rimiducid (AP1903) / Bellicum - LARVOL DELTA

A nucleic acid sensing system for selective therapeutic protein expression in breast cancer (SABCS 2025) - "Transfection of both linear and gap fusion-targeting sensors into MCF7 cells and subsequent treatment with iCaspase9 inducer drug AP1903 resulted in a significant reduction in cell viability (up to 84% 36-hours post sensor transfection vs. non-targeting controls, p < 0.0001)... This study demonstrates the successful design and in vitro proof-of-principle of a biomolecule sensing system that selectively triggers a therapeutic protein effector in the presence of a cancer-specific nucleic acid. These findings have the potential to establish a novel therapeutic paradigm-in which an RNA medicine can repurpose cancer-defining nucleic acid sequences into a targeted, modular, and precise cell-killing mechanism. Our ongoing efforts focus on optimizing sensor design, interrogating mechanisms of sensor-mediated cell killing with diverse protein payloads, and addressing challenges of in vivo delivery."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ADAR • ER • FGFR • HER-2 • NTRK • SOX9 • SULF2

Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: UNC Lineberger Comprehensive Cancer Center | Recruiting ➔ Active, not recruiting | N=30 ➔ 19 | Trial completion date: Mar 2043 ➔ Jul 2040 | Trial primary completion date: Mar 2027 ➔ Aug 2025

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Classical Hodgkin Lymphoma • Follicular Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • ALK • BCL2 • BCL6 • IRF4

P-BCMA-ALLO1-001: P-BCMA-ALLO1 Allogeneic CAR-T Cells in the Treatment of Subjects With Multiple Myeloma (clinicaltrials.gov) - P1 | N=275 | Recruiting | Sponsor: Poseida Therapeutics, Inc. | Trial completion date: Dec 2039 ➔ Mar 2042 | Trial primary completion date: Dec 2027 ➔ Mar 2029

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

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

Potent and Effective Targeting of AML with 'Off-the-Shelf' Engineered CD45-Targeting CAR T-Cells (ASH 2024) - "To prevent targeting of donor HSCs by residual DKO CD45CAR T-cells during SCT, we incorporated an iCaspase9 suicide gene and showed that DKO CD45CAR T-cells were efficiently deleted by treatment with Rimiducid in vitro...Moreover, generating DKO CD45CAR T-cells from an allogeneic healthy donor will enhance CAR T-cell fitness and allows a bank of "off-the-shelf" CAR T-cells to be used for multiple patients, reducing complexity and cost. Based on these data we are now planning to test this approach in a clinical study where DKO CD45CAR T-cells will be used as adjunctive immunotherapy prior to SCT in adult patients with ELN high risk AML."

CAR T-Cell Therapy • IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Oncology • CD123 • CD33 • IL3RA • PTPRC

Genetic screens to identify novel functional modules for a NOT gate (SITC 2025) - "The functional screen platform was extended to screen for a signal 1 booster that activated T cell signaling in the presence of a small molecule (rimiducid)...Following the functional screen in Jurkat cells, a more complex booster library of ~100,000 variants was designed and screened directly in primary T cells to identify variants with proliferative and/or survival advantage.Conclusions The screening system described here identifies active blockers and boosters from large libraries of variants. Its throughput is sufficient to generate datasets to train machine learning models to help predict and optimize behavior of logic-gated cell therapeutics."

Oncology

Development of rejection resistant allogeneic CAR-NKT cell therapy for CD19-positive B cell malignancies (SITC 2025) - P1 | "The iC9 switch did not significantly decrease ADR+NKT expansion and mediated effective apoptosis of ADR+ cells within 24hrs of rimiducid administration...Future experiments will use an MHC-KO lymphoma mouse model to identify a CAR+ADR.NKT product with optimal in vivo persistence and resistance to allo-rejection. Results will inform the development of off-the-shelf NKT products for immunotherapy of B-cell malignancies and other types of cancer."

Hematological Malignancies • Lymphoma • Oncology • IL15

Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL (clinicaltrials.gov) - P1/2 | N=17 | Active, not recruiting | Sponsor: UNC Lineberger Comprehensive Cancer Center | Trial completion date: Aug 2040 ➔ Sep 2037 | Trial primary completion date: Dec 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • CD19

Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL (clinicaltrials.gov) - P1/2 | N=17 | Active, not recruiting | Sponsor: UNC Lineberger Comprehensive Cancer Center | Recruiting ➔ Active, not recruiting | N=54 ➔ 17 | Trial completion date: Apr 2041 ➔ Aug 2040 | Trial primary completion date: Apr 2026 ➔ Dec 2025

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • CD19

A Phase I Study of Autologous CAR-T Cells Targeting the B7-H3 Antigen and Containing the Inducible Caspase 9 Safety Switch in Subjects with Refractory Pancreatic Ductal Adenocarcinoma (PDAC) Free (AACRPanCa 2025) - "Fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2, administered intravenously (IV), is used as a conditioning regimen, and rimiducid is used to activate the iCas9 safety switch as needed...Although two patients experienced grade 3 CRS requiring tocilizumab, they did not require treatment with rimiducid...ConclusionsThe use of iC9-CAR.B7-H3 T cells therapy in patients with refractory PDAC is safe at DL1. Continued dose escalation and longitudinal follow-up are ongoing to determine the safety, tolerability, recommended dose and early evidence of efficacy.""

CAR T-Cell Therapy • Clinical • IO biomarker • P1 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD276

Phase 2 Trial of CD70.CAR NK Cells for Patients With Primary Refractory or Early Relapsed Diffuse Large B-Cell Lymphoma and Hodgkin Lymphoma (clinicaltrials.gov) - P2 | N=100 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

New P2 trial • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/phase 2 trial. (PubMed, Nat Med) - P1/2 | "Grade 3 immune effector cell-associated neurotoxicity syndrome was diagnosed in four children and rapidly controlled with the activation of the inducible caspase-9 suicide gene by rimiducid. These results confirm that GD2-CART01 can induce durable remissions in children with high-risk metastatic, relapsed, or refractory neuroblastoma. ClinicalTrials.gov identifier: NCT03373097 ."

Journal • P1 data • P2 data • Neuroblastoma • Oncology • Solid Tumor

Side_by_Cide: T Lymphocytes (LT) Expressing iCASP9 and ΔCD19 in Allogeneic Haematopoietic Transplantation. (clinicaltrials.gov) - P1/2 | N=2 | Terminated | Sponsor: Centre Hospitalier Universitaire de Besancon | N=12 ➔ 2 | Unknown status ➔ Terminated; not enough recruitment because of new therapeutic alternatives

Enrollment change • Trial termination • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Chronic Myeloid Leukemia • Graft versus Host Disease • Hematological Malignancies • Hodgkin Lymphoma • Immunology • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • Transplantation

T-Cell Therapy for Advanced Breast Cancer (clinicaltrials.gov) - P1 | N=186 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • HER-2 • MSLN • PD-L1

ROR1-Specific CAR T-Cells: Advancing Targeted Immunotherapy for Cancer (EACR 2025) - "Anti-ROR1 CAR T-cells showed a significant inhibitory rate against multiple targets, indicating that the new approach could be considered for further in vivo evaluations."

CAR T-Cell Therapy • IO biomarker • Breast Cancer • Colorectal Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Mantle Cell Lymphoma • Melanoma • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP9 • ROR1

A Study to Evaluate the Safety, Tolerability, Cellular Kinetics, Pharmacodynamics, and Efficacy of P-CD19CD20-ALLO1 in Participants With Severe, Treatment-refractory Systemic Lupus Erythematosus (SLE) (clinicaltrials.gov) - P1 | N=162 | Not yet recruiting | Sponsor: Genentech, Inc.

New P1 trial • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Enhancing Liver DNA Delivery with a Fully Non-Viral Multifunctional LNP Approach for In Vivo Transposon-Mediated Genomic Integration of Large DNA Cargo (ASGCT 2025) - "Subsequent IV doses of rimiducid (0.001–1.0 mg/kg) reduced hFVIII to between 31% and ~1% of normal, dose-dependently, with no hepatotoxicity. The non-viral platform presented here may enable a safer, tunable, and durable solution for genetic medicines with broad applicability for rare and non-rare diseases. Disease Focus of Abstract:None"

Preclinical • Genetic Disorders • Inflammation • Rare Diseases • CASP9

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

P-FVIII-101 is a Non-viral Genetic Medicine with the Potential for Controlled Modulation of FVIII Transgene Expression to Match Patient Needs (ASGCT 2025) - "The standard of care for patients with severe hemophilia A (HemA) has dramatically improved in recent decades with the advent of prophylactic bispecific antibodies such as emicizumab...Delivery of small molecule rimiducid induces activation of iCasp9 in transduced cells triggering their death...Future preclinical studies will further explore the tunability of these systems to deliver tailored therapeutic levels that provide a durable solution for FVIII restoration in HemA patients. Disease Focus of Abstract:Hemophilia"

Clinical • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Pain • Pediatrics • Rare Diseases

Functional screen to optimize logic gate potency and selectivity (AACR 2025) - "In another set of experiments, a library of almost 30,000 variants of a signal 1 booster that activate signaling in the presence of a small molecule (rimiducid) was screened. The screening system described here identifies active blocker receptors and boosters from large libraries of variants. Its throughput is sufficient to generate large datasets and train machine learning models to better predict and optimize the function and control of logic-gated cell therapeutics."

Oncology

Mantle Cell Lymphoma in sight: development of anti-ROR1 CAR T-cell therapy, andenhancement of its safety profile by iCasp9 suicidal gene expression (ITOC 2025) - "AP1903 was used to activate the iCasp9 system, and fluorescence microscopy was used for apoptosis markers investigation...While the engineered CAR T-cells showed limited efficacy against MCL in terms of cytotoxicity, the successful integration and activation of the iCasp9 suicide gene highlight its utility in mitigating side effects by enabling CAR T-cell depletion. Future efforts will focus on perfecting the CAR design and conducting more in vitro and in vivo studies."

CAR T-Cell Therapy • Clinical • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CASP9 • ROR1

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

THE USE OF ICASP9 SUICIDE GENE IS INCREASING THE SAFETY PROFILE OF ANTI ROR1 CAR T CELLS IN MANTLE CELL LYMPHOMA (EBMT 2025) - "Flow cytometry with 7-amino actinomycin D and PO-PRO1 staining solutions was conducted, using LSRII/Fortessa flow cytometer...Time of dosing AP1903 has a direct correlation with how many CAR T-cells die, with close to all undergoing apoptosis within the first hour... The novel anti ROR1 CAR T cells have limited inhibitory effect against MCL. Moreover, it was noted that mCherry expression decreased in subsequent passages, which may limit the utility of using this suicide gene in the clinical setting. Further tests will undergo to determine the efficacy of the CAR construct when killing tumor cells."

CAR T-Cell Therapy • Clinical • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • CASP9 • IL6 • ROR1 • TNFA

P-MUC1C-ALLO1-001: P-MUC1C-ALLO1 Allogeneic CAR-T Cells in the Treatment of Subjects with Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=180 | Active, not recruiting | Sponsor: Poseida Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • Colorectal Cancer • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatology • Lung Cancer • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

P-PSMA-101 CAR-T Cells in the Treatment of Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC) and Advanced Salivary Gland Cancers (SGC) (clinicaltrials.gov) - P1 | N=40 | Terminated | Sponsor: Poseida Therapeutics, Inc. | N=60 ➔ 40 | Trial completion date: Sep 2036 ➔ Sep 2024 | Active, not recruiting ➔ Terminated; Study closed

Enrollment change • Trial completion date • Trial termination • Adenoid Cystic Carcinoma • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Salivary Gland Cancer • Solid Tumor • Squamous Cell Carcinoma • Urology