Cancer metastatic to the pleura is uniformly fatal with a median survival of six months and quality of life that is diminished by dyspnea and discomfort. There is currently no curative treatment once metastatic disease has occurred. Current standard of care treatment for malignant pleural effusions (MPE) is exclusively palliative, consisting of drainage, followed by systemic therapy (chemotherapy, endocrine, or immunotherapy). Our institutional experience with systemic immune checkpoint blockers indicates a marginal improvement in overall survival in a small subset of patients. Clearly, the incidence of MPE and lack of effective treatments has created an urgent unmet need to develop an effective treatment.
Our studies of the pleural secretome in non-small cell lung cancer and mesothelioma, as well as extensive secretomic data in MPE from other cancers, indicate that the IL-6/IL-6Rα axis is prominent in pleural effusions and drives the epithelial to mesenchymal transition (EMT). We have identified additional cytokines that are absent in normal pleural fluid but prominent in malignant effusions. We have also found that MPE T cells, removed from their environment, are capable of expansion in culture, polyfunctional cytokine response, and are cytolytic to autologous tumor. Because the pleural space is lined with mesothelial cells joined by tight junctions, we hypothesize that it acts as a cytokine-rich bioreactor which promotes EMT in cancer cells metastatic to the pleura, and redirects the abundant immune infiltrate to promote, rather than inhibit, tumor growth. We hypothesize that as a master cytokine, IL-6 and its soluble receptor drive this process. Therefore, local blockade of sIL-6Rα will alter the pleural cytokine milieu, inhibiting aggressive tumor behavior and promoting anti-tumor immune response. Once unleashed in the pleural space, tumor-specific T cells could be expected to migrate to the periphery through the draining lymphatics and respond to extra-pleural metastases. Further, based on our current data, we are confident that the 100 million MPE T cells that are routinely recovered during routine therapeutic MPE drainage can be expanded in culture for an adoptive cellular therapy product that is faster, better and cheaper than conventional solid-tumor derived culture-expanded tumor infiltrating lymphocytes (TIL).
What remains to be determined is whether blockade of dominant cytokines in MPE together with anti-PD-1/PD-L1 therapy can condition the pleural environment sufficiently to support and expand the existing anti-tumor responses.
Combining the knowledge derived from these studies we propose to devise a personalized combined treatment strategy that conditions the pleural environment without incurring systemic toxicities and facilitates local and systemic anti-tumor immune response.
