CCL3 and IL-7 Synergistically Enhance CAR-T Efficacy in Solid Tumors

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise but faces limitations in solid tumors, including poor infiltration, reduced activity, and antigen escape.
• Intratumoral T cell responses are modulated by chemokines like CCL3, but its monotherapy is insufficient for durable tumor killing due to T cell death.

Purpose of the Study:

• To investigate the synergistic effect of combining CCL3 with interleukin-7 (IL-7) to enhance CAR T cell therapy for solid tumors.
• To elucidate the mechanisms by which CCL3 and IL-7 improve CAR T cell function and anti-tumor efficacy.

Main Methods:

• CAR T cells were engineered to co-express CCL3 and IL-7 (3P7-CAR-T).
• Evaluation of CAR T cell infiltration, survival, cytotoxicity, and anti-tumor efficacy in solid tumor models.
• Analysis of molecular mechanisms, including RUNX3 expression, tissue-resident memory T cell (Trm) differentiation, and immune microenvironment remodeling.

Main Results:

• The combination of CCL3 and IL-7 demonstrated a potent synergistic effect, significantly improving CAR T cell infiltration and longevity in solid tumors.
• 3P7-CAR-T treatment led to robust anti-tumor efficacy without significant side effects or systemic toxicity.
• Mechanistically, CCL3 plus IL-7 promoted RUNX3 expression and the differentiation of CD69+CD103+ Trm cells, while remodeling the tumor immune landscape to enhance antigen presentation and endogenous T cell responses.

Conclusions:

• CCL3 synergizes with IL-7 to overcome critical challenges in CAR T cell therapy for solid tumors.
• This combination enhances CAR T cell persistence, function, and promotes a favorable tumor immune microenvironment, leading to improved therapeutic effectiveness.