Probiotic-guided CAR-T cells for solid tumor targeting

Abstract

A major challenge facing tumor-antigen targeting therapies such as chimeric antigen receptor (CAR)–T cells is the identification of suitable targets that are specifically and uniformly expressed on heterogeneous solid tumors. By contrast, certain species of bacteria selectively colonize immune-privileged tumor cores and can be engineered as antigen-independent platforms for therapeutic delivery. To bridge these approaches, we developed a platform of probiotic-guided CAR-T cells (ProCARs), in which tumor-colonizing probiotics release synthetic targets that label tumor tissue for CAR-mediated lysis in situ. This system demonstrated CAR-T cell activation and antigen-agnostic cell lysis that was safe and effective in multiple xenograft and syngeneic models of human and mouse cancers. We further engineered multifunctional probiotics that co-release chemokines to enhance CAR-T cell recruitment and therapeutic response.

Synthetic bacteria with programmed cell targeting and protein injection suppress tumor growthin vivo

“…Targeting tumor cells by recognizing a cell-surface antigen and generating a cytotoxic response are the key elements of CAR-T cells 5 for achieving durable therapeutic responses in hematological malignancies. Major efforts are underway to improve CAR-T cell therapies for the treatment of solid tumors, including their combination with engineered bacteria 20 . The SIEC-X bacteria reported here provide a novel therapeutic approach in this global effort against solid tumors and represent a step forward in BLTs.…”

“…This ability has spurred the engineering of bacteria for the local delivery of antitumor molecules 15,16 . Major recent achievements in this field have utilized synthetic biology to program bacteria for tumor immunotherapies, by depleting the levels of immunosuppressive metabolites 17 , producing signaling molecules activating the immune response 18 , releasing nanobodies (Nbs) that block antiphagocytic receptors and immunological checkpoints 19 , or delivering synthetic antigens recognized by CAR-T cells 20 . However, these successes invariably rely on the natural tropism of the bacterial chassis to colonize a specific niche (e.g., tumor or gut), where the therapeutic molecule is released locally into the environment either by active protein secretion or by bacterial lysis 16 .…”

Cellular mechanisms underlying beneficial versus detrimental effects of bacterial antitumor immunotherapy

“…Indeed, direct IT injection of an FDA-approved seasonal influenza vaccine demonstrated antitumor activity in a mouse cancer model 88 . Alternatively, the generation of CAR T cells against E. coli in combination with the seeding of E. coli into the TME was shown to robustly control tumors 89 . Mechanistically, the infiltration of a large number of Lmspecific CD8 T cells that cannot directly target and kill tumor cells still could control tumors by inducing local tissue damage or impacting the blood vasculature that supports tumor growth [90][91][92]12,19,77 .…”

Rationally designed approaches to augment CAR-T therapy for solid tumor treatment

“…Engineered microbes like bacteria can produce functional proteins at targeted tumor sites [ 101 , 102 ]. Vincent et al engineered E. coli Nissel 1917 (EcN) to synchronize lysis and produce CAR tags, which are composed of PIGF-2123-144 (heparin-binding domain), linker, and sfGFP (CAR target) [ 103 ]. These secreted CAR targets can easily decorate on tumor matrix and tumor cell membrane surface and expose the CAR target sfGFP exterior.…”