Clinical evaluation of ex vivo expanded MUC1-specific peripheral blood T Cells for adoptive immunotherapy in relapsed/refractory multiple myeloma

PURPOSE: Naturally occurring tumor-specific T cells derived from peripheral blood (PB) offer a clinically accessible source for adoptive immunotherapy. However, expansion of these T cells from cancer patients remains a challenge. We hypothesized that mimicking innate immune activation could optimally stimulate antigen-driven T cell expansion in vitro, unlocking the therapeutic potential of PB-derived T cells. EXPERIMENTAL DESIGN: We previously developed an ex vivo culture system that selectively expands tumor antigen-activated T cells from PB mononuclear cells (PBMCs), generating multiclonal effector and central memory T cells. In this hypothesis generating study, we evaluated the therapeutic potential of MUC1-activated T cells in patients with relapsed and/or refractory multiple myeloma (r/rMM) in a phase I clinical trial (NCT05411497). MUC1 is an oncoprotein overexpressed in r/rMM. We translated our small-scale culture into GMP-compliant, large-scale manufacturing which achieved expansion of T cells from heavily pre-treated patients' PBMCs without exhaustion. Five patients were treated with escalating doses of up to 1x10^10 T cells. RESULTS: While the cell infusions were well tolerated, no objective responses occurred. One patient, who received the highest dose, has had stable disease for two years post-infusion. This patient exhibited transient dermatitis with localized MUC1 and CD3 staining, as potential evidence of on-target, off-tumor T cell reactivity, perhaps contributing to disease stabilization. TCR sequencing revealed the T cell product in four of the patients' blood, which correlated with the product's degree of polyfunctionality and MUC1-reactivity. CONCLUSION/DISCUSSION: These findings demonstrate the feasibility, safety, and biological activity of PB-derived, MUC1-specific T cells as adoptive immunotherapy.