Using silent cells improves tumor homing and efficacy of of cell therapy for cancer

A Morales-Molina(1) M A Rodríguez-Milla(1) S Gambera(1) P Garcia-Rodriguez(1) J García-Castro(1)

1:Instituto de Salud Carlos III

Cell therapy for cancer is evolving rapidly. From the variety of strategies, cells can be used as carriers for delivering immunotherapeutic agents to the tumors. However, selection of the appropriate cells to produce effective clinical outcomes is critical. We have studied a cohort of cancer patients treated with an immunotherapy consisting of mesenchymal stromal cells (MSCs) carrying oncolytic adenoviruses. The results indicated that patients treated with cells presenting deficit in stimulating the immune system showed better clinical outcomes.

We hypothesize that therapies based on cells presenting low pro-inflammatory profiles (‘silent cells’) upon systemic administration would result in better antitumor responses. We studied our hypothesis in immunocompetent mice treated with MSCs deficient for TLR4, MyD88 or MAVS as models of silent cells.

Interestingly, in vivo tumor homing after systemic administration of silent cells was significantly higher. This better homing to the tumor site was highly related to the mild immune response triggered by these silent cells in peripheral blood, evading the attack of the immune system against the carrier cell. As a result, the use of silent cells significantly improved the antitumor efficacy of the treatment in comparison to the use of wildtype MSCs. Moreover, it also increased the density of tumor-infiltrating T cells and induced the activation of the NF-κB pathway in the tumor.

In conclusion, while cell therapies in cancer generally aim to boost local immune responses in the tumor microenvironment, low systemic inflammation after systemic administration of the treatment may indeed enhance tumor-homing and the overall antitumor effect.