U.S. Army personnel exposed to asbestos in construction projects, ships, brakes, clutches, and military gas masks are at risk for developing malignant pleural mesothelioma (MPM), a locally aggressive cancer with a median survival of 4-12 months. Although surgery is the mainstay of multimodality therapy for MPM and the only option for prolonged disease-free survival, only 10% to 20% of patients presenting for evaluation are considered candidates for resection. In the largest series to date reported from our institution with 945 MPM patients screened and selected for surgical resection, one-third of the patients were unresectable at the time of surgery due to locally advanced tumor. Only 8% of MPM patients had distant metastases at initial presentation. The localized nature, potential accessibility to the pleural cavity, and relative lack of distant disease make MPM a candidate for regional targeted therapies. In patients with MPM, high levels of CD8+ tumor-infiltrating lymphocytes (immune cells that specifically target and kill cancer cells) remained an independent prognostic factor associated with delayed recurrence and better survival.

We have successfully developed and tested the efficacy of mesothelin targeted T cells, human primary immune cells redirected to target mesothelin, a common cancer antigen expressed in MPM patients. The strategies we wish to pursue via this proposal aim to increase recognition of tumor antigens, enhance anti-tumoral functions, and sustain T cell persistence and function in MPM patients. Furthermore, our research strategy in this application reflects well thought out integration of immunotherapy into current standard of care of MPM patients. Our 2009 application to the "Therapeutic and Technology Development Awardv was ranked as an "alternate" for funding among 76 applications (2 funded). From the 2009 proposal, we have completed Aim 1(a); the results are listed in the preliminary data in this application. The current proposal's Aim 1 expands on our results to further investigate the mechanistic reasons for potential synergy with combination therapies.

We propose to administer tumor antigen targeted human T lymphocytes systemically (adoptive T cell therapy) or regionally into the chest cavity and to further enhance the efficacy of such targeted T cells by regional costimulation. This approach is predicated on recent successes in adoptive T cell therapies in melanoma. The occurrence of some remarkable albeit infrequent complete responses in patients with metastatic disease underscores the potential of targeted T cells but also the need to increase the potency of these therapies through improvements in the host conditioning. The cancer antigen we choose to target, mesothelin, is overexpressed in MPM cells and plays a key role in tumor aggressiveness and survival. The cancer antigen receptors being tested against MPM in this proposal are highly specific. In order to facilitate effective clinical translation, we propose to investigate the beneficial effect of combining targeted T cell therapy with existing chemoradiation therapy with solid scientific reason. Although T cells may be targeted to disease site, their survival and function are dependent on co-stimulation, and such co-stimulatory molecules may not reach the pleura in adequate concentration without causing systemic toxicity. We will deliver IL-12, a powerful cytokine already proven to be beneficial in MPM therapy, regionally into the pleural cavity and thereby avoid potential toxicity reported with its systemic administration. The regional delivery approach proposed in this application is practical in MPM patients owing to the ease of repeated access to the pleural cavity with minimally invasive image-guided intervention methods.

Our laboratory has pioneered adoptive T cell therapies for leukemia and prostate cancer using genetically targeted T cells. Our Gene Transfer and Somatic Cell Engineering facility within the Center for Cell Engineering is well equipped and has developed an Food and Drug Administration-approved process to rapidly generate tumor-targeted T cells from peripheral blood T cells. We anticipate being in a position to initiate a Phase 1 clinical trial by the end of this award. The regional intrapleural or intratumoral delivery proposed in this research proposal is practical. With our recently established Center for Image-guided Intervention, we will be able to regionally administer cytokines repeatedly into mesothelioma pleural tumors. Since the end result of adoptive T cell therapy is tumor lysis, we believe the bulk of the tumor may be reduced, allowing more patients to be eligible for surgery. Following surgical resection, post-operative chemoradiation therapy to the pleural cavity, a standard in MPM patient management, may provide a fertile ground for pursuing combination immunotherapeutic strategies.