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.
