CARCIK-CD19 / CoImmune - LARVOL DELTA

Role of Microenvironment in Influencing the Activity of CD19 CAR T Cells in B-Cell Precursor Acute Lymphoblastic Leukemia (B-ALL) (ASH 2023) - P1/2 | " We conducted an academic phase I/II study (NCT03389035) with donor-derived anti-CD19 CAR T cells generated with Sleeping Beauty transposon (CARCIK-CD19) in B-ALL patients relapsed after alloHSCT... Through sc-RNAseq and spectral flow cytometry, we have characterized changes in the BM TME after CAR T cell therapy. Specifically, CAR T cells-mediated myeloid activation is associated with pathways of immune dysregulation that may dampen CAR T cell expansion and antagonize the effects of the therapy. Furthermore, these data support the hypothesis that transcriptomic interrogation can infer pathways relevant to the communication between CAR T cells and the TME."

CAR T-Cell Therapy • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD4 • CD8

Cord Blood-Derived Carcik Cells As Off-the-Shelf Non-Viral Cell Therapy for Hematological Malignancies (ASH 2024) - "Our work has proven feasibility and safety of using Peripheral Blood (PB) healthy donor cells to generate CARCIK-CD19 cells1...Metabolic and transcriptomic analyses revealed that CB-CARCIK cells exhibit a lower glycolytic score and a higher memory score compared to those derived from peripheral blood (PB), indicating advantageous CAR T cell characteristics. Furthermore, we established the scalability of a GMP-grade manufacturing process for deriving CARCIK cells from CB, enabling the production of readily available, banked, third-party CARCIK cells for treating hematological malignancies."

IO biomarker • Gene Therapies • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • IL15 • IL2 • IL7 • NCAM1

CD19 CAR T Cells Drive a Remodeling of the Immune Microenvironment Associated with T-Cell Dysfunction in Acute Lymphoblastic Leukemia (ASH 2024) - P1/2, P2 | "Data in this study were generated from patients enrolled in the FT01CARCIK Phase I/IIb clinical trial (NCT03389035), in the FT03CARCIK Phase II study (NCT05252403) or who received autologous CAR T cells as part of a Phase I/II trial or commercial cell therapy...Conclusions This study highlights the critical role of the tumor microenvironment on CAR T-cell fate and endogenous immunity in B-ALL. We demonstrate that IFN response, hypoxia, and TGF-β signaling lead to general immune suppression after treatment, resulting in endogenous T-cell exhaustion and compromising CAR T-cell efficacy."

CAR T-Cell Therapy • IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • CD4 • CD8 • HIF1A • PD-1 • TGFB1 • TGFBR2

Remodeling of the Immune Microenvironment influences CD19 CAR T Cell Activity in B Cell Acute Lymphoblastic Leukemia (ESGCT 2024) - P1/2 | "Our group performed an academic phase I/II study (NCT03389035) with donor-derived anti-CD19 CAR T cells generated with Sleeping Beauty transposon in patients with B-ALL relapsed after allogeneic hematopoietic stem cell transplantation...Using the same tool, we observed that myeloid cells induced significant signalling in both CAR T cells and endogenous T cells.We have characterized changes in BM TME after CAR T infusion. CAR T cells-mediated myeloid activation is associated with pathways of immune dysregulation that may dampen CAR T cell expansion and antagonize the effects of the therapy."

CAR T-Cell Therapy • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • CD4 • CD8

ACQUISITION OF AN IMMUNOSUPPRESSIVE MICROENVIRONMENT AFTER CD19 CAR T CELL TREATMENT IS ASSOCIATED WITH T-CELL DYSFUNCTION AND RESISTANCE IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2025) - P1/2, P2 | "Our group performed phase 1 and 2 academic studies (NCT03389035 and NCT05252403) with donor-derived anti-CD19 CAR T cells generated with Sleeping Beauty transposon in patients with B-ALL relapsed after allogeneic hematopoietic stem cell transplantation... In conclusion, excessive CAR T-cell-mediated myeloid activation is associated with pathways of immune dysregulation that may antagonize the effects of therapy. Our study highlights the critical role of the tumor microenvironment on CAR T-cell fate and endogenous immunity in B-ALL."

CAR T-Cell Therapy • IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • CD4 • CD8 • HIF1A • PD-1 • TGFB1 • TGFBR2

Efficacy, safety, and biological properties of Sleeping Beauty-engineered CAR T cells in patients with B-cell acute lymphoblastic leukemia (ASGCT 2025) - "To offer a more streamlined and cost-effective approach to achieve stable gene transfer, we utilized Sleeping Beauty transposon to engineer donor-derived anti-CD19 CAR T cells (CARCIK-CD19) for B-ALL patients relapsed after allogeneic hematopoietic stem cell transplantation (alloHSCT)...In conclusion, CAR T cells-mediated myeloid activation is associated with pathways of immune dysregulation that may dampen CAR T cell expansion and antagonize the effects of the therapy. Disease Focus of Abstract:Leukemia"

CAR T-Cell Therapy • Clinical • IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Gene Therapies • Hematological Malignancies • Leukemia • Oncology • CD19 • CD8 • HIF1A • PD-1 • TGFB1 • TGFBR2

Optimized GMP-grade production of non-viral Sleeping Beauty-generated CARCIK cells for enhanced fitness and clinical scalability. (PubMed, J Transl Med) - P1/2 | "Optimizing non-viral CARCIK cell production using G-Rex bioreactors and refined timing adjustments has streamlined the workflow, enhanced cell fitness, and resulted in a highly effective therapeutic product with demonstrated in vivo efficacy in mice. These improvements reduced manipulation and contamination risks, while optimizing logistics and space efficiency, facilitating allogeneic CARCIK generation for a current phase I/II clinical trial (NCT05869279) in patients with R/R CD19 + non-Hodgkin Lymphoma (B-cell NHL) and Chronic Lymphocytic Leukemia (CLL), confirming the approach's scalability and clinical potential."

Journal • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Donor-derived CARCIK-CD19 cells engineered with Sleeping Beauty transposon in acute lymphoblastic leukemia relapsed after allogeneic transplantation. (PubMed, Blood Cancer J) - "These data demonstrated that SB-engineered CAR-T cells are safe and induce durable remission in heavily pretreated patients with BCP-ALL relapsed after alloHSCT. Trial registration: The phase 1/2 and phase II trials are registered at www.clinicaltrials.gov as NCT#03389035 and NCT#05252403."

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

ACQUISITION OF AN IMMUNOSUPPRESSIVE MICROENVIRONMENT AFTER CD19 CAR T CELL TREATMENT IN B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2024) - P1/2 | " Our group performed an academic phase I/II study (NCT03389035) with donor-derived anti-CD19 CAR T cellsgenerated with Sleeping Beauty transposon in patients with B-ALL relapsed after allogeneic hematopoieticstem cell transplantation... We have characterized changes in BM TME after CAR T infusion. CAR T cells-mediatedmyeloid activation is associated with pathways of immune dysregulation that may dampen CAR T cellexpansion and antagonize the effects of the therapy."

CAR T-Cell Therapy • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD4 • CD8

Allogeneic CARCIK-CD19 in Adults/Pediatric B-cell NHL or Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1/2 | N=29 | Recruiting | Sponsor: Fondazione Matilde Tettamanti Menotti De Marchi Onlus | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics • BCL2

IN VIVO LOWER CD4/CD8 CARCIK-CD19 CELL RATIO IS ASSOCIATED WITH EARLY TREATMENT RESPONSE IN PATIENTS WITH RELAPSE/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (EBMT 2024) - P1/2, P2 | "The analysis included 33 patients, 4 of whom were pediatric patients. Circulating CARCIK-CD19 cells peaked in median at day 10 (range, 7-150 days). Median CARCIK-CD19 cell peak was 44.16/"

IO biomarker • Preclinical • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Transplantation • CD4 • CD8 • PD-1

Immunesuppressive Microenvironment Influences CAR-T Cells Activity in B-acute Lymphoblastic Leukemia (EBMT-EHA 2024) - P1/2 | "We have characterized changes in BM TME after CAR T infusion. CAR T cells-mediated myeloid activation is associated with pathways of immune dysregulation that may dampen CAR T cell expansion and antagonize the effects of the therapy. Clinical Trial Registry: NCT03389035 Study Details; Transposon-manipulated Allogeneic CARCIK-CD19 Cells in Pediatric and Adult Patients With r/r ALL Post HSCT; ClinicalTrials.gov"

CAR T-Cell Therapy • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Transplantation • CD4 • CD8

SLEEPING BEAUTY PLATFORM FOR ENGINEERING CAR-CIK CELLS TOWARD A MULTI-TARGETING STRATEGY IN B-ALL (EHA 2023) - "To overcome viral method's limitations in T cell engineering, our group developed an anti-CD19 CAR engineered Cytokine Induced Killer (CIK) cells through a Sleeping –Beauty (SB) trasposon-based platform (CARCIK-CD19)... In this study we demonstrated the efficacy, quality and safety of donor-derived SB-transfected CARCIK-CD22 with a remarkable anti-tumor activity in vitro and in in vivo mice models. Further experiments are ongoing forevaluating the activity of BAFFR CAR T cells in vivo. Overall, we demonstrated the feasibility of CARCIK-CD22 and CARCIK-BAFFR non-viral engineering to be employed in the context of multi-targeting approach to prevent and treat CD19 negative B-ALL relapses."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD4 • CD8 • NCAM1

Allogeneic CARCIK-CD19 in Adults/Pediatric B-cell NHL or Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1/2 | N=29 | Not yet recruiting | Sponsor: Fondazione Matilde Tettamanti Menotti De Marchi Onlus

New P1/2 trial • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics • BCL2

Transposon-manipulated Allogeneic CARCIK-CD19 Cells in Pediatric and Adult Patients With r/r ALL Post HSCT (clinicaltrials.gov) - P1/2 | N=21 | Completed | Sponsor: Fondazione Matilde Tettamanti Menotti De Marchi Onlus | Active, not recruiting ➔ Completed | Trial completion date: Mar 2022 ➔ Dec 2022

Trial completion • Trial completion date • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Transplantation • CD19

Phase I/II Trials with Sleeping Beauty Engineered CAR T Cells of Donor Origin for B-cell Acute Lymphoblastic Leukemia (ASGCT 2023) - P1/2 | "After lymphodepletion with Fludarabine and Cyclophosphamide, patients received a single infusion...Although 10 out of 27 had experienced GvHD after the previous allo-SCT, GvHD never occurred after treatment with CARCIK-CD19...No signs of genotoxicity by transposon insertions could be observed. SB-engineered CAR T cells of donor origin showed an excellent safety profile with anti-leukemia activity in heavily pretreated patients with B-ALL."

CAR T-Cell Therapy • P1/2 data • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Oncology • Transplantation • CD19

Carcik-CD19 Cells Expand In Vivo Toward a CD8+ Memory Phenotype and Their Persistence Is Associated with a Longer Duration of Response (ASH 2022) - P1/2 | "Patients underwent fludarabine and cyclophosphamide-based lymphodepletion, before CARCIK-CD19 infusion. CR was defined as absence of leukemia in the BM at day 28. CARCIK-CD19 peak was defined as the maximum amount of CAR+"

Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD19

Final Results of Phase I/II Study of Donor-Derived CAR T Cells Engineered with Sleeping Beauty in Pediatric and Adult Patients with B-Cell Acute Lymphoblastic Leukemia Relapsed Post-HSCT (ASH 2022) - P1/2 | "After lymphodepletion with Fludarabine (30 mg/m2/day x 4 days) and Cyclophosphamide (500 mg/m2/day x 2 days), patients received a single CARCIK-CD19 infusion. By univariate analysis, EFS was significantly associated with the % of blasts after lymphodepletion (≥ 5% vs <5%) (p=0.0245). Conclusions In this phase I/II dose-finding study, SB-engineered CAR T cells demonstrated an excellent safety profile with anti-leukemia activity in heavily pretreated patients with B-ALL relapsed after HSCT."

CAR T-Cell Therapy • Clinical • P1/2 data • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Oncology • Pediatrics • Transplantation • CD19

Flow Cytometry Detection of CAR-T Cells (EHA-EBMT-CART 2023) - P1/2 | "Peripheral blood samples from patients enrolled in the CARCIK-CD19 clinical trial (Eudract N. 2017-000900-38) were used to assess and compare the stain indexes as well as the sensitivity and specificity of the different assays...This method clearly detected both Tisagenleleucel (Novartis) and Axicabtagene ciloleucel cells (Kite), demonstrating the broad applicability of the method to different CAR-T cells products... Three different CAR detection methods were compared with each other, the two indirect staining assays showed better results. The CD19-his and CD19-bio gave similar results, but CD19-his is more cost-effective compared to CD19-bio. CAR detection with CD19-his was validated with parallel real time PCR data."

CAR T-Cell Therapy • IO biomarker • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD4 • CD8

CoImmune Announces Presentation of Results from Phase I/II Clinical Trial of CARCIK-CD19 in B-Cell Acute Lymphoblastic Leukemia at ASH Annual Meeting and Exposition (PRNewswire) - P1/2 | N=27 | CARCIK (NCT03389035) | "CoImmune...announced the presentation of results from a Phase I/II clinical trial evaluating CARCIK-CD19, an investigational treatment based on the company's chimeric antigen receptor (CAR) modified cytokine induced killer (CIK) cell platform, in pediatric and adult patients with B-cell acute lymphoblastic leukemia (B-ALL) who had relapsed following hematopoietic stem cell transplantation (HSCT). The results are being presented at the American Society of Hematology's (ASH) 64th Annual Meeting and Exposition held December 10-13 in New Orleans....In the two highest dose groups, 16 out of 21 patients (76.2%, 95%CI=52.8-91.8%) achieved CR, with 13 of the responders at the highest dose (81.3%) MRD-negative. The median follow-up was 2.8 years (range, 0.05-4.4 years, last update as of July 2022)."

P1/2 data • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology

Donor-Derived CAR T Cells Engineered with Sleeping Beauty in Pediatric and Adult Patients with Acute Lymphoblastic Leukemia Relapsed Post-HSCT (ASH 2021) - P1/2 | "All patients underwent lymphodepletion with Fludarabine (30 mg/m 2 /day x 4 days) and Cyclophosphamide (500 mg/m 2 /day x 2 days), before proceeding to CARCIK-CD19 infusion. Robust CARCIK-CD19 cell expansion was achieved in most patients and CARCIK-CD19 cells were measurable for up to 22 months. Conclusions SB-engineered CAR T cells induce sustained responses in B-ALL patients relapsed after HSCT irrespective of the donor type and without severe toxicities."

CAR T-Cell Therapy • Clinical • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Pediatrics • Transplantation

IMPACT OF CARCIK-CD19 TUMOR LOAD AND PEAK LOAD IN PATIENTS WITH ACUTE B-CELL LEUKEMIA RELEASED AFTER ALLOGENIC TRANSPLANTATION TREATED WITH CARCIK-CD19 (SIE 2022) - No abstract available

Clinical • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD19

Residual Disease Driven Strategy for CARCIK (CD19) in Adults/Pediatric BCP-ALL (clinicaltrials.gov) - P2 | N=35 | Recruiting | Sponsor: Fondazione Matilde Tettamanti Menotti De Marchi Onlus

New P2 trial • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD19

Transposon-manipulated Allogeneic CARCIK-CD19 Cells in Pediatric and Adult Patients With r/r ALL Post HSCT (clinicaltrials.gov) - P1/2 | N=21 | Active, not recruiting | Sponsor: Fondazione Matilde Tettamanti Menotti De Marchi Onlus | Recruiting ➔ Active, not recruiting | Trial completion date: Apr 2021 ➔ Mar 2022 | Trial primary completion date: Dec 2020 ➔ Mar 2021

Enrollment closed • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Transplantation • CD19

CoImmune Announces Positive Results from Phase 1/2 Clinical Trial of Allogeneic CAR-CIK Cells in Pediatric and Adult Patients with Acute Lymphoblastic Leukemia (GlobeNewswire) - P1/2, N=21; "CoImmune, Inc...announced that results from a Phase 1/2 clinical trial evaluating CARCIK-CD19, an investigational treatment based on the company’s chimeric antigen receptor (CAR) modified cytokine induced killer (CIK) cell platform, demonstrated sustained responses in pediatric and adult patients with B-cell acute lymphoblastic leukemia (B-ALL) who had relapsed after allogeneic hematopoietic stem cell transplantation....Of the 21 patients infused in the multi-center dose-escalation trial, CARCIK-CD19 cells were obtained by HLA-identical sibling (n=6, 29%), matched unrelated (n= 7, 33%), and haploidentical donors (n=8, 38%)."

P1/2 data • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology