Industry updates from the field of stem cell research and regenerative medicine in October 2021

Business development

Co-development agreement: Harvard University & National Resilience

Harvard University (MA, USA; www.harvard.edu) and National Resilience (CA, USA; https://resilience.com), a manufacturing and technology company, have established a 5-year research and development (R&D) alliance with a US$30 million commitment from Resilience directed toward the development of complex medicines, including biologics, vaccines, nucleic acids and cell and gene therapies [1]. Under the alliance agreement coordinated by Harvard’s Office of Technology Development (OTD; https://otd.harvard.edu), Resilience will fund faculty-initiated research focused on certain novel therapeutic and biomanufacturing technologies pioneered in university labs. The alliance also anticipates that these Harvard innovations may be commercially advanced by new companies formed by Resilience expressly to drive these technologies into clinical development and commercialization. An initial technology platform has already been identified for incubation under the alliance, with promising applications in skeletal muscle disorders.

Collaboration agreement: Astellas Pharma & Juntendo University Graduate School of Medicine

Astellas Pharma (Japan; www.astellas.com) and Juntendo University Graduate School of Medicine (Japan; www.juntendo.ac.jp) have established a joint research program, Direct Reprogramming Regenerative Medicine Course [2]. This joint research course aims to create a new modality that maximizes the therapeutic effect for diseases with high unmet medical needs, such as Type 1 diabetes, by direct reprogramming using the K factor. K factor is a gene that significantly enhances the efficiency of direct reprogramming. Juntendo University Graduate School of Medicine will be acquiring the basic data including the study of the optimal combination of direct reprogramming factors that include the K factor, and Astellas will be conducting the applied research for disease treatment by gene therapy using this factor and selection of the optimal modality. Direct reprogramming is a biology that directly converts the fate of cells without passing through the pluripotent state.

Collaboration agreement: RxCell & Singaporean biotechnology

RxCell (CA, USA; www.rxcellinc.com) company focused on therapeutic applications of induced pluripotent stem cells (iPSCs), together with the Agency for Science, Technology and Research (A*STAR)’s Institute of Molecular and Cell Biology (Singapore; www.a-star.edu.sg/imcb), Yong Loo Lin School of Medicine at the National University of Singapore (Singapore; https://medicine.nus.edu.sg) and the Singapore Eye Research Institute (Singapore; www.snec.com.sg/research-innovation), announced a co-funded collaboration to develop cellular therapeutics for age-related diseases [3]. Through this collaboration, RxCell will contribute their clinical grade iPSC as well as hypoimmunogenic iPSC generated by their proprietary technologies – which confer the advantage of being able to evade the host’s immune system and avoid an unwanted immune response. This will complement Institute of Molecular and Cell Biology expertise in retinal diseases and animal modeling, National University of Singapore expertise in age-related cell therapy strategies and Singapore Eye Research Institute expertise in rabbits and non-human primate ocular disease models.

Collaboration & licensing agreement: Poseida Therapeutics & Takeda Pharmaceutical

Poseida Therapeutics (CA, USA; www.poseida.com), a clinical-stage biopharmaceutical company utilizing proprietary genetic engineering platform technologies to create cell and gene therapeutics, has entered into a research collaboration and exclusive license agreement with Takeda Pharmaceutical (Japan; www.takeda.com) to utilize Poseida’s piggyBac, Cas-CLOVER, biodegradable DNA and RNA nanoparticle delivery technology and other proprietary genetic engineering platforms for the research and development of up to eight gene therapies [4]. The collaboration will focus on developing nonviral in vivo gene therapy programs, including Poseida’s Hemophilia A program.

Poseida will receive an upfront payment of US$45 million and preclinical milestones that together could potentially exceed US$125 million in the aggregate, if milestones for six programs are achieved. Poseida is also eligible to receive future clinical development, regulatory and commercial milestone payments with a total potential value over the course of the partnership of up to US$2.7 billion if milestones for all six programs are achieved, and up to US$3.6 billion if the milestones related to the two optional programs are also achieved. Poseida will lead research activities up to candidate selection, after which Takeda will assume responsibility for further development and commercialization.

Licensing agreement: Sana Biotechnology & Beam Therapeutics

Sana Biotechnology (WA, USA; https://sana.com), a company focused on creating and delivering engineered cells as medicines, today announced that the company entered into an agreement with Beam Therapeutics (MA, USA; https://beamtx.com) for nonexclusive commercial rights to Beam’s CRISPR Cas12b nuclease system for certain ex vivo engineered cell therapy programs [5]. Cas12b is a CRISPR-based nuclease with a high degree of specificity and efficiency that can be used to knock out and/or knock in genes in certain cell types. Under the agreement, Beam granted Sana non-exclusive rights to utilize its Cas12b system with certain allogeneic T cell and stem cell-derived programs, including the ability to make gene edits for Sana’s hypoimmune platform. The license does not include any rights to base editing using Cas12b, which remain at Beam. Under the terms of the agreement, Sana agreed to pay Beam an upfront payment of US$50 million. Beam is also eligible to receive certain target option exercise fees, certain milestone payments upon the achievement of certain development and sales milestones and certain royalties on net sales of royalty-bearing products by Sana, its affiliates, its sublicensees and affiliates of its sublicensees.

Strategic partnership: Exacis Biotherapeutics & CCRM

Exacis Biotherapeutics (MA, USA; www.exacis.com), a development-stage immuno-oncology company working to harness the immune system to cure cancer, has announced initiation of a strategic partnership with Centre for Commercialization of Regenerative Medicine (CCRM; ON, Canada; https://www.ccrm.ca) for specialty manufacturing services related to the development of Exacis’ innovative, iPSC-derived mRNA-engineered natural killer cell products to treat cancer [6]. The partnership also includes a cash investment into Exacis by CCRM Enterprises Holdings, the for-profit venture investment arm of CCRM, which will be used to fund operations.

Collaboration agreement: Atara Biotherapeutics & Pierre Fabre

Atara Biotherapeutics (CA, USA; www.atarabio.com) and Pierre Fabre (France; www.pierre-fabre.com) announced an exclusive commercialization agreement for tabelecleucel (tab-cel^®) in Europe, the Middle East, Africa and other select emerging markets for Epstein–Barr virus (EBV) positive cancers [7]. Atara will retain full rights to tab-cel in other major markets, including North America, Asia Pacific and Latin America. Under the terms of the agreement, Atara will receive an upfront payment of US$45 million, and up to approximately US$320 million in additional regulatory and sales milestone payments, plus significant double-digit tiered royalties as a percentage of net sales. Atara will continue to be responsible for the pivotal ALLELE study [8] as well as submitting the EU marketing authorization application for tabelecleucel in patients with EBV-positive post-transplant lymphoproliferative disease (EBV+ PTLD). Atara will also remain responsible for the Phase II multicohort study, which is evaluating tab-cel in six additional patient populations with the goal of label expansion in EBV-driven cancers. Pierre Fabre will lead all commercialization and distribution activities in the territories, as well as medical and regulatory activities after the anticipated marketing authorization application approval in Europe. As part of the transaction, Atara will also provide manufacturing services for tab-cel to be paid by Pierre Fabre. Tab-cel has been granted Breakthrough Therapy Designation by the US FDA and Priority Medicines (PRIME) designation by the EMA.

Launching new products, services…

Celogics

Curi Bio (WA, USA; www.curibio.com) developer of human stem cell-based platforms for disease modeling and drug discovery, and NEXEL (Korea; www.nexel.co.kr), with a focus on iPSC technology, have announced the formation of Celogics, a joint venture company focused on the development and commercialization of human iPSC-derived cell products for drug discovery, drug safety testing and biological research [9]. Celogics iPSC production and distribution headquarters will be in Seattle, WA.

Celogics will provide Nexel’s iPSC-derived cell products, including Cardiosight^®-S cardiomyocytes, to US and global markets and will launch a Seattle-based iPSC production facility to support rapid growth and iPSC contract development and manufacturing services. Celogics will also develop and commercialize next-generation iPSC-derived cell products. Curi’s 3D engineered tissue platform (Mantarray™) can be used in combination with iPSC-derived cell models to develop advanced 3D heart and muscle tissue models for phenotypic screening. NEXEL launched the Cardiosight -S in 2018 which is as a pure and functional population of hiPSC-derived cardiomyocytes. Other product lines include the Hepatosight^®-S (iPSC-derived hepatocytes) and the Neurosight^®-S (iPSC-derived neurons).

OrganaBio

OrganaBio (FL, USA; www.organabio.com) is expanding its product portfolio with the addition of current Good Manufacturing Practices (cGMP)-compliant and current Good Tissue Practices-compliant perinatal umbilical cord blood and leukopak products [10]. Obtained from fully consented donors, under institutional review board-approved protocols, with comprehensive testing and supporting documentation to meet the regulatory requirements of the FDA and other regulatory agencies, OrganaBio’s cGMP compliant products further deliver on OrganaBio’s commitment to providing high quality critical starting materials to cell therapy and cancer immunotherapy developers. Marketed under the HematoPAC™-GMP and LeukoPAC™-GMP brands, these products are a source of hematopoietic stem cells (HSCs) and lymphoid- and myeloid-derived immune cells, including T cells, natural killer cells, Tregs, gamma delta T cells, macrophages and B cells, which are critical raw materials for allogeneic regenerative medicine, cell therapy and immunotherapy development and manufacturing.

Achievements

Arbor Life Labs

Arbor Life Labs (ON, Canada; www.arborlifelabs.com) has published the results of a clinical trial on hair loss in women [11,12]. The trial enrolled 46 women from 24 to 64 years of age with conditions including female patterned hair loss, hair thinning or diffuse hair loss [13]. The researchers found that the patent-pending botanical Replenology^® hair system (www.replenology.com) increased total scalp hair density by 33.9 hairs/cm² and 18.6% more than the placebo. This result is a fourfold improvement in hair growth and response rates in just 24 weeks when compared with clinical trials of currently available hair loss products. The researchers also found hair regrowth accelerated during the trial. The publication concluded that a woman may restore her normal hair density with extended use of the Replenology hair system.

Mesoblast

Mesoblast (Australia; www.mesdoblast.com), has published the results showing that children with steroid-refractory acute graft-versus-host disease (SRaGVHD) and biomarkers predictive for highest mortality had 64% survival when treated with remestemcel-L compared with only 10% survival when treated with other available therapies, including ruxolitinib or other biologics [14,15]. The study compared outcomes in 25 children from Mesoblast’s Phase III trial of remestemcel-L in SRaGVHD with 27 closely matched children from the Mount Sinai Acute GVHD International Consortium (MAGIC) 2, who participated in a prospective natural history study and were matched for the Phase III trial entry criteria. The objective of the study was to evaluate whether outcomes differed according to treatment with remestemcel-L versus other therapies in children at highest risk of death, namely those with baseline MAGIC algorithm probability (MAP) biomarker levels ≥0.291, a level predictive of very high mortality and poor responses to therapy in SRaGVHD. MAP combines the serum concentrations of two biomarkers, Reg3α and ST2, into a single value that predicts long-term outcomes and significant gastrointestinal tract damage. MAP levels ≥0.291 were present in 48% of remestemcel-L treated children (12/25) and 37% of the MAGIC cohort (10/27). Treatment with remestemcel-L resulted in 67% day 28 overall response and 64% day 180 overall survival compared with 10% day 28 overall response and 10% day 180 survival in the MAGIC cohort (both p = 0.01) when treated with various biologics, including ruxolitinib. These results extend previous observations showing that children who achieved clinically meaningful responses and survival after treatment with remestemcel-L had significant reductions in the ST2 biomarker of inflammation, consistent with healing of the gastrointestinal tract.

Clinical trials

Pluripotent stem cells

Vertex Pharmaceuticals

Vertex Pharmaceuticals (MA, USA; www.vrtx.xom) has announced positive day 90 data for the first patient from the Phase I/II clinical trial of VX-880, an investigational stem cell-derived, fully differentiated pancreatic islet cell replacement therapy for people with Type 1 diabetes [16]. This is the first demonstration of a patient with Type 1 diabetes achieving robust restoration of islet cell function from such a cell therapy.

The patient was treated with a single infusion of VX-880 at half the target dose in conjunction with immunosuppressive therapy. The patient achieved successful engraftment and demonstrated rapid and robust improvements in multiple measures, including increases in fasting and stimulated C-peptide, improvements in glycemic control, including HbA1c and decreases in exogenous insulin requirement. VX-880 was generally well tolerated.

Mesenchymal stromal/stem cells

BioCardia

BioCardia (CA, USA; www.biocardia.com), a company focused on developing cellular and cell-derived therapeutics for the treatment of cardiovascular and pulmonary diseases, have announced the treatment of the first patient in its Phase III pivotal CardiAMP Cell Therapy Chronic Myocardial Ischemia Trial for patients with no option chronic myocardial ischemia with refractory angina [17,18]. These patients experience frequent angina attacks that are uncontrolled by optimal drug therapy but are not suitable candidates for stent placement or bypass surgery, leaving them with no therapeutic options. CardiAMP cell therapy uses autologous bone marrow cells delivered to the heart in a minimally invasive, catheter-based procedure to potentially stimulate the body’s natural healing response.

The CardiAMP Cell Therapy Chronic Myocardial Ischemia Trial is expected to enroll up to 343 patients at up to 40 centers. The primary end point will evaluate improvement in exercise tolerance at 6 months following the study procedure. The trial is intended to have an adaptive statistical analysis plan with an initial assessment for efficacy when 100 patients reach their primary end point, although aspects of the statistical analysis plan remain the subject of study considerations with the FDA.

In unrelated news, the company announced the treatment of the first crossover patient in the ongoing Phase III Pivotal CardiAMP^® Cell Therapy in Heart Failure Trial for the treatment of ischemic heart failure [19,20]. A crossover patient is one who was previously in the control group of the study, has completed follow-up and elects to receive therapy. The FDA approved a detailed protocol amendment to shorten the trial’s primary end point to a 6-month follow-up from 1 year, and to harmonize details of the protocol to correspond with the actively enrolling CardiAMP Cell Therapy Heart Failure Trial, which has incorporated best practices from significant interactions with study centers and the FDA. Both trials have a Category B designation from FDA and the Center for Medicare and Medicaid Services, enabling study sites to receive Center for Medicare and Medicaid Services reimbursement for both the standard of care procedures and the investigational CardiAMP Cell Therapy System.

A protocol amendment approved by the FDA allows patients in the trial who were initially randomly assigned to the control arm and did not receive therapy to elect to crossover and receive the investigational autologous CardiAMP Cell Therapy after completing the 2-year follow-up. The approval of the study’s crossover arm was based in part on the study’s Data Safety Monitoring Board’s formal assessments during the trial. The amendment also included provisions for following crossover patients for a period of one additional year under the clinical protocol.

Other

BioLineRx

BioLineRx (Israel; www.biolinerx.com), a late clinical-stage biopharmaceutical company focused on oncology, had announced positive results from a pharmacoeconomic study evaluating the cost–effectiveness of using investigational drug motixafortide as a primary stem cell mobilization agent on top of G-CSF versus G-CSF alone, in multiple myeloma patients undergoing autologous stem-cell transplantation (ASCT) [21].

The study concluded that the addition of motixafortide to G-CSF (the current standard of care) is associated with a statistically significant decrease in health resource utilization during the ASCT process, compared with G-CSF alone.

Based on the significantly higher number of mobilized cells and the lower number of apheresis sessions, lifetime estimates show quality-adjusted life-year benefits and net cost savings of approximately US$17,000 (not including the cost of motixafortide), versus G-CSF alone. The study findings, combined with model estimates, suggest that the use of motixafortide, on top of G-CSF, as the standard of care in mobilization for ASCT, could be a cost-effective option in the USA, based on accepted willingness-to-pay values for healthcare payers.

Regulations, approvals & acquisitions…

Green light

AlloVir

AlloVir (MA, USA; www.allovir.com), a late clinical-stage cell therapy company, has announced that the FDA has granted orphan drug designation to posoleucel (Viralym-M, ALVR105) for the treatment of virus-associated hemorrhagic cystitis (HC) [22]. Virus-associated HC is a well-described complication after hematopoietic stem-cell transplantation in which a viral infection causes the bladder lining to become inflamed, resulting in hematuria or blood in the urine. More than half of patients with HC experience clot formation and/or severe bladder hemorrhage with renal impairment. Bleeding may be life-threatening, requiring urologic interventions including cystectomy or the removal of the urinary bladder. Clinical manifestations of HC include kidney dysfunction or failure, blood in the urine and severe abdominal pain frequently requiring narcotics. With no approved or effective antiviral treatments, virus-associated HC is primarily managed with supportive care, including forced diuresis, continuous bladder irrigation, platelet transfusion and anti spasmodics, in addition to urinary and opioid analgesics.

The patients with virus-associated HC had a 70% higher risk of mortality, and the viral disease was associated with significantly prolonged hospitalization, including increased intensive care unit stay and hospital readmission rates. HC can be caused by several viruses, including atadenovirus (AdV) and cytomegalovirus (CMV); however, up to 90% of HC cases are caused by BK virus (BKV). HC is the primary clinical manifestation associated with BKV following hematopoietic stem cell transplantation, occurring in up to 25% of pediatric patients and up to 54% of adult patients.

Posoleucel is an investigational, allogeneic, off-the-shelf, multivirus specific T-cell therapy under development for the treatment and prevention of serious diseases caused by six devastating viral pathogens: BKV and the related polyomavirus JC virus, CMV, human herpes virus (HHV)-6, EBV and AdV. In addition to this orphan drug designation, posoleucel has been granted regenerative medicine advanced therapy designation from the FDA, and orphan medicinal product and PRIME designations from the EMA. Posoleucel is one of the first seven investigational therapies to receive both PRIME and regenerative medicine advanced therapy designations.

Kite Pharma

Kite Pharma (CA, USA; www.kitepharma.com), a Gilead Company (CA, USA; www.gilead.com), has announced that the FDA has granted approval for Tecartus^® (brexucabtagene autoleucel) for the treatment of adult patients (18 years and older) with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) [23]. Following FDA breakthrough therapy designation and a priority review, Tecartus is the first and only chimeric antigen receptor (CAR)-T cell therapy approved for adults with ALL. There is a high unmet need, as half of this patient population will relapse, and median overall survival is only approximately 8 months with current standard-of-care treatments. Patients can access Tecartus through 109 authorized treatment centers across the USA.

The approval is based on results from ZUMA-3, a global, multicenter, single-arm, open-label study in which 65% of the evaluable patients (n = 54) achieved complete remission (CR) or CR with incomplete hematological recovery (CRi) at a median actual follow-up of 12.3 months [24]. The duration of CR was estimated to exceed 12 months for more than half the patients. Among efficacy-evaluable patients, median duration of remission was 13.6 months. Among the patients treated with Tecartus at the target dose (n = 78), Grade 3 or higher cytokine release syndrome and neurologic events occurred in 26 and 35% of patients, respectively, and were generally well managed.

Precigen

Precigen (MD, USA; www.precigen.com), a biopharmaceutical company specializing in the development of innovative gene and cell therapies, has announced that the FDA has cleared the investigational new drug application to initiate the Phase I/IB clinical trial of PRGN-3007 in advanced ROR1+ hematological and solid tumors [25]. PRGN-3007 is a first-in-class investigational therapy based on the next generation of Precigen’s UltraCAR-T^® platform and incorporates intrinsic PD-1 blockade.

ROR1 is overexpressed in various cancers with minimal expression in healthy adult tissues. ROR1 is aberrantly expressed in multiple hematological tumors, including chronic lymphocytic leukemia, mantle cell leukemia, ALL and diffuse large B-cell lymphoma (DLBCL) and solid tumors, including breast adenocarcinomas encompassing triple negative breast cancer, pancreatic cancer, ovarian cancer and lung adenocarcinoma.

PRGN-3007 UltraCAR-T is an investigational multigenic, autologous CAR-T cell therapy utilizing Precigen’s clinically validated advanced nonviral gene delivery system and the well-established overnight, decentralized manufacturing process. Precigen has further advanced the UltraCAR-T platform to address the inhibitory tumor microenvironment by incorporating intrinsic checkpoint blockade without the need for complex and costly gene editing techniques. PRGN-3007 is engineered using a single multicistronic transposon plasmid to simultaneously express a CAR targeting ROR1, mbIL-15, a kill switch and a novel mechanism for the intrinsic blockade of PD-1 gene expression.

The PD-1/PD-L1 pathway plays a vital role in how tumor cells evade immune response. While the blockade of the PD-1/PD-L1 pathway has demonstrated considerable benefit for treating various cancers, the use of systemic checkpoint inhibitors can lead to side effects associated with autoimmune response. The innovative design of PRGN-3007, where the blockade of PD-1 expression is intrinsic and localized to UltraCAR-T cells, is aimed at avoiding systemic toxicity and the high cost of checkpoint inhibitors by eliminating the need for combination treatment.

The Phase I/IB clinical trial is an open-label study designed to evaluate the safety and efficacy of PRGN-3007 in patients with advanced ROR1+ hematological (Arm 1) and solid (Arm 2) tumors. The target patient population for Arm 1 includes relapsed or refractory chronic lymphocytic leukemia, relapsed or refractory mantle cell leukemia, relapsed or refractory ALL and relapsed or refractory DLBCL. The target patient population for Arm 2 includes locally advanced unresectable or metastatic histologically confirmed triple negative breast cancer. The study will enroll in two parts: an initial 3 + 3 dose escalation in each arm followed by a dose expansion at the maximum tolerated dose. Arm 1 and Arm 2 will enroll in parallel.

Pending

Novartis

Novartis (Switzerland; www.novartis.com) has announced that the FDA and the EMA have accepted the company’s supplemental biologics license application and Type II variation, respectively, for Kymriah (tisagenlecleucel) in adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two prior lines of treatment [26]. Kymriah was previously granted orphan medicinal product designation by the European Commission for FL. The FDA has also granted priority review to the company’s supplemental biologics license application for Kymriah in adult patients with r/r FL. Kymriah is currently approved by the FDA, EMA and other regulatory authorities for the treatment of r/r pediatric and young adult (up to and including 25 years of age) ALL and r/r adult DLBCL.

Acquisitions & mergers

Takeda Pharmaceutical & GammaDelta Therapeutics

Takeda Pharmaceutical (Japan; www.takeda.com) has announced the exercise of its option to acquire GammaDelta Therapeutics (UK; https://gammadeltatx.com) a company focused on exploiting the unique properties of gamma delta (γδ) T cells for immunotherapy [27]. Committed to transforming the treatment of patients living with cancer, the GammaDelta is developing an ‘off-the-shelf’ therapy based on one of the body’s own immune cells, a subtype of the γδ T-lymphocyte, known as the Vδ1+ T cell. The company has developed proprietary technologies to generate both blood-and tissue-derived allogeneic immunotherapies based on Vδ1 γδ T cells for the treatment of hematological malignancies and solid tumors. Both platforms have enabled the creation of non engineered and genetically engineered allogeneic cell therapies, which demonstrate cellular activity and tumor cell killing capacity in preclinical models. Through the acquisition, Takeda will obtain GammaDelta’s allogeneic variable delta 1 (Vδ1) γδ T-cell therapy platforms, which includes both blood-derived and tissue-derived platforms, in addition to early-stage cell therapy programs. The acquisition follows a multiyear collaboration between Takeda and GammaDelta Therapeutics formed in 2017 to develop GammaDelta’s novel γδ T-cell therapy platforms, in which Takeda received an equity stake and an exclusive right to purchase GammaDelta.

Capital market & finances

Kadimastem

Kadimastem (Isrtael; www.kadimastem.com), a clinical stage cell therapy company, has announced a NIS₪515.8 million (US$5 million) private placement [28]. In addition to the placement announced today, the investors were also given an option to purchase an additional NIS₪15.1  million (US$4.8 million) in shares in the future. This investment will be used to support Kadimastem’s future clinical trial activity and fund multiple strategic collaborations involving both the company’s amyotrophic lateral sclerosis (ALS) and diabetes programs.

Kadimastem is a clinical stage cell therapy company, developing and manufacturing ‘off-the-shelf’, allogeneic, proprietary cell products based on its technology platform for the expansion and differentiation of human embryonic stem cells into functional cells. AstroRx^®, the company’s lead product, is an astrocyte cell therapy in clinical development for the treatment for ALS. IsletRx^® is the company’s second product in development. IsletRx is comprised of functional, insulin producing, pancreatic islet cells intended to treat and cure patients with insulin dependent diabetes. IsletRx demonstrated safety and efficacy in a proof-of-concept preclinical study.

Leucid Bio

Leucid Bio (UK; www.leucid.com), a biotech company pioneering next-generation cell therapies for hard-to-treat cancers, has successfully raised US$15.2 million (£11.5 million) in a Series A financing round. Leucid’s LEU-011 program is a NKG2D CAR-T cell therapy in preclinical development for the treatment of solid tumors and hematological malignancies [29]. The NKG2D receptor is an activating immune receptor that triggers cell death upon recognition of human NKG2D ligands expressed on transformed, infected or damaged cells. LEU-011 has potential for the treatment of multiple cancer types as NKG2D ligands are expressed on more than 80% of human tumor cells.