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1024 Adaptive Manufacturing of LV20.19 CAR T-Cells for Relapsed, Refractory Mantle Cell Lymphoma

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: CAR-T Cell Therapies for Multiple Myeloma and B Cell Lymphomas
Hematology Disease Topics & Pathways:
Biological therapies, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Therapies
Monday, December 11, 2023: 5:15 PM

Nirav N. Shah, MD1, Fateeha Furqan, MBBS2, Aniko Szabo, PhD2*, Tyce Kearl, MD3*, Anthony Zamora, PhD2*, Jessica Neumann4*, Parameswaran N. Hari, MD, MBBS5, Dina Schneider, PhD6, Walter Longo, MD7*, Peiman Hematti, MD5, Bryon D. Johnson, PhD5*, Mehdi Hamadani, MD8 and Timothy S. Fenske, MD1*

1Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI
2Medical College of Wisconsin, Milwaukee, WI
3Division of Hematology/Oncology, Medical College of Wisconsin, MIlwaukee, WI
4Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee
5Department of Medicine, Medical College of Wisconsin, Milwaukee
6Lentigen Technology, Inc, A Miltenyi Biotec Company, Gaithersburg, MD
7Medical College of Wisconsin, Division of Hematology/Oncology, Milwaukee, WI
8Division of Hematology and Oncology, The Medical College of Wisconsin Inc, Milwaukee, WI


Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy characterized by the presence of t(11;14) and bright CD20 expression. Approved CD19 CAR T-cell therapy for relapsed/refractory (R/R) MCL is limited by both relapse and high rates of Grade 3+ cytokine release syndrome (CRS) and ICANS with 15% and 31% patients (pts) experiencing such toxicities, respectively. To improve outcomes we utilized dual targeted lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T-cells with an adaptive manufacturing (MF) process to optimize the final CAR product as part of a Phase 1/2 clinical trial in R/R MCL.


We conducted a Phase 1/2 single center, prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10e6 cells/kg for pts with R/R B-cell non-Hodgkin Lymphoma. We report results of MCL pts from a fully enrolled Phase I safety run-in and Phase II efficacy cohort. The primary outcome for the Phase II cohort was day 90 complete response (CR) rate. The Phase II cohort utilized an adaptive 8/12 day MF process to enhance the percentages of T-SCM (stem cell-like memory) and T-CM (central memory) CAR T-cells in the final product by shortening culture time. CAR T-cells were harvested either on day 8 of MF or extended to a 12-day MF process depending on achieving target cell dose in culture. Fludarabine/cyclophosphamide lymphodepletion was started during MF to facilitate fresh infusion in eligible pts. Descriptive statistics were utilized for demographic data and the Kaplan Meier methodology for survival analysis.


In total 17 pts with R/R MCL received LV20.19 CAR T-cells (Phase 1=3 pts and Phase 2=14 patients). All pts achieved target cell dose. 13 pts received an 8-day product while 4 received a 12-day product. 14/17 pts received a fresh (non-cryopreserved) infusion. 8-day products were enriched for T-SCM/CM phenotype cells with significantly lower number of terminally differentiated effector memory (EMRA) T-cells in the CD4 compartment (p<0.05) than 12-day products.

The median age was 63 (50-74 years) and 15 (88%) were cisgender male. The median number of lines of therapy was 4 (3-8). p53 deletions or mutation were present in 7 pts. Day 28 overall response rate (ORR) was 100%; CR rate=76% and partial response (PR) =24%. Initial ClonoSEQ MRD assay performed within the first 90 days of LV20.19 CAR T (n=13) was negative in 10 pts (77%). Among Phase II patients with day 90 results available (n=12) the ORR was 100%, CR rate=92% and PR rate=8% exceeding the Phase II efficacy threshold. Two pts have relapsed to date, +8 months and +2 years after infusion. There were two non-relapse mortality (NRM) events that occurred beyond day 28: gram negative rod sepsis & COVID19 infection resulting in a 1-year NRM rate of 12%. The 1-year progression free survival (PFS) was 77%, 1-year duration of response (DOR) was 92%, and 1-year overall survival (OS) of 84%. Median PFS/DOR/OS have not been met with median follow-up of 14 months of surviving pts (Figure 1).

In terms of safety, 94% (n=16) experienced CRS, all grade 1-2. 18% (n=3) had ICANS in the first 28-days, 2 pts with Grade 3 toxicity. There were two pts with late (>day 28) episodes of Grade 1 neurological toxicity. Both pts had immense expansion of lymphocytes in the CSF (total nucleated cell count of 386/µLand 1005/µL) with CAR+ T cells present. 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.

Disclosures: Shah: TG therapeutic: Consultancy; Umoja: Consultancy; LOXO-Lilly: Consultancy, Other: Travel support; BMS/Juno: Consultancy; Tundra Therapeutics: Current holder of stock options in a privately-held company; Novartis: Consultancy; Janssen: Consultancy; Epizyme: Consultancy; Seattle Genetics: Consultancy; Gilead/Kite: Consultancy; Incyte: Consultancy; Abbvie: Consultancy; Lilly Oncology: Consultancy, Research Funding; Miltenyi Biotec: Consultancy, Other: Travel support, Research Funding. Schneider: Lentigen Technology, a Miltenyi Biotec Company: Current Employment. Johnson: Miltenyi Biotech: Research Funding. Hamadani: Novartis: Consultancy; MorphoSys: Consultancy; Myeloid Therapeutics: Honoraria; Genentech: Honoraria; SeaGen: Consultancy; Caribou: Consultancy; Incyte: Consultancy; Astra Zeneca: Speakers Bureau; Genmab: Consultancy; Legend Biotech: Consultancy; BeiGene: Speakers Bureau; Gamida Cell: Consultancy; Kadmon: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; BeiGene: Speakers Bureau; CRISPR: Consultancy; Omeros: Consultancy; Genmab: Consultancy; Bristol Myers Squibb: Consultancy; AstraZeneca: Speakers Bureau; Takeda: Research Funding; Spectrum Pharmaceuticals: Research Funding; Sanofi Genzyme: Speakers Bureau; Astellas: Research Funding; Abbvie: Consultancy; ADC therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fenske: Kite (Gilead): Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; MorphoSys: Consultancy, Speakers Bureau; Pharmacyclics (AbbVie): Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; SeaGen: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Speakers Bureau; Astrazeneca: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Speakers Bureau.

*signifies non-member of ASH