Results from a Phase 1/2 Study of Tandem, Bispecific Anti-CD20/Anti-CD19 (LV20.19) CAR T-Cells for Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with variable clinical course. The disease is characterized by presence of t(11;14) and bright CD20 expression. While frontline immunochemotherapy plus autologous hematopoietic cell transplant (HCT) has improved progression-free survival, invariably MCL patients (pts) relapse. Approved CD19 CAR T-cell therapy for relapsed/refractory (R/R) MCL provides durable disease control but is limited by high rates of Grade 3+ cytokine release syndrome (CRS) and neurological events with 15% and 31% of pts experiencing such toxicities. We hypothesized that bispecific, tandem, lentiviral CAR-T cell targeting both CD20 and CD19 B-cell antigens (LV20.19 CAR) with 4-1BB co-stimulatory signaling will improve clinical outcomes in R/R MCL and that expansion in IL7 and IL15 would produce less "exhausted” CAR product with more durable clinical activity.

Methods: 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 below outcomes from a Phase 1/2 cohort of MCL pts. LV20.19 CAR T-cells were manufactured onsite in the CliniMACS Prodigy device with IL7+15 for cell expansion with goal of fresh infusion at varying lengths of manufacturing (8 vs 12 days). After safety run-in, we opened a 14 patient single stage Phase II arm with flexible 8/12-day manufacturing with fresh infusion for MCL pts. Descriptive statistics were utilized for baseline characteristics and survival analyses were calculated utilizing the Kaplan-Meier method and differences between groups were evaluated via log-rank test.

Results: To date, 10 MCL pts have received LV20.19 CAR T-cells at the specified dose of 2.5x10e6 cells/kg (Phase 1=3 pts and Phase 2=7 pts). 8 of 10 pts received 8-day manufactured CAR-T cells whereas two pts received a 12-day product in the Phase 1 cohort. Manufacturing was successful in 100% of pts and all received a fresh (non-cryopreserved) product. Median age was 62 years and median prior lines of therapy were 4 (range: 3-8). Three pts progressed after prior autologous HCT and 2 pts progressed after prior allogeneic HCT. Eight of 10 pts had progressed on a Bruton's Tyrosine Kinase inhibitor (BTKi) and 4 of these pts had additionally progressed on a non-covalent BTKi (pirtorbrutinib) administered on a clinical trial (Table 1).

LV20.19 CAR T-cells produced in the CliniMACS Prodigy with IL-7/IL-15 had robust expansion with mean 5.4x10e8 CAR T-cells obtained on Day 7 of manufacturing. CAR T-cells from pts mostly consisted of central-memory and effector-memory phenotype T-cells with robust in-vivo expansion typically starting Day +4 after infusion. The Day 28 ORR was 100% (CR=60% and PR=40%). 7 of 9 pts with MRD assessed between Day 28-60 post CAR were negative. No patient has relapsed with a median follow-up of 18 months of among surviving pts. Regarding toxicity, all 10 pts (100%) had Grade 1-2 CRS (no grade 3+ events). Immune effector cell associated neurotoxicity syndrome (ICANS) occurred in 2 pts with one patient experiencing Grade 2 and the other Grade 3 toxicity. The patient with Grade 3 ICANS experienced a non-relapse mortality event due to gram negative sepsis after Day 28 evaluation. At 1-year the cumulative incidence of relapse and NRM were 0% and 10%, respectively while the 1-year PFS and OS were 90% each (Figure 1).

Conclusions: 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.

Shah:Novartis: Consultancy; Miltenyi Biotec: Consultancy, Research Funding; Lilly Oncology: Consultancy, Honoraria; Epizyme: Consultancy; Bristol Myers Squibb: Consultancy; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; TG therapeutics: Consultancy; Kite Pharma: Consultancy. Hari:AbbVie: Honoraria; GlaxoSmithKline: Honoraria; Kite: Consultancy, Honoraria; Incyte: Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pharmacyclics: Consultancy; Millennium: Research Funding; Spectrum Pharmaceuticals: Research Funding; Iovance: Current Employment. Schneider:Lentigen Technology, a Miltenyi Biotec Company: Current Employment. Johnson:Miltenyi Biotec: Research Funding. Hamadani:Medical University of Wisconsin: Current Employment; SeaGen: Consultancy; Gamida Cell: Consultancy; MorphoSys: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Incyte Corporation: Consultancy; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; Omeros: Consultancy; Kadmon: Consultancy; Takeda: Research Funding; Legend Biotech: Consultancy; Kite: Consultancy; Astellas Pharma: Research Funding; Spectrum Pharmaceuticals: Research Funding; Sanofi Genzyme: Speakers Bureau; AstraZeneca: Speakers Bureau; BioGene: Speakers Bureau. Fenske:Adaptive Biotechnologies: Consultancy, Speakers Bureau; Beigene: Consultancy; Bristol-Meyers-Squibb: Consultancy, Speakers Bureau; CSL Therapeutics: Consultancy; Karyopharm: Consultancy; Kite (Gilead): Consultancy, Speakers Bureau; MorphoSys: Consultancy, Speakers Bureau; Pharmacyclics (AbbVie): Consultancy; SeaGen: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau; Sanofi: Speakers Bureau.