CaspaCIDe DLI (rimiducid activated rivogenlecleucel) / Bellicum - LARVOL DELTA

Improved T- and B-Cell Neogenesis in Children with Acute Leukemia Given an Alpha-Beta T-Cell Depleted Haplo-HSCT Combined with the Infusion of Donor T-Cells Genetically Modified with Inducible Caspase 9 Suicide Gene (Rivo-cel) (ASH 2023) - P1/2 | "Our data confirm the detrimental effect of both acute and chronic GvHD in recovery of thymic function and B-cell neogenesis. In this perspective, the possibility to successfully control/abrogate GvHD through the apoptosis of Rivo-cel triggered by the infusion of the dimerizing agent (AP1903) offers also the advantage of, at least partly, preventing the detrimental effect played by this complication on immune recovery."

Clinical • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplantation

Improved ApoptiCIDe ™ Safety Switch Provides a Novel, Controllable Therapeutic Platform for Regulated Klotho Anti-Aging Gene Therapy (ASGCT 2025) - "Currently, the rimiducid/inducible Caspase-9 (ApoptiCIDe™) system remains the most clinically validated attenuator for cell and gene therapy; however, it's broadest adoption is limited by the burden of a 2-hour infusion of the rim activating agent, along with infusion reactions that can occur as a result of the current excipient, Solutol hydroxy stearate (HS) 15. We screened a large number of combinations of excipient combinations and chose one formulation compatible with subcutaneous and intramuscular injection, with bioavailability above 30%, named PTC-1202, for further clinical development. Formal stability testing revealed 99.8% stability under accelerated conditions (40°C, 75% relative humidity) over 3 months. To demonstrate in vivo utility, bioluminescent (BLI) reporter, N-Luc, was co-expressed with ApoptiCIDe under the constitutive CMV promoter/enhancer and delivered to mice using AAV2 and AAV9 vectors via IV, IM, IP and SQ routes."

Clinical • Gene therapy • Gene Therapies • Metabolic Disorders • Pediatrics • Sarcopenia

POST-TRANSPLANT INFUSION OF RIVO-CEL IMPROVES OUTCOME OF T-CELL RECEPTOR ΑΒ+(TCRΑΒ+)/CD19+CELL-DEPLETED HAPLOIDENTICAL TRANSPLANTATION (TCRΑΒ-HAPLOHSCT) FOR INBORN ERRORS OF IMMUNITY (IEIS): FINAL RESULTS OF BP-004-EU MULTICENTER TRIAL (EBMT 2025) - P1/2 | "SCID patients uniformly received treosulfan-based conditioning, while non-SCID patients underwent busulfan- or treosulfan-based regimens tailored to their specific disease. Anti-thymocyte globulins (ATLG Neovii® 4-5 mg/kg/day) were administered on days -4 to -2 and Rituximab on day -1...Six aGVHD patients received Rimiducid for activating iC9, with an overall response rate of 83% (3 complete and 2 partial responses)... TCRαβ-haploHSCT followed by Rivo-cel infusion is a safe and effective transplantation strategy for various IEIs, yielding excellent outcomes in SCID patients. Rivo-cel infusion accelerated adaptive immunity recovery, achieving protective CD3+CD4+ levels within 3 months post-transplant. Despite the high number of HLA-disparate donor T-cells infused, acute and chronic GVHD incidence remained remarkably low."

Clinical • Post-transplantation • Acute Graft versus Host Disease • Bone Marrow Transplantation • Chronic Graft versus Host Disease • CNS Disorders • Genetic Disorders • Graft versus Host Disease • Hemophagocytic lymphohistiocytosis • Immunology • Infectious Disease • Nontuberculous Mycobacterial Disease • Pediatrics • Primary Immunodeficiency • Rare Diseases • Respiratory Diseases • Transplantation • CD4

T- AND B-CELL NEOGENESIS RECOVERS EFFICIENTLY IN CHILDREN WITH ACUTE LEUKEMIA GIVEN AN ALPHA-BETA T-CELL DEPLETED HAPLO-HSCT FOLLOWED BY INFUSION OF GENETICALLY MODIFIED DONOR T-CELLS (EBMT 2025) - "In αβhaplo-HSCT, the IR pattern conferred by Rivocel is particularly favorable; furthermore, Rivo-cel provides immune protection also by accelerating thymic activity and promoting the recovery of the naïve T-cell compartment."

Clinical • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD4 • CD8

T- AND B-CELL NEOGENESIS RECOVERS EFFICIENTLY IN CHILDREN WITH ACUTE LEUKEMIA GIVEN AN ALPHA-BETA T-CELL DEPLETED HAPLO-HSCT FOLLOWED BY INFUSION OF GENETICALLY MODIFIED DONOR T-CELLS (EBMT 2025) - "In αβhaplo-HSCT, the IR pattern conferred by Rivocel is particularly favorable; furthermore, Rivo-cel provides immune protection also by accelerating thymic activity and promoting the recovery of the naïve T-cell compartment."

Clinical • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD4 • CD8

Haploidentical transplantation: An optimal platform for graft manipulation and cellular therapies. (PubMed, Blood Rev) - "Advances in in vivo graft manipulation techniques, such as post-transplant cyclophosphamide (PTCy) and ex vivo approaches, including TCRα/β and CD19 depletion, have shown promise in reducing the risk of severe GvHD without increasing the relapse rates. Innovative strategies, such as haploidentical donor lymphocyte infusions, "suicide-switch" mechanisms, ORCA-Q product infusions, and CAR based therapies offer potential to further optimize outcomes. This review examines the graft manipulation modalities in the haplo-HCT setting, highlighting their role in advancing cellular therapies and providing new hope in the fight against life-threatening diseases."

Journal • Review • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Oncology • Transplantation

Safety Study of Gene Modified Donor T Cell Infusion After Stem Cell Transplant for Non-Malignant Diseases (clinicaltrials.gov) - P1 | N=1 | Terminated | Sponsor: Bellicum Pharmaceuticals | Active, not recruiting ➔ Terminated; due to lack of enrollment and changes to the sponsor development portfolio

Trial termination • Aplastic Anemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Immunology • Metabolic Disorders • Primary Immunodeficiency • Rare Diseases • Transplantation • CD34 • HLA-B

Long Term Follow-up Study for Patients Enrolled on the BP-004 Clinical Study (clinicaltrials.gov) - P1/2 | N=187 | Terminated | Sponsor: Bellicum Pharmaceuticals | Trial completion date: Jun 2033 ➔ Apr 2023 | Active, not recruiting ➔ Terminated

Trial completion date • Trial termination • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Anemia • Aplastic Anemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics • Primary Immunodeficiency • Sickle Cell Disease

Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant (clinicaltrials.gov) - P1/2 | N=187 | Terminated | Sponsor: Bellicum Pharmaceuticals | Active, not recruiting ➔ Terminated; Sponsor decision

Trial termination • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Anemia • Aplastic Anemia • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics • Primary Immunodeficiency • Sickle Cell Disease • Transplantation • HLA-B • HLA-DQB1 • HLA-DRB1

"BPX-501 = rivo-cel, and we don't talk about rivo-cel! $BLCM https://t.co/GD2migTUdv" (@JacobPlieth)

Successful haplo-identical stem cell transplant after αβTCR+ depletion in a patient with Interferon gamma receptor 1 deficiency (EBMT 2017) - P1/2; "...Her conditioning regimen included busulfan (4 mg/kg/day for 4 days) and cyclophosphamide (50 mg/kg/day for 4 days). Fludaragbne, TLI (900 cGy) . GVH prophylaxis with ATG/Rituximab...To our knowledge, this is the first patient with IFNR1 deficiency transplanted successfully with a haplo-identical donor and alive without any active mycobacterial infection. This report suggests that using a highly immunopotent graft depleted of only aßTCR+ T cells while retaining other immune effectors might offer a potential strategy to engraft these high risk patients using haplo-identical donors thereby allowing access to virtually all patients in need."

Clinical • Biosimilar • Graft versus Host Disease • Immunology

OUTCOME OF CHILDREN WITH WISKOTT-ALDRICH SYNDROME (WAS) GIVEN TCRALPHA-BETA/CD19 DEPLETED HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) FROM AN HLA-HAPLOIDENTICAL RELATIVE (EBMT 2022) - P2 | ">All subjects received a myeloablative conditioning regimen, combining pharmacokinetic-adjusted Busulfan with Thiotepa and Fludarabine. Pre-transplant anti-thymocyte globulins (from day -4 to day -2) were given to modulate bi-directional donor/recipient alloreactivity, while rituximab was administered on day -1 to prevent PTLD... TBdepl-haploHSCT is a highly effective curative option for children with WAS, being characterized by high engraftment rate with fast recovery of both neutrophils and platelets, low incidence of aGvHD and no occurrence of cGVHD. This approach should be offered without delay to those patients with severe WAS who lack a matched donor. Infusion of BPX-501 cells contributes to accelerate the recovery of adaptive T-cell immunity, further increasing the safety of the procedure."

Clinical • Acute Graft versus Host Disease • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Gene Therapies • Graft versus Host Disease • Immunology • Primary Immunodeficiency • Transplantation • CD19

Outcome of Children with Wiskott-Aldrich Syndrome (WAS) Given TCR Alpha-Beta/CD19 Depleted Hematopoietic Stem Cell Transplantation (HSCT) from an HLA-Haploidentical Relative (ASH 2021) - P2 | "All patients received a myeloablative conditioning regimen, combining pharmacokinetic-adjusted busulfan with Thiotepa and Fludarabine. Pre-transplant anti-thymocyte globulins (from day -4 to day -2) were given to modulate bi-directional donor/recipient alloreactivity, while rituximab was administered on day -1 to prevent PTLD...None of these 3 patients required activation of iC9 with rimiducid and no cases of chronic GVHD (cGvHD) were observed...Given the prognostic impact of age in determining HSCT outcome in WAS and prompt availability of haploidentical family donors, our data suggest that this approach should be offered without delay to those patients with WAS who lack a matched donor. Infusion of BPX-501 cells contribute to accelerate the recovery of adaptive T-cell immunity, further increasing the safety of the procedure."

Clinical • Acute Graft versus Host Disease • Atopic Dermatitis • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Dermatology • Gene Therapies • Graft versus Host Disease • Hematological Disorders • Immunology • Infectious Disease • Oncology • Pediatrics • Primary Immunodeficiency • Thrombocytopenia • Transplantation • Vasculitis • CD19

Identification of Dual Positive CD19+/CD3+ T Cells in an Apheresis Product Undergoing Chimeric Antigen Receptor (CAR) Transduction (ASH 2019) - P2; "We subsequently treated the apheresis product with Rimiducid in vitro and observed elimination of the CD19+/CD3+ cell subset in a dose dependent manner, thus confirming that these cells were BPX-501 cells (Fig 1b). We aim to bring attention to this cell phenotype that may be recognized with greater frequency as CAR T therapy and engineered α/Β haplo-HSCT are increasingly coupled. We additionally suggest consideration towards using alternative markers to CD19 as a synthetic identifier for post-transplant add-back products, as CD19-expression on effector T cells may complicate subsequent treatment using CD19-directed therapy."

CASP9 • CD8

Administration of BPX-501 Cells Following Αβ- T and B-Cell-Depleted HLA-Haploidentical HSCT in Children with Fanconi Anemia (ASH 2018) - P2; "The polyclonal nature of the BPX-501 provides broad virus and tumor-specific immunity, while the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid which induces dimerization and activation of iC9, inducing apoptosis of BPX-501. Conclusion These data indicate that the adoptive transfer of BPX-501 following αβ-T and B-cell depleted haplo-HSCT represents a novel and highly effective transplantation strategy for pediatric patients with FA. Further, despite the addition of BPX-501, low rates and severity of both acute and chronic GvHD was observed, a finding that could translate into significant long-term benefit, in terms of reduction of squamous cell carcinoma a well-known complication occurring in FA patients after HSCT."

Clinical • Anemia • Biosimilar • Graft versus Host Disease • Hematological Disorders • Immunology • Oncology • Transplantation

Characterization of Allogeneic T Cells Expressing Inducible Caspase-9 Following Adoptive Transfer in Children Receiving an HLA-Haploidentical Hematopoietic Stem Cell Transplant for the Treatment of Myeloid Malignancies (ASH 2018) - P2; "To leverage the anti-tumor effects of allogeneic polyclonal T cells while minimizing GvHD, we have genetically modified donor T cells with the inducible caspase-9 (iC9) safety switch, which induces apoptosis following exposure to the small molecule ligand rimiducid. Summary: Allogeneic T cells engineered with the iC9 safety switch engraft, expand and demonstrate long-term persistence following adoptive transfer into patients receiving a haplo-HSCT. LAA-specific T cells and alloreactive T cells within the BPX-501 product are detectable in the peripheral blood following infusion and likely contribute to elimination of myeloid malignancies."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Biosimilar • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Administration of Rimiducid Following Haploidentical BPX-501 Cells in Children with Malignant or Non-Malignant Disorders Who Develop Graft-Versus-Host-Disease (GvHD) (ASH 2018) - P2; "...Aims To evaluate the safety and efficacy of rimiducid in the treatment of GvHD following administration of BPX-501 T cells in pediatric patients with malignant or non-malignant disorders given an αβ T-cell receptor and B-cell depleted haplo-HSCT...The conditioning regimens varied according to the original disease and were Treosulfan-based (14.9%), Busulfan-based (28.9%), TBI-based (34.9%) or other (19.3%)...Conclusion These data suggest that administration of rimiducid for treatment of steroid-refractory GvHD represents a novel and highly effective treatment approach in pediatric patients with non-malignant or malignant disorders who received a αβ-T-cell and B-cell depleted haplo-HSCT followed by infusion of BPX-501 cells. The administration of rimiducid in children given BPX-501 T cells allows for effective control of GvHD occurring after the adoptive transfer of genetically modified T cells."

Clinical • Biosimilar • Graft versus Host Disease • Immunology • Transplantation

Administration of BPX-501 Following Αβ-T and B-Cell Depleted Haplo-HSCT in Children with Transfusion-Dependent Thalassemia (ASH 2018) - P2; "...The polyclonal nature of the BPX-501 provides broad virus and tumor-specific immunity, while the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid which induces dimerization and activation of iC9, inducing apoptosis of BPX-501...The majority (83.3%) of patients received a busulfan-based conditioning regimen...Conclusion An αβ-T and B-cell depleted haplo-HSCT followed by infusion of BPX-501 is a suitable and effective option for children with transfusion-dependent b-thalassemia major lacking an HLA-identical donor. The low cumulative incidence of TRM and the absence of severe aGvHD or chronic GvHD observed support further study in this patient population."

Clinical • Biosimilar • Gene Therapies • Graft versus Host Disease • Immunology • Transplantation

Umbilical & Cord Blood (CB) Derived CAR-Engineered NK Cells for B Lymphoid Malignancies (clinicaltrials.gov) - P1/2 | N=44 | Completed | Sponsor: M.D. Anderson Cancer Center | Active, not recruiting ➔ Completed | Trial completion date: Jun 2024 ➔ Mar 2023 | Trial primary completion date: Jun 2023 ➔ Mar 2023

Trial completion • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • IL15

Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant (clinicaltrials.gov) - P1/2 | N=187 | Active, not recruiting | Sponsor: Bellicum Pharmaceuticals | Phase classification: P2 ➔ P1/2

Phase classification • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Anemia • Aplastic Anemia • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics • Primary Immunodeficiency • Sickle Cell Disease • Transplantation • HLA-B • HLA-DQB1 • HLA-DRB1

THE USE OF BPX-501 DONOR T CELL INFUSION (WITH INDUCIBLE CASPASE 9 SUICIDE GENE) TOGETHER WITH HLA-HAPLOIDENTICAL STEM CELL TRANSPLANT TO TREAT CHILDREN WITH HEMOGLOBINOPATHIES AND ERYTHROID DISORDERS (EHA 2017) - P1/2; "...Conditioning regimen included busulfan, thiotepa and fludarabine...These data suggest that Haplo-HSCT combined with infusion of BPX-501 T cells with a suicide gene may be a safe and curative option for children with hemoglobinopathies and ED who lack a matched donor. Infusion of gene modified T cells with an inducible suicide mechanism, combined with selective αβ T-cell depletion, offers the potential to rapidly reverse GvHD and eliminate the need for the use of GvHD prophylaxis. Additionally, this approach results in rapid hematological and immune reconstitution for Haplo-HSCT recipients."

Biomarker • Clinical • Biosimilar • Gene Therapies • Graft versus Host Disease • Hematological Malignancies

Donor T Cells Genetically Modified with a Novel Suicide Gene (inducible Caspase 9, iC9) Expand and Persist over Time after Post-Allograft Infusion in Patients Given αβ T-Cell and B-Cell Depleted HLA-Haploidentical Allogeneic Stem Cell Transplantation (αβ haplo-HSCT) Contributing to Accelerate Immune Recovery (ASH 2017) - P2; "...Six patients given Rimiducid, the agent activating iC9, were censored at time of drug infusion... Our results indicate that BPX-501 cells infused after αβ haplo-HSCT expand in vivo and persist over time, contributing to fasten adaptive immunity recovery. Their peak of expansion is reached at 9 months after the allograft, but they are consistently detected also at 2 years after infusion. CMV reactivation is the main driver of BPX-501 cell expansion, this finding suggesting that BPX-501 cells cooperate to the viral clearance."

Biosimilar • Cytomegalovirus Infection • Graft versus Host Disease • Leukemia

Long Term Follow-up Study for Patients Enrolled on the BP-004 Clinical Study (clinicaltrials.gov) - P1/2 | N=193 | Active, not recruiting | Sponsor: Bellicum Pharmaceuticals | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Anemia • Aplastic Anemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics • Primary Immunodeficiency • Sickle Cell Disease

Bellicum Reports First Quarter 2022 Financial Results and Provides Operational Update (GlobeNewswire) - "R&D Expenses: Research and development expenses were $4.5 million for the first quarter 2022, compared to $6.5 million for the first quarter 2021. The decrease in R&D expenses for the first quarter 2022 was primarily due to reduced expenses related to rivo-cel activities, a discontinued development program."

Commercial • Acute Graft versus Host Disease • Graft versus Host Disease

Administration of BPX-501 Cells Following Αβ T and B-Cell-Depleted HLA-Haploidentical HSCT (haplo-HSCT) in Children with Malignant or Non-Malignant Disorders (ASH 2018) - P2; "Despite the addition of BPX-501, overall rates of GvHD were low with few cases of high-grade aGvHD or cGvHD. Rimiducid was shown to be an effective treatment for patients who developed steroid-refractory GvHD."

Clinical • Biosimilar • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplantation