Background:
* Despite being the leading cause of cancer-related death worldwide, there is only limited knowledge of tumor heterogeneity in lung cancer. There is also limited knowledge of tumor heterogeneity of other less common thoracic malignancies, such as thymic epithelial tumors and mesothelioma. The extent and causes of intra-tumor and inter-metastatic heterogeneity in thoracic malignancies and how they compare to other tumor types is of utmost importance in managing lung cancer. Newer approaches of treating malignancies by targeting immune cells or tumor microenvironment are emerging. Adoptive cellular therapy (ACT) is one such approach. How this therapy affects individual metastatic sites and specific clones of tumor cells is poorly understood.
* Little is known about the clonal architecture of advanced, heavily-treated urothelial carcinoma or the dynamics that lead to metastasis and chemotherapy and immunotherapy resistance. Urothelial carcinomas have a high somatic mutation rate similar to that of non-small cell lung cancer and melanoma. Urothelial carcinoma tumors are extremely heterogenous and the extent of heterogeneity post treatment is an important area of research that should be further explored. Understanding the genetic and clonal evolution of urothelial carcinoma tumors will eventually help guide management of treatment-resistant metastatic tumors.
* Ovarian carcinoma is frequently associated with poor clinical outcome and metastatic disease. Although metastatic processes are becoming more understandable, the genomic landscape and metastatic progression in ovarian cancer has not been elucidated. Despite prior efforts such as The Cancer Genome Atlas (TCGA) and other analyses that were predominantly focused on samples from patients who had upfront debulking surgery, an understanding of the molecular and cellular heterogeneity of ovarian cancer based on highly clinically annotated samples is lacking.
* There is a major need for effective immunotherapies against the common epithelial cancers that account for the vast majority of cancer deaths. Even for lung cancer, where checkpoint inhibition has some efficacy, the majority of these patients do not respond. One option to address these cancers is the adoptive transfer of tumor reactive T-cells (Adoptive Cell Therapy, ACT), which has already demonstrated durable complete cancer regression in a few cases. This approach requires ways to either enrich for tumor-reactive T-cells from tumor infiltrating lymphocytes (TIL) or to rapidly clone mutation-reactive T-cell receptors and use them to engineer T-cell populations for administration. The T-cell response to tumor specific mutations (neoantigens) is highly patient specific and greatly affected by tumor heterogeneity. Developing better ways to d select TIL and TCR for clinical use are needed to advance ACT.
* Tumor heterogeneity can be evaluated in a comprehensive manner by deep sequencing and globally analyzing genomic and proteomic alterations of simultaneous core biopsies from several areas of the primary tumor and metastases. These analyses correlated with clinical outcomes can further the evaluation of tumor heterogeneity. However, such studies are not feasible in a clinical setting.
* Tissue procurement by rapid autopsies provides an effective way for such an investigation.
Objectives:
\- Procure primary and metastatic tissue of thoracic malignancies, ovarian cancer, bladder cancer, epithelial cancer (breast, colorectal, pancreatic, stomach or biliary cancers) and from patients treated with an ACT shortly after death, to investigate tumor heterogeneity and immune microenvironment intratumorally, between paired primary and metastatic sites, and among inter-metastatic tumors using integrated genomic, immunologic and proteomic analysis.
Eligibility:
\- Adult patients with metastatic non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), extrapulmonary small cell cancer (ESCC), pulmonary neuroendocrine tumor (pNET), thymic epithelial tumor, mesothelioma, bladder cancer (including urothelial carcinoma and other rare bladder or kidney histology), ovarian cancer, epithelial cancer and patients treated with an ACT, with no expected chance of cure and an expected survival of less than 3 months.
Design:
* The accrual ceiling for the study will be set at 275 in order to account for subjects that for whatever reason do not undergo autopsy.
* Patients will be admitted for inpatient hospice when an investigator evaluates that death is clinically imminent.
* Upon expiration, rapid autopsy will be performed and tissue will be obtained from the primary tumor site, if identifiable, and multiple metastatic sites to assess tumor heterogeneity and immune microenvironment using deep sequencing and global genomic and proteomic analyses.
* Archival tissue from patients, if available, will be used to evaluate these changes from several stages of tumor progression.
