CAR-20/19-T Cells / Medical College of Wisconsin, Miltenyi Biotec - LARVOL DELTA

Phase I/II Study of Adaptive Manufactured Lentiviral Anti-CD20/Anti-CD19 Chimeric Antigen Receptor T Cells for Relapsed, Refractory Mantle Cell Lymphoma. (PubMed, J Clin Oncol) - P1/2 | "In conclusion, we demonstrate that on-site adaptive manufactured LV20.19 CAR T cells are feasible, safe, and efficacious for R/R MCL with best ORR of 100%, a favorable safety profile, and few relapses to date."

Journal • P1/2 data • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • Transplantation

LV20.19 CAR T-Cells in Combination With Pirtobrutinib for Relapsed, Refractory B-cell Malignancies (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Medical College of Wisconsin | Not yet recruiting ➔ Recruiting

Enrollment open • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Extranodal Marginal Zone Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Splenic Marginal Zone Lymphoma

PRO00037171: CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell Malignancies (clinicaltrials.gov) - P1/2 | N=100 | Recruiting | Sponsor: Medical College of Wisconsin | Trial completion date: Jan 2025 ➔ Jun 2028 | Trial primary completion date: Jan 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Extranodal Marginal Zone Lymphoma • Follicular Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Primary Mediastinal Large B-Cell Lymphoma • Secondary Central Nervous System Lymphoma • Splenic Marginal Zone Lymphoma • BCL2

Improved Predication of Response and Relapse in Nodal B-Cell Lymphomas with the Use of Ctdna As Compared to Cellular Assays for Measurable Residual Disease (TCT-ASTCT-CIBMTR 2025) - P1/2 | "Improved tools are needed to predict depth of response after novel therapies such as CAR T-cell treatment. We previously identified that the use of cells for MRD performs poorly in predicting clinical response after LV20.19 CAR T-cell therapy among pts with DLBCL and FL. ctDNA assessment may represent an improvement in MRD testing for these pts."

Circulating tumor DNA • Residual disease • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Phase 1 Study of Trispecific Anti-CD20, Anti-CD19, Anti-CD22 (CAR20.19.22) T Cells for Relapsed, Refractory B-Cell Malignancies (ASH 2024) - P1 | "Standard fludarabine/cyclophosphamide lymphodepletion was administered prior to infusion...In terms of safety, two patients had Grade 1 CRS and received tocilizumab for management...From a product characteristic standpoint, CAR20.19.22 T cells had similar cytotoxicity, CD4 : CD8 ratios, CD3 T-cell expansion during manufacture, and transduction efficiency as patients treated with LV20.19 CAR T cells on a prior clinical trial...While preclinical xenograft studies for this vector demonstrated potent in-vivo efficacy, these data demonstrate the importance of human investigation and how manipulations in CAR design can impact construct efficacy. To our knowledge this is the first ICOS CAR administered to humans, and these early findings suggest careful consideration is needed for future CARs dependent on ICOS signaling rather than traditional 41BB or CD28 co-stimulation."

IO biomarker • P1 data • Trispecific • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Burkitt Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD4 • CD8 • ICOS

Cytogenetic Abnormalities Following CAR T Cell Therapy for B-Cell Malignancies (ASH 2024) - P1, P1/2 | "All patients received fludarabine and cyclophosphamide combinations as part of lymphodepletion...Conclusions Cytogenetic abnormalities were common in the bone marrow in patients receiving LV20.19 CAR T cell therapy as part of a clinical trial. However, most findings did not correlate with development of a new hematological malignancy, and others were transient in nature with no clinical consequence. These data demonstrate the importance of long-term follow-up of CAR T cell therapy patients given evolving cytogenetic abnormalities post-treatment."

CAR T-Cell Therapy • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Bone Marrow Transplantation • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology

CAR-20/19-T Cells in Patients With Relapsed/Refractory B Cell ALL (clinicaltrials.gov) - P1 | N=24 | Suspended | Sponsor: Medical College of Wisconsin | Recruiting ➔ Suspended

Trial suspension • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia

Single-cell multimodal functional analysis of bispecific CD20/CD19 chimeric antigen receptor T-cells provides better clinical correlates compared to traditional bulk potency assays (SITC 2024) - P1/2 | "To compare whether the traditional or multimodal assays provide a more accurate depiction of how these cells behave after administration to patients with NHL, we compared the functional readouts from the assays and determined which parameters were associated with clinical response using LV20.19 CAR-Ts from 6 subjects enrolled in an ongoing clinical trial (NCT04186520) at the Medical College of Wisconsin...All operations were under principles of Good Clinical Practice with established Standard Operating Procedures and protocols for sample receipt, processing, freezing, and analysis. Samples are de-identified for compliance with HIPAA rules."

CAR T-Cell Therapy • Clinical • Hematological Malignancies • Lymphoma • Oncology • CD20 • CD4

Combination of Pirtobrutinib and Lentiviral Transduced Bispecific Anti-CD20/CD19 (LV20.19) CAR T-Cell Therapy to Improve Outcomes in Patients With Relapsed/Refractory Lymphoma (SOHO 2024) - P1, P1/2 | "These data represent the largest experience of pirtobrutinib prior to CAR-T apheresis and demonstrate that pirtobrutinib can be safely used as a bridge to LV20.19 CAR-T without negatively impacting their immunophenotype and potentially improving functionality. These data support our planned phase 1 clinical trial to assess the safety of pirtobrutinib as bridging and maintenance therapy with LV20.19 CAR T-cell therapy (NCT05990465)."

CAR T-Cell Therapy • Clinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • CD4 • CD8

Combination of pirtobrutinib and lentiviral transduced bispecific anti-CD20/CD19 (LV20.19) CAR T-cell therapy to improve outcomes in patients with relapsed/refractory lymphoma. (ASCO 2024) - P1, P1/2 | "These data represent the largest experience of pirto prior to CAR-T apheresis and demonstrate that pirto can be safely used as a bridge to LV20.19 CAR-T without negatively impacting their immunophenotype and potentially improving functionality. These data support our planned phase 1 clinical trial to assess the safety of pirto as bridging and maintenance therapy with LV20.19 CAR-T (NCT05990465)."

CAR T-Cell Therapy • Clinical • Complement-mediated Rare Disorders • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Novel Coronavirus Disease • Oncology • CD4 • CD8

PRO00037171: CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell Malignancies (clinicaltrials.gov) - P1/2 | N=100 | Recruiting | Sponsor: Medical College of Wisconsin | Trial completion date: Dec 2025 ➔ Jan 2025 | Trial primary completion date: Dec 2025 ➔ Jan 2025

CAR T-Cell Therapy • Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

LV20.19 CAR T-Cells in Combination With Pirtobrutinib for Relapsed, Refractory B-cell Malignancies (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: Medical College of Wisconsin | Trial completion date: Feb 2025 ➔ Jul 2027 | Initiation date: Apr 2024 ➔ Jul 2024 | Trial primary completion date: Nov 2024 ➔ Jul 2026

CAR T-Cell Therapy • Combination therapy • Trial completion date • Trial initiation date • Trial primary completion date • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Phase 1 Trial of LV20.19 CAR T-Cells for Relapsed, Refractory CLL and Richter's Transformation (TCT-ASTCT-CIBMTR 2024) - P1/2 | "12 pts (86%) had disease progression on covalent BTKi and venetoclax...In terms of safety, 100% (n=14) developed CRS and 93% (n=13) required tocilizumab...Six (66%) IEC-HS pts required anakinra for management... While LV20.19 CAR T cells were efficacious in CLL and RT it was limited by high rates of IEC-HS especially among CLL pts, a phenomena not commonly seen with other histologies. With two DLTs in the CLL cohort, the dose for future CLL pts was reduced to 1x10e6 cells/kg. Additional studies are needed to understand how CLL biology drives CAR IEC-HS."

CAR T-Cell Therapy • P1 data • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Immunology • Oncology • Rare Diseases • Richter's Syndrome • TP53

Fresh Versus Cryopreserved LV20.19 CAR T-Cell Therapy for Relapsed, Refractory DLBCL and Follicular Lymphoma (TCT-ASTCT-CIBMTR 2024) - P1/2 | "Cryopreservation of LV20.19 CAR T-cell therapy had no meaningful impact on ORR, DOR, toxicity profile, time to CRS, or in-vivo expansion. Although fresh products facilitate shorter time from apheresis to infusion, cryopreservation may allow for rapid advancement of products to multicenter trials and licensure."

CAR T-Cell Therapy • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

Adaptive Manufacturing of LV20.19 CAR T-Cells for Relapsed, Refractory Mantle Cell Lymphoma (ASH 2023) - P1/2 | "Fludarabine/cyclophosphamide lymphodepletion was started during MF to facilitate fresh infusion in eligible pts...Both received only a single dose of intrathecal hydrocortisone (no systemic steroids) with resolution of neurotoxicity within 24 hours of administration... Bispecific LV20.19 CAR T-cells with adaptive MF process is feasible, safe, and efficacious for R/R MCL with ORR 100%, no Grade 3+ CRS and low rates of Grade 3+ ICANS (12%). Adaptive MF enriched the final product with higher percentages of T-SCM/T-CM CAR cells and allowed most pts to receive CAR-T cells within 8 days of apheresis. Dual targeting of CD20 and CD19 with CAR-T cells may improve outcomes in pts with relapsed, refractory MCL."

CAR T-Cell Therapy • IO biomarker • Hematological Malignancies • Infectious Disease • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Novel Coronavirus Disease • Oncology • Septic Shock • CD4 • TP53

LV20.19 CAR T-Cells in Combination With Pirtobrutinib for Relapsed, Refractory B-cell Malignancies (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: Medical College of Wisconsin | Initiation date: Oct 2023 ➔ Feb 2024

Trial initiation date • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

LV20.19 CAR T-Cells in Combination With Pirtobrutinib for Relapsed, Refractory B-cell Malignancies (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: Medical College of Wisconsin

CAR T-Cell Therapy • Combination therapy • New P1 trial • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

CAR-20/19-T Cells in Patients With Relapsed/Refractory B Cell ALL (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Medical College of Wisconsin | Trial completion date: Feb 2024 ➔ Jun 2026 | Trial primary completion date: Oct 2023 ➔ Jun 2025

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia

RESULTS FROM A PHASE 1/2 STUDY OF TANDEM, BISPECIFIC ANTI-CD20/ANTI-CD19 (LV20.19) CAR T-CELLS FOR MANTLE CELL LYMPHOMA (EHA 2023) - P1/2 | "After safety run-in, we opened a 14-patient single stage Phase II MCL arm with flexible 8/12-day manufacturing (MF) and goal of fresh infusion with a target complete response (CR) rate of 50% to exceed the historical CR rate of Ibrutinib in R/R MCL of 20%...Eleven of 14 pts (79%) progressed on a Bruton's Tyrosine Kinase inhibitor (BTKi) and 5 (36%) of these pts also progressed on a non-covalent BTKi (pirtobrutinib) administered on a clinical trial...Bispecific LV20.19 CAR T-cells expanded with IL7/IL15 and manufactured onsite are safe and efficacious for R/R MCL with a day 90 ORR of 100%, and only one relapse to date with a median follow-up of nearly 2-years. Toxicity profile was encouraging with no Grade 3+ CRS and low rates of Grade 3+ ICANS. Dual targeting of CD19 and CD20 with CAR-T cells may improve outcomes in pts with R/R MCL."

CAR T-Cell Therapy • IO biomarker • P1/2 data • Hematological Disorders • Hematological Malignancies • Immune Modulation • Infectious Disease • Lymphoma • Mantle Cell Lymphoma • Oncology • Septic Shock • IL15 • IL7

PRO00037171: CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell Malignancies (clinicaltrials.gov) - P1/2 | N=100 | Recruiting | Sponsor: Medical College of Wisconsin | N=65 ➔ 100 | Trial primary completion date: Dec 2023 ➔ Dec 2025

CAR T-Cell Therapy • Enrollment change • Trial primary completion date • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

Results from a Phase 1/2 Study of Tandem, Bispecific Anti-CD20/Anti-CD19 (LV20.19) CAR T-Cells for Mantle Cell Lymphoma (ASH 2022) - P1/2 | "Bispecific LV20.19 CAR T-cells expanded with IL7+15 are safe and efficacious for R/R MCL with ORR 100%, no relapses with a median follow-up of >1.5 years, and no Grade 3+ CRS and low rates of Grade 3+ ICANS (10%). All pts on the Phase II arm had CAR T-cells manufactured on-site utilizing an 8-day platform with fresh CAR T-cell infusion and lymphodepletion starting during manufacturing. Dual targeting of CD19 and CD20 with CAR-T cells may improve outcomes in pts with relapsed, refractory MCL."

CAR T-Cell Therapy • IO biomarker • P1/2 data • Hematological Malignancies • Immune Modulation • Infectious Disease • Inflammation • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Septic Shock • Transplantation • CD19 • IL15 • IL7

Results from a Phase 1/2 Study of Tandem, Bispecific Anti-CD20/Anti-CD19 (LV20.19) CAR T-Cells for Mantle Cell Lymphoma (TCT-ASTCT-CIBMTR 2023) - P1/2 | "Nine of 11 pts had progressed on a Bruton’s Tyrosine Kinase inhibitor (BTKi) and 4 of these pts had also progressed on a non-covalent BTKi (pirtobrutinib) administered on a clinical trial (Table 1). Bispecific LV20.19 CAR T-cells expanded with IL7/IL15 are safe and efficacious for R/R MCL with an ORR of 100%, no relapses with a median follow-up of >1.5 years, no Grade 3+ CRS, and low rates of Grade 3+ ICANS (9%). All pts on the Phase II arm had CAR T-cells manufactured on-site in 8 days with fresh CAR T-cell infusion and lymphodepletion starting during MF. Dual targeting of CD19 and CD20 with CAR-T cells may improve outcomes in pts with R/R MCL."

CAR T-Cell Therapy • IO biomarker • P1/2 data • Hematological Malignancies • Immune Modulation • Infectious Disease • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Septic Shock • CD19 • IL15 • IL7

Bispecific Anti-CD20/Anti-CD19 (LV20.19) CAR T-Cells for Richter’s Transformation (TCT-ASTCT-CIBMTR 2023) - P1, P1/2 | "At time of RT diagnosis, all patients received R-CHOP chemotherapy as frontline management. Bispecific LV20.19 CAR T-cell therapy resulted in robust early and durable responses in patients with heavily pre-treated CLL and RT. To date, there is limited data on outcomes for RT with CAR T-cell therapy. Given historical outcomes, bispecific LV20.19 CAR T cells offer a promising strategy for R/R RT."

CAR T-Cell Therapy • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • IL15 • IL2 • IL7

Single Cell Cytokine Analyses of Bispecific, Tandem, Anti-CD20, Anti-CD19 CAR T-Cells from Patients with Relapsed, Refractory B-Cell Malignancies (ASH 2022) - P1, P1/2 | "There were 15 patients in the IL-2 trial and 22 patients in the IL-7+15 trial with adequate LV20.19 CAR T-cells for analysis. For cells expanded in IL-7+15 vs IL-2, the global PFA was 53.14% vs 40.12%, p=0.01, CD8 PFA was 51.15% vs 41.24% p=0.01, while the CD4 PFA was 55.05% vs 46.23%, p=0.08, (Figure 1A). Similarly, the global PSI was 1508 vs 956 p=0.0003, CD8 PSI was 1333 vs 865 p=0.0009, and CD4 PSI was 1580 vs 865, p<0.0001."

CAR T-Cell Therapy • Clinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD4 • CD8 • CSF2 • GZMB • IFNG • IL15 • IL2 • IL7

Manufacturing Bispecific LV20.19 CAR T-Cells with IL-7 & IL-15 for a Shorter Duration Improves CAR T-Cell Immunophenotype While Maintaining Target Cell Dose (ASH 2021) - P1/2 | "Given the composition of CAR-T products has been shown to impact anti-tumor efficacy, this suggests that manufacturing bispecific CAR T-cells in IL7+15 for a shorter duration could lead to greater clinical efficacy without negatively impacting attainment of cell dose. Clinical outcomes of 8- vs 12-day manufactured IL-7+15 expanded LV20.19 CAR T-cells will be reported separately."

CAR T-Cell Therapy • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • HAVCR2 • IL15 • IL2 • IL7 • LAG3 • PD-1