Malignant mesothelioma (MM) is an aggressive tumor that results from asbestos exposure and can present among military personnel and veterans. MM is largely refractory to conventional therapies, and the median survival after symptom onset is less than 12 months. Surgery, radiotherapy, and chemotherapy have improved quality of life but have made little impact on survival with this tumor. Therefore, there is an immediate unmet need for more effective treatment approaches for this deadly disease.

The immune system in our body is capable of eradicating cancer in the same way that is able to combat infectious diseases. It is well known that MM is can be recognized by the immune system and can induce an immune response. There is a clear logic to develop a therapy type (called immunotherapy), which harnesses the power of the body's immune system to destroy MM cells. However, MM often develops ways to evade and neutralize these immune attacks resulting in cancer progression. In the past decades, researchers have investigated a way to resolve the evasion mechanisms, and many immunotherapies have been tested in animal models and clinical trials in this regard. Unfortunately, we have not found an effective and safe immunotherapy for MM mainly because of the insufficient efficacy and side effects of these methods. We propose that the key to the success here is the stimulation of immune responses to MM with simultaneous blockade of immune evasion mechanisms.

A stress-induced protein called "heat shock protein 70 (Hsp70)" is well-known to stimulate immune responses. We fused this protein to an antibody, which can effectively recognize a marker protein of the surface of tumor cells named mesothelin that is highly present on MM cells and otherwise found at low levels on normal cells. We have studied the effect of this fusion protein in a mouse model of ovarian cancer that resembles the human disease and also has mesothelin on its surface. We showed that our immune therapeutic fusion protein, called VIC-007, slowed down the growth of the disease significantly and stimulated the immune responses against ovarian cancer without side effects. Our idea now is to test our new immune therapeutic fusion protein to MM in mice.

One of the ways MM is thought to avoid the immune system involves the selective retention of a cell type called "regulatory T cells" in the tumor. The role of these cells is normally to prevent excessive immune responses, but MM effectively "hijacks" this system and uses it to neutralize the immune attack against it. Recently, our research group identified a protein called CXCL12 produced by ovarian cancer that mediates the selective accumulation of regulatory T cells in the tumor. There is a clinically approved drug, called AMD3100, that can selectively block the interaction of CXCL12 with its receptor CXCR4. We have reported that a new use of this drug that involves the blockade of the interaction between CXCR4 and CXCL12 in mice with ovarian cancer slowed down tumor growth and increased immune responses in the same mouse model by keeping Tregs out of the tumor. Since MM also expresses both CXCL12 and CXCR4, we plan to explore the targeting of these proteins in this disease with AMD3100.

In this proposal, we propose an innovative combination treatment approach for MM, which combines the new VIC-007 and AMD3100 as a one-two punch: VIC-007 inducing a targeted immune attack on MM and AMD3100 augmenting the impact of VIC-007. The relevance of this work to the clinical setting is maximized by the fact that both active elements of the combination are approved for use in humans with cancer. We will also test the hypothesis that the presence of mesothelin and/or CXCL12/CXCR4 in MM may help us to predict a response of this tumor to the combination immune therapy in the same mouse model. We expect that this study could be finished in 2 years, and if this study is successful, a clinical study could be initiated shortly thereafter to treat patients with MM who do not have other treatment options. Approximately 1,000 veterans per year are diagnosed with MM, and the long latency period of the disease makes it likely that MM will continue to be diagnosed in veterans for many years to come. We expect to see synergistic effects of both drugs, resulting in a full-recovery of immune responses in the body and possible eradication of MM.