Background: Checkpoint immunotherapies have revolutionized the treatment of solid tumors yet durably benefit a minority of patients because they rely on endogenous anti-tumor T cells. In patients lacking functional anti-tumor T cells, a solution is engineering their T cells with exogenous T cell receptors (TCRs) to efficiently target and kill tumor cells. Initial clinical trials with TCR engineered T cell therapies (TCR-Ts) only produced partial, short-lasting responses because they targeted single tumor antigens. Solid tumors are notoriously heterogenous not only with highly variable antigen expression levels but also with recently identified HLA gene losses occurring in up to 40% of solid tumors, enabling tumor cells to evade T cell attack. Methods: To overcome this heterogeneity, TScan has developed T-Plex, a multiplexed therapy comprising 2-3 different TCR-Ts, chosen from a collection of TCR-Ts called the ImmunoBank, to target different tumor antigens presented on different HLA types with confirmed tumor expression. Results: To deepen clinical responses, TCR-T cells are engineered to express the CD8α/β co-receptors that, in preclinical experiments, enable CD4+ helper T cells to become >100-fold more cytotoxic and secrete cytokines at >100-fold lower target antigen levels. Finally, to enable T cell persistence despite immunosuppressive TGF-β in the tumor microenvironment, engineered TCR-T cells express the dominant negative TGF-β receptor allowing ~10-fold improved proliferation and ~2-fold improved cytokine production in the presence of TGF-β. The inclusion of these additional genes is enabled by a transposon manufacturing system with no cargo limit. Patient selection for the Phase 1 study uses a separate screening protocol to identify patients any time during standard clinical care so they can rapidly enroll into the treatment protocol upon progression. Screening comprises germline HLA testing, then archival tumor testing for antigen expression and HLA loss. Treatment includes standard lymphodepletion followed by 2 doses of T-Plex infused 28 days apart. T-Plex initially starts with 2 TCR-Ts targeting different MAGE-A1 antigens presented either on HLA-A*02:01 or HLA-C*07:02. Dose escalation starts with testing the single TCR-Ts individually in dose levels 1 and 2. The two TCR-Ts will then be combined and escalated in dose levels 3 and 4. Additional TCR-Ts added to the ImmunoBank will go through dose levels 1 and 2 as single therapies before becoming available for multiplexed dose levels 3 and 4. Primary endpoints include safety and feasibility, secondary endpoints are response rates and duration of response and exploratory endpoints measure T cell persistence. Conclusions: Four additional TCR-Ts are on track to be added to the ImmunoBank in 2023 which makes 50-80% of patients with common solid tumors eligible for multiplexed TCR-T therapy.