Immune checkpoint blockade combined with IL-6 and TGF- inhibition improves the therapeutic outcome of mRNA-based immunotherapy

Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include but are not limited to (i) adaptive expression of inhibitory checkpoint molecules in response to the proinflammatory environment and (ii) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self-renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission. Several individual therapeutic agents have so far been developed to revert T-cell exhaustion or disrupt the cross-talk between cancer stem cells and the tumor-promoting microenvironment. Here, we demonstrate that a three-arm combination therapyconsisting of an mRNA-based vaccine to induce antigen-specific T-cell responses, monoclonal antibodies blocking inhibitory checkpoint molecules (PD-1, TIM-3, LAG-3), and antibodies targeting IL-6 and TGF-improves the therapeutic outcome in subcutaneous TC-1 tumors and significantly prolongs survival of treated mice. Our findings point to a need for a rational development of multidimensional anticancer therapies, aiming at the induction of tumor-specific immunity and simultaneously targeting multiple resistance mechanisms. What's new? Tumors can become resistant to immunotherapy via multiple mechanisms, necessitating a search for new therapeutic approaches to combat recurrent tumor disease. Here, single combination therapy of an mRNA vaccine with inhibitors of either immune checkpoint molecules or the IL-6/TGF- pathway was investigated in a TC-1 tumor cell mouse model. The combination of mRNA vaccine with either of the other agents showed limited therapeutic efficacy in a long-established TC-1 tumor model. By contrast, the three approaches togetherIL-6/TGF- pathway disruption, concurrent blockade of three different immune checkpoint molecules, and mRNA-based anticancer immunotherapysignificantly improved therapeutic control of long-established tumors.