ABSTRACT This application presents MT-601, a novel multi-tumor associated antigen (mTAA)-specific T cell product for the treatment of Non-Hodgkin’s Lymphoma (NHL). NHL is the most common hematologic malignancy with ~80,550 new cases and >20,000 deaths in the US expected in 2023. Adoptive T cell transfer, e.g., CAR T cells, have impressive potency in NHL yet are also associated with cytokine release syndrome (CRS) and neurotoxicity. Additionally, relapse rates are up to 60% post-CAR T therapy due to low antigen levels or loss of CD19 expression. To date there are no approved therapies for NHL patients who relapsed after CAR T cell therapy, resulting in a huge unmet medical need for alternate treatment options for NHL. MT-601 represents a novel T cell-based immunotherapy that simultaneously targets 6 tumor-associated antigens (TAA) (PRAME, NY-ESO1, survivin, MAGE-A4, SSX2, WT1) that are overexpressed in NHL but absent or with limited expression in healthy tissue, thereby minimizing tumor escape and enhancing anti-tumor response. Manufactured from autologous apheresis material, MT-601 recognizes target cells via native T cell receptors by interacting with tumor antigen-expressing target cells presenting antigen in the context of both class I and II HLA, leading to killing of tumor cells expressing any of these antigens and recruiting the patient’s immune system in the anti-tumor response. Although other cellular immunotherapies attempt to address CD19 CAR T cell failures by targeting 2-3 antigens, they are limited by 1) narrow epitope recognition, and 2) leaving the tumor susceptible to relapse. In addition to broad-spectrum antigen targeting, MT-601 is the only cellular therapy being explored in NHL patients who relapsed following CAR T therapy. Additional advantages of MT-601 include out-patient administration and no genetic engineering. Furthermore, Marker’s multiTAA-specific technology was proven clinically safe in >180 patients with various kinds of cancer. In a phase 1 trial of lymphoma patients using multiTAA-specific T cells targeting 5 TAAs, patients had durable responses for much longer than those typically associated with CAR T cells (6 years versus 28 months). Notably, Marker recently treated our first CAR T cell relapsed NHL patient, who shows a complete response at 12 weeks post-infusion. Based on this promising clinical data, Marker proposes a single-arm Phase 1 clinical study to advance MT-601 for patients with NHL that relapsed after third line CAR T treatment and do not have other approved therapy options. The objective of Specific Aim 1 is to manufacture MT-601 and execute the clinical protocol by treating NHL patients who have relapsed after CD19 CAR T cell therapy with MT-601. Specific Aim 2 will correlate biological characteristics in the product profile with clinical safety and efficacy outcomes. Successful completion of this grant will provide clinical proof of concept for MT-601 as a treatment for CAR relapsed NHL patients, ...