Live attenuated bacterium limits cancer resistance to CAR-T therapy by remodeling the tumor microenvironment

Area of Science:

• Oncology
• Immunology
• Microbiology

Background:

• Tumor microenvironment (TME) immune checkpoints hinder anti-cancer immunity.
• Antigen-expressing viruses and bacteria show potential for inducing antitumor immunity.
• Bacterial antitumor therapies face safety and targeting concerns.

Purpose of the Study:

• To evaluate the safety and efficacy of an attenuated bacterial strain, Brucella melitensis 16M ∆vjbR (Bm∆vjbR), as an antitumor agent.
• To investigate Bm∆vjbR's ability to remodel the TME and enhance anti-cancer immune responses.
• To assess the combination therapy of Bm∆vjbR with chimeric antigen receptor (CAR) T-cells.

Main Methods:

• Utilized an attenuated bacterial strain, Bm∆vjbR, previously confirmed as safe.
• Administered live Bm∆vjbR to a murine model of solid cancer.
• Analyzed TME changes, including macrophage polarization and CD8+ T cell activity.
• Combined Bm∆vjbR treatment with adoptive transfer of CAR T-cells targeting carcinoembryonic antigen.

Main Results:

• Bm∆vjbR effectively homed to tumor tissue and improved the TME.
• Live Bm∆vjbR induced M1 polarization of tumor macrophages and increased CD8+ T cell numbers and activity.
• Combination therapy with CAR T-cells resulted in near-complete abrogation of tumor growth and 100% host survival in a colon adenocarcinoma model.

Conclusions:

• Live attenuated bacterial treatment, specifically Bm∆vjbR, can overcome cancer resistance to CAR T-cell therapy.
• Bm∆vjbR remodels the TME to promote macrophage and T cell-mediated antitumor immunity.
• This approach offers a promising strategy for enhancing the efficacy of adoptive T-cell therapies in solid cancers.