PROJECT SUMMARY/ABSTRACT The Medical College of Wisconsin (MCW) hematopoietic cell transplant (HCT) and cellular therapy program proposes to continue its contributions as a BMT CTN Core Center with its expertise in HCT, novel cell and gene therapies, and continued stellar accrual to BMT CTN trials along with high-quality data submission. We also propose a trial addressing a high-priority concept identified at the 2021 BMT CTN State of the Science Symposium (SOSS) that builds on MCW’s experience in developing a first-in-human bispecific chimeric antigen receptor (CAR T) cell product targeting two B cell antigens, CD19 and CD20 (CAR20.19). Results of a Phase 1 dose-escalation study published in Nature Medicine in 2020 identified a safe dose for Phase II studies while providing preliminary efficacy and safety data in patients with B-cell malignancies. This led to the development of a Phase I/II single-center study at MCW for relapsed, refractory (R/R) mantle cell lymphoma (MCL) (NCT04186520). Despite advances in therapies for MCL that have improved progression-free survival (PFS), patients with adverse features, including TP53 mutation, 17p deletions, complex karyotype, and blastoid histology, continue to have poor outcomes and survival. As MCL is known to have both CD19 and CD20 expression, we hypothesized that dual targeting with CAR20.19 T cells could improve PFS and overall survival in R/R MCL compared to currently available therapies. We can now report promising results in 17 patients with an overall response rate of 100% and only two patients relapsing to date with a median follow-up of 1 year for all patients. Excitingly, these responses occurred in the setting of limited CAR-associated toxicity with no patients with grade 3-4 cytokine release syndrome. We now propose a Phase II multicenter study of MB-CART2019.1 (zamtocabtagene autoleucel) therapy as frontline consolidation for high-risk Mantle Cell Lymphoma. As identified in the SOSS report in 2021, improving outcomes with novel cell-based therapies for high-risk MCL is an unmet clinical need. Given our preliminary single center data with excellent efficacy, a favorable toxicity profile, and our in-depth experience with this product (>90 patients with B-cell non-Hodgkin lymphoma treated with CAR20.19 T cells since 2017), we are uniquely poised to develop and lead this trial within the BMT CTN. As high-risk MCL represents a small subset of patients in a disease that only represents 5% of all newly diagnosed lymphomas, the BMT CTN is the optimal organization to successfully conduct the proposed cell therapy trial. We hypothesize that dual-targeted CAR20.19 T-cell therapy will improve outcomes for high-risk MCL patients compared to historical outcomes and represent an important innovation in the field to redefine the treatment approaches for patients with adverse prognostic MCL.