Improving CAR T-cell function in solid tumors: a combination approach with interferon gene therapy in a new mouse model of glioblastoma multiforme

Chimeric Antigen Receptor (CAR) T cells are an emergent immunotherapeutic class of agents gaining relevant breakthroughs against blood malignancies, while displaying limitations in the treatment of solid tumors mainly because of poor CAR T-cell trafficking and the presence of an immune suppressive tumor milieu. To improve CAR T cell function in glioblastoma (GBM), a combination approach with cell and gene therapy delivery of interferon (IFN)-α is here proposed, aimed at reverting the immune inhibition within the tumor milieu. A new mouse GBM cell line was modified to express an inactive form of CD19. This cell line was orthotopically injected in immune competent mice that received engineered hematopoietic stem and progenitor cells to exploit the ability of their TIE2-positive myeloid progeny to deliver IFN-α in the tumor and synergize with anti-CD19 CAR T therapy. Persistence, trafficking and activation of CAR T cells, along with tumor immune infiltrate were evaluated by cytometric analyses and efficacy by magnetic resonance. IFN-α gene therapy leads to improved CAR T cell persistence, tumor homing and decreased exhaustion. Increased dendritic cells and eosinophils within the tumor infiltrate are other signs of the IFN-mediated immune reprogramming. No conclusive notes can be drawn about efficacy, even if mice treated with the combination therapy displayed reduced mean tumor growth. Altogether, these results evidence an improved function of CAR T cells when combined with IFN-α gene therapy in a reliable GBM mouse model. This can pave the way for a versatile strategy able to restore efficacy of other CAR T-cell therapies for solid tumors in the clinic avoiding the need of new target identification