licensed or optioned to Roche and the parties’ future collaboration programs, Poseida will conduct the phase I studies and manufacture clinical materials before transitioning the programs to Roche for further development and commercialization. Roche will be solely responsible for the late-stage clinical development and global commercialization of all products that are subject to the collaboration.

Under the agreement, Poseida will receive U$110 million upfront and could receive up to U$110 million in near-term milestones and other payments in the next several years. In addition, Poseida is eligible to receive research, development, launch and net sales milestones and other payments potentially up to U$6 billion in aggregate value, as well as tiered net sales royalties into the low double digits, across multiple programs.

Partnership agreement: ElevateBio & CIRM

ElevateBio (MA, USA; www.elevatebio.com), a technology driven company focused on powering transformative cell and gene therapies, has partnered with the California Institute for Regenerative Medicine ([CIRM]; CA, USA; www.cirm.ca.gov) to advance the discovery and development of regenerative medicine as part of CIRM’s Industry Alliance Program [2]. With US$5.5 billion in funding from the state of California, CIRM has funded 81 clinical trials and currently supports over 161 active regenerative medicine research projects spanning candidate discovery through phase III clinical trials. As part of CIRM’s expansion of its Industry Alliance Program to incorporate industry resource partners, this partnership will provide CIRM awardees the option to license ElevateBio’s induced pluripotent stem cell (iPSC) lines produced in xeno-free, feeder-free conditions using non integrating technologies and have the ability to gain access to other enabling technologies, including gene editing, cell and vector engineering and end-to-end services within ElevateBio’s integrated ecosystem, which are essential for driving the development of regenerative medicines.

Partnership agreement: ElevateBio & University of Pittsburgh

ElevateBio (MA, USA; www.elevatebio.com), and the University of Pittsburgh (PA, USA; www.pitt.edu) have entered into a long-term strategic partnership to accelerate the development of highly innovative cell and gene therapies. Through this agreement, ElevateBio will locate one of its next BaseCamp process development and GMP manufacturing facilities in Pittsburgh, fully equipped with its enabling technologies, including gene editing, iPSC and cell, vector and protein engineering capabilities [3]. The University of Pittsburgh has long been a research powerhouse and is consistently among the top US institutions in NIH research funding.

The Richard King Mellon Foundation announced a US$100 million grant to the University of Pittsburgh in November 2021 to create the Pitt BioForge BioManufacturing Center. The grant was the largest single project grant in the Foundation’s 75-year history. The new facility is expected to generate more than 170 permanent full-time jobs, 900 construction jobs and 360 off-site support jobs.

In addition, the Commonwealth of Pennsylvania (PA, USA; www.pa.gov) and the County of Allegheny have provided incentive grants to ElevateBio in support of this partnership to build a biomanufacturing center and establish Pittsburgh as a premier biomanufacturing destination.

Launching new products, services…

ElevateBio

ElevateBio (MA, USA; www.elevatebio.com), a technology driven company focused on powering transformative cell and gene therapies, has formed a new company cofounded by Boston Children’s Hospital to develop allogeneic immune cell therapies based on a novel platform that generates functionally mature immune cells from iPSCs [4,5]. This proprietary differentiation process overcomes the tendency of iPSCs to generate immature, embryonic blood cell types, and enables the generation of multiple subtypes of immune cells that display mature molecular signatures similar to T cells from adult blood. The peer-reviewed publication showed that iPSC-derived mature αβ T cells exhibited antitumor activity and cytokine secretion and could serve as an ideal source for the development of allogeneic ‘off-the-shelf’ therapies. This is the first company to emerge from the previously announced 5 year collaboration between Boston Children’s Hospital and ElevateBio to accelerate the development of novel cell and gene therapies.

Regen Biopharma

Regen BioPharma (CA, USA; www.regenbiopharmainc.com) has announced a development of a novel immunotherapy for treatment of solid tumors [6]. Current cellular approaches to kill cancer involve administration of a specific type of modified T cell called ‘CAR’ T cell. Despite significant progress being made in using CAR-T cells to treat leukemia, little progress has been made in solid tumors such as those found in lung, brain, breast, prostate and colon. It is believed that solid tumors possess an abnormal ‘microenvironment’ which physically prevents T cells from entering the tumor, as well as inactivating T cells that do manage to enter. The microenvironment consists of surrounding blood vessels, immune cells, fibroblasts, signaling molecules and an extracellular matrix. The solid tumor is surrounded by its microenvironment and constantly interacts with it.

The current approach developed by the Company, for which a provisional patent application has been submitted, involves initial treatment of the tumor microenvironment with cells of the innate immune system called CAR-M and CAR-NK cells. These cells, which also begin to attack the tumor, are able to ‘normalize’ the tumor microenvironment, thus allowing CAR-T cells to enter and attack the tumor.

Achievements

LinkoCare

A total of 20 people with diseased or damaged corneas had significant improvements in their vision after they received implants engineered out of protein from pigskin by LinkoCare (Sweden; www.linkocare.com) [7,8]. To create the implant, LinkoCare team dissolved pig tissue to form a purified collagen solution. That was used to engineer a hydrogel that mimics the human cornea.

The patients, in Iran and India, all suffered from keratoconus, a condition in which the protective outer layer of the eye progressively thins and bulges outward. 14 of the patients were blind before they received the implant, but 2 years after the procedure, they had regained some or all of their vision [8,9]. Three had perfect vision after the surgery.

Renewal.bio

Renewal Bio (Israel; www.renewal.bio) aims to make humanity younger and healthier by leveraging the power of the new stem cell technology [10–13]. The company established by researchers from the Weizmann Institute of Science (Israel; www.weizmann.ac.il), made artificial mouse embryos from stem cells – no sperm or eggs required – and used an innovative bioreactor to nurture their creations for longer than any previous embryo models. According to the company, the technology can be applied to a wide variety of human ailments including infertility, genetic diseases and longevity.

Clinical trials

Hematopoietic stem cells

Graphite Bio

Graphite Bio (CA, USA; https://graphitebio.com), a clinical-stage, next-generation gene editing company harnessing the power of high-efficiency precision gene repair to develop therapies with the potential to cure serious diseases, has announced that the first patient has been dosed with GPH101, now called nulabeglogene autogedtemcel (nula-cel), in the company’s phase I/II CEDAR trial in people with sickle cell disease (SCD) [14,15]. Nula-cel is an investigational gene editing therapy designed to directly correct the genetic mutation that causes SCD and definitively cure the disease.

The CEDAR trial is a phase I/II open-label, single-dose clinical trial evaluating the safety, preliminary efficacy and pharmacodynamics of nula-cel in approximately 15 patients with severe SCD. The trial is currently enrolling patients at multiple sites in the USA. Participants will receive GPH101 via iv. infusion following myeloablative conditioning in an autologous hematopoietic stem cell transplant setting.

Graphite Bio’s UltraHDR™ gene editing platform takes CRISPR beyond cutting and harnesses the power of high-efficiency precision DNA repair, also known as homology directed repair, to precisely correct genetic mutations, replace entire disease-causing genes with functional genes or insert new genes into predetermined, safe locations.

Immune cells

Gamida Cell

Gamida Cell (Israel; www.gamida-cell.com), the developer of nicotinamide (NAM) enabled cell therapy candidates for patients with hematologic and solid cancers and other serious diseases, has announced dosing of the first patient in a company-sponsored phase I/II study evaluating a cryopreserved, readily available formulation of GDA-201 for the treatment of follicular and diffuse large B-cell lymphomas [16,17].

The phase I portion of the study is a dose escalation phase, designed to evaluate the safety of GDA-201, and will include patients with follicular lymphoma, diffuse large B-cell lymphoma/high-grade B-cell lymphoma, marginal zone lymphoma or mantle cell lymphoma. The phase II expansion phase is designed to evaluate the safety and efficacy of GDA-201 in 63 patients comprised of two cohorts of patients with either follicular lymphoma or diffuse large B-cell lymphoma. The study will include patients who have relapsed or refractory lymphoma after at least two prior treatments, which may include CAR-T or stem cell transplant.

Leveraging the unique properties of NAM, Gamida Cell can expand and metabolically modulate multiple cell types – including stem cells and NK cells – with appropriate growth factors to maintain the cells’ active phenotype and enhance potency. Additionally, NAM improves the metabolic fitness of cells, allowing for continued activity throughout the expansion process.

Innovative Cellular Therapeutics

Innovative Cellular Therapeutics ([ICT]; MD, USA; www.ictbio.com), a clinical-stage biotechnology company developing a comprehensive portfolio of CAR T-cell therapies for solid tumors, has announced that the first patient has been enrolled in its phase I trial of GCC19CART for relapsed/refractory metastatic colorectal cancer [18,19]. The study is an open-label, single-arm, multicenter, phase I, dose-escalation clinical trial evaluating the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of GCC19CART in patients with relapsed or refractory metastatic colorectal cancer in the USA. GCC19CART is ICT’s lead product candidate from the Company’s CoupledCAR^® technology. It has been tested in 35 patients in an Institutional Review Board-approved trial in China.

Orca Bio

Orca Bio (CA, USA; https://orcabio.com), a late-stage biotechnology company developing high-precision cell therapies for the treatment of cancer, genetic blood disorders and autoimmune diseases, has announced Precision-T, its pivotal phase III study, is open, enrolling and treating patients at multiple clinical trial sites. Precision-T is expected to enroll approximately 174 patients at more than 20 transplant centers across the US [20,21].

Precision-T is a randomized, open-label multicenter study that is evaluating the safety and efficacy of Orca Bio’s lead investigational high-precision cell therapy, Orca-T, compared with standard of care allogeneic hematopoietic stem cell transplant (standard allo-hematopoietic stem cell transplant). Orca Bio received guidance from the US FDA on the design of Precision-T, which will evaluate Orca-T in patients with acute myeloid leukemia, acute lymphocytic leukemia and high-risk myelodysplastic syndromes.

The primary end point of the Precision-T study is the rate of moderate-to-severe chronic GvHD-free survival. The secondary end points are graft-versus-host-disease and relapse-free survival, moderate-to-severe chronic GvHD and relapse-free survival. The randomized phase III trial is being conducted concurrently with Orca Bio’s ongoing single-arm, phase Ib trial of Orca-T.

Orca-T is an investigational high precision allogeneic cellular therapy consisting of infusions containing Treg, conventional T-cells and CD34⁺ stem cells derived from peripheral blood from either related or unrelated matched donors. Orca-T has received regenerative medicine advanced therapy designation from the FDA and is being studied to treat multiple hematologic malignancies.

Regulations, approvals, acquisitions…

Acquisitions & mergers

Lykan & Roslin

RoslinCT (UK; www.roslinct.com), a cell and gene therapy Contract Development and Manufacturing Organization (CDMO) and Lykan Bioscience (MA, USA; www.lykanbio.com), an innovative CDMO focused on cell-based therapies, have entered into a business combination agreement to form a global leading innovative advanced therapies CDMO [22].

The combined group will offer process development expertise and current GMP (cGMP) manufacturing for a broad range of autologous and allogeneic cell therapies, with unparalleled expertise in gene editing and industry leading iPSC capabilities.

The group will benefit from significantly expanded capacity, with process and analytical development laboratories and cGMP manufacturing facilities in Scotland and in Massachusetts. Lykan has a 6000 m² state-of-the-art cell therapy manufacturing facility and innovation/development laboratories with 16 cGMP processing suites running by the end of 2022. Further laboratory and cGMP capacity expansion in Scotland is planned to build on RoslinCT’s existing 3700 m² facilities, including eight cGMP suites.

With demand for high-quality development and manufacturing capacity increasing across the world, this complementary pairing of RoslinCT and Lykan will shorten development and manufacturing timelines for advanced therapy sponsors, facilitating clinical and commercial GMP product release on both sides of the Atlantic.

Earlier in 2022, Global Healthcare Opportunities or GHO Capital Partners LLP (UK; https://ghocapital.com), the European specialist investor in global healthcare, announced its investment in RoslinCT. As part of the new agreement, GHO is making a majority investment in Lykan and is backing the funding of the combined entity. WindRose Health Investors (NY, USA; www.windrose.com), previously the majority owner of Lykan Bioscience, have reinvested in the new combined group along with Lykan Management.

RoslinCT CEO and Lykan President & CEO will remain in their current roles. Together, the new entity will have a global headcount of ~300 employees.

Green light

bluebird

bluebird bio (MA, USA; www.bluebirdbio.com) has announced the FDA has approved ZYNTEGLO (betibeglogene autotemcel), also known as beti-cel, a one time gene therapy custom designed to treat the underlying genetic cause of beta-thalassemia in adult and pediatric patients who require regular red blood cell transfusions [23].

The approval of ZYNTEGLO is the culmination of nearly 10 years of clinical research of gene therapy in patients with transfusion dependent beta-thalassemia. ZYNTEGLO works by adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells to allow them to make normal to near normal levels of total hemoglobin without regular regular red blood cell transfusions. The functional beta-globin gene is added into a patient’s cells ex vivo, and then infused into the patient. Though ZYNTEGLO is designed to be administered to the patient once, the treatment process is comprised of several steps that may take place over the course of several months.

Due to the complex nature of gene therapy, ZYNTEGLO will be available exclusively at Qualified Treatment Centers (QTC) which are carefully selected based on their expertise in relevant areas such as stem cell transplantation, cell and gene therapy and beta-thalassemia; and receive specialized training to administer ZYNTEGLO. Information on bluebird’s QTC network, as well as personalized support focused on the needs of each patient throughout their treatment journey and information on insurance coverage and access will be available through bluebird’s patient support program (www.mybluebirdsupport.com) [24].

Calidi

Calidi Biotherapeutics (CA, USA; https://calidibio.com), a clinical-stage biotechnology company that is pioneering allogeneic cell-based platforms to revolutionize oncolytic virus therapies, has announced that City of Hope has received FDA authorization to proceed with a phase I physician sponsored clinical trial that will use Calidi’s licensed oncolytic virotherapy platform, neural stem cell (NSC)-CRAd-S-pk7 (NeuroNova [NNV]), in patients with recurrent high-grade glioma (Calidi’s NNV-2 program) [25].

The NeuroNova platform, NSC-CRAd-S-pk7, is an allogeneic, ‘off-the-shelf’ therapy comprised of an immortalized NSC line loaded with an engineered oncolytic adenovirus. Upon surgical resection of a tumor, NSC-CRAd-S-pk7 is injected into the walls of the resection cavity, resulting in viral infection and destruction of any remaining tumor cells. Calidi holds an exclusive worldwide licensing agreement for patents covering the NSC-CRAd-S-pk7 technology.

The phase I physician sponsored clinical trial will be an open-label, non-randomized, multicenter study. Once the phase I trial is funded, it will address the safety and tolerability of administering serial doses of NeuroNova in adult patients with recurrent histologically confirmed high-grade gliomas (WHO grade III or IV). Secondary end points will evaluate treatment efficacy, including progression-free and overall survival as well as any immune response to NeuroNova.

A previously completed phase I dose escalation clinical trial, in newly diagnosed glioma patients, of a single dose of NSC-CRAd-S-pk7 (NeuroNova) given as an adjunct to radiation and temozolomide (Calidi’s NNV-1 program) demonstrated that NeuroNova was well tolerated in the patient population and showed promising preliminary results of efficacy [26].

Cellectis

Cellectis (France; https://cellectis.com/en), a clinical stage biotechnology company using gene-editing platform to develop cell and gene therapies, has announced that the FDA has cleared Cellectis investigational new drug application to initiate a phase I/IIa clinical trial of UCART20x22 for patients with relapsed or refractory non-Hodgkin lymphoma [27]. The Company plans to begin enrolling patients in the NatHaLi-01 study in the second half of the year.

UCART20x22 features TALEN^®-mediated disruptions of the TRAC gene (that has been shown to reduce the risk of graft-versus-host disease) and of the CD52 gene (to allow using a CD52-directed monoclonal antibody in patients preconditioning regimen and enhancing CAR T engraftment, expansion and persistence).

Celyad

Celyad Oncology (Belgium; https://celyad.com), a clinical stage biotechnology company focused on the discovery and development of CAR T-cell therapies for cancer, has announced that the FDA has lifted the clinical hold on the CYAD-101-002 (KEYNOTE-B79) phase Ib trial after the Company made changes to the eligibility criteria for the trial [28]. As previously disclosed, on 28 February 2022, the Company announced that it was voluntarily pausing the CYAD-101-002 trial to investigate reports of two fatalities in the study. The trial was subsequently put on clinical hold in March 2022 by the FDA.

The CYAD-101-002 phase Ib trial evaluates the T-cell receptor inhibitory molecule-based allogeneic NKG2D CAR T cell investigational therapy CYAD-101 with MSDs anti-PD-1 therapy KEYTRUDA^® (pembrolizumab) in patients with refractory metastatic colorectal cancer with microsatellite stable/mismatch repair proficient disease.

Century

Century Therapeutics (PA, USA; www.centurytx.com), a company developing iPSC derived cell therapies in immuno-oncology, has been notified by the FDA that the Company’s ELiPSE-1 clinical study may proceed to assess CNTY-101 in patients with relapsed or refractory CD19 positive B-cell malignancies [29,30].

CNTY-101 is an investigational off-the-shelf cancer immunotherapy product candidate that utilizes iPSC-derived natural killer (NK) cells with a CD19-directed CAR and includes Century’s core Allo-Evasion™ edits designed to overcome the three major pathways of host versus graft rejection – CD8⁺ T cells, CD4⁺ T cells and NK cells. In addition, the product candidate is engineered to express IL-15 to provide homeostatic cytokine support, which has been shown preclinically to improve functionality and persistence. Further, to potentially improve safety, the iNK cells were engineered with an EGFR safety switch, and proof-of-concept studies have demonstrated that the cells can be quickly eliminated by the administration of cetuximab, an antibody against EGFR approved by the FDA for certain cancers. Initiation of the phase I, ELiPSE-1 trial in relapsed or refractory CD19-positive B-cell malignancies in multiple centers in the USA is anticipated to begin in the second half of 2022.

The phase I trial, ELiPSE-1, is intended to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of CNTY-101 in patients with relapsed or refractory CD19-positive B-cell malignancies. All patients will receive an initial standard dose of conditioning chemotherapy consisting of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) for 3 days. Schedule A of the trial includes a single-dose escalation of CNTY-101 and subcutaneous IL-2. Schedule B will evaluate a three-dose schedule per cycle of CNTY-101. Patients who demonstrate a clinical benefit are eligible for additional cycles of treatment with or without additional lymphodepletion pending FDA consent.

Century’s proprietary Allo-Evasion technology is used to engineer cell therapy product candidates with the potential to evade identification by the host immune system so they can be dosed multiple times without rejection, enabling increased persistence of the cells during the treatment period and potentially leading to deeper and more durable responses. More specifically, Allo-Evasion 1.0 technology incorporates three gene edits designed to avoid recognition by patient/host CD8⁺ T cells, CD4⁺ T cells and NK cells. Knockout of beta-2-microglobulin or β2M, designed to prevent CD8⁺ T cell recognition, knock-out of the Class II Major histocompatibility complex transactivator or CIITA, designed to prevent CD4⁺ T cell recognition and knock-in of the HLA-E gene, designed to enable higher expression of the HLA-E protein to prevent killing of CNTY-101 cells by host NK cells. Allo-Evasion technology may allow the implementation of more flexible and effective repeat dosing protocols for off-the-shelf product candidates.

Charles River

Charles River Laboratories International (TN, USA; www.criver.com) has received regulatory approval, in the form of GMP certification, to commercially produce allogeneic cell therapy drug products for distribution in Europe, from the EMA [31]. The approval follows an inspection by the cell and gene therapy experts from the Italian inspectorate, Agenzia Italiana del Farmaco (AIFA), performed on the EMA’s behalf. The GMP certification of Charles River’s Memphis CDMO facility complements an existing GMP license for investigational medicinal product production. The Memphis site can manufacture and ship drug products intended for EU distribution. The approval recognizes Charles River’s industry-leading expertise, multidisciplinary team, regulatory know-how and quality standards. Charles River’s Memphis cGMP CDMO facility is suitable to manufacture clinical (early- and late-phase) as well as commercial cell and gene modified cell therapies. With the 2021 acquisitions of Cognate BioServices, Cobra Biologics and Vigene Biosciences, Charles River significantly expanded its cell and gene therapy portfolio to include end-to-end CDMO capabilities (plasmid DNA, viral vector and cellular therapies). These capabilities have been integrated with Charles River’s legacy services resulting in a ‘concept-to-cure’ cell and gene therapy portfolio.

King Abdulaziz Medical City

King Abdulaziz Medical City (Saudi Arabia; https://ngha.med.sa/English/MedicalCities/AlRiyadh) has received internationally recognized accreditation by the Foundation for the Accreditation of Cellular Therapy (FACT; NE, USA; www.factglobal.org) [32]. It is the first and only cellular therapy program in Saudi Arabia to be recognized by FACT. The program is accredited for adult and pediatric allogeneic and autologous hematopoietic progenitor cell transplantation, marrow and peripheral blood cellular therapy product collection, and cellular therapy product processing.

Capital market & finances

3T Biosciences

3T Biosciences (CA, USA; https://3tbiosciences.com), an immunotherapy company working on treatment for solid tumors and other immune-mediated diseases, has announced its launch from stealth backed by US$40 million Series A financing [33]. As part of its launch, 3T announced it has exclusively in-licensed from Stanford University a precise antibody-based peptide-HLA therapeutic discovery platform and development-stage MAGE-A3 T-cell receptor-T assets to rapidly expand 3T’s therapeutic portfolio.

Poseida

Poseida Therapeutics (CA, USA; https://poseida.com), a clinical-stage biopharmaceutical company utilizing proprietary genetic engineering platform technologies to create cell and gene therapeutics with the capacity to cure, has announced the closing of its previously announced underwritten public offering of 23,000,000 shares of its common stock at a public offering price of US$3.50 per share, including 3,000,000 shares sold pursuant to the full exercise of the underwriters’ option to purchase additional shares [34–36]. All of the shares were sold by Poseida. Including the option exercise, the aggregate gross proceeds to Poseida from the offering, before deducting underwriting discounts and commissions and other offering expenses, were US$80.5 million.

Financial & competing interests disclosure

The author Dusko Ilic has received an honorarium from Future Science Group for the contribution of this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

Financial & competing interests disclosure The author Dusko Ilic has received an honorarium from Future Science Group for the contribution of this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.