LANDscape MApping of Epitopes and T Cell Receptors for Selected Cancers

Official Title

LANDscape MApping of Epitopes and T Cell Receptors for Selected Cancers

Summary:

This is a correlative research project aimed at characterizing the T cell mediated immune responses to hepatocellular carcinoma (HCC), as well as Epstein-Barr virus (EBV)- and human papillomavirus (HPV)-related cancers. This study will enroll approximately 105 patients over 48 months. Of these 105 patients, 30 are EBV-related cancer, 45 are HPV-related cancer, and 30 are HCC. Patients will have blood samples collected one time to identify cancer specific T cells and T cell receptors in their blood. They will also have tissue samples collected one time to study the different types of immune cells, especially the T cells and their receptors. The 105 patients enrolled in this study will be compared to retrospective samples (N=210; 30 from EBV-related cancer cohort, 180 from HPV-related cancer cohort).

Trial Description

Primary Outcome:

• Identifying the p-HLA epitopes across diverse HLA alleles

Secondary Outcome:

• Characterizing tumour-antigen specific TCR repertoire diversity across diverse HLA alleles, and further provide a comprehensive functional analysis that identifies immunodominant epitopes important for tumour control

The cloning of genes encoding the T cell receptor (TCR), the identification of tumour-associated antigens and the subsequent characterization of the first HLA-restricted T cell-defined antigenic epitope, were key findings illustrating direct recognition of cancer cells by T cells. These discoveries provided a mechanistic foundation for ensuing work examining the dynamic nature of lymphocyte-dependent recognition and elimination of neoplastic cells. Furthermore, preclinical and clinical investigations illustrate an important role for T cell mediated anti-tumour immunity in human disease, and have characterized the complexity of cancer-associated immune responses that are not always sufficient for tumour elimination. Importantly however, therapeutic targeting of the immune system has demonstrated the power of immunomodulatory drugs for the restoration of anti-tumour immune responses for cancer treatment. Presence of lymphocytes in a variety of human cancers is well documented, and T cells isolated from tumours that recognize cancer antigens can be harnessed for effective treatment. T cells isolated from patient tumours can be ex vivo expanded, and reinfused back into patients in a regime of cellular therapy termed adoptive cell transfer (ACT). This ACT therapy can be further directed to specific tumour antigens with the genetic manipulation of T cells to express TCR recognizing known p-HLA epitopes with dominant expression on cancer cells. However, the peptide-HLA (p-HLA) epitope landscape of tumour associated antigens, and their cognate TCR are not well described, and those which have been described are primarily limited to the class I HLA-A*02:01 allele dominant only in European-Caucasian populations. The purpose of this study is to further document the cancer epitope landscape and provide a comprehensive characterization of TCR specificities in a range of malignancies, for a wide variety of class I and class II HLA alleles. In addition, we aim to elucidate not only TCR repertoires important for anti-tumour immunity, but further clarify the role antigen presenting cells play in shaping these T cell repertoires. The objectives involve the identification of cancer-associated/specific antigen p-HLA epitopes and their cognate TCR, and the subsequent structural and functional characterization these TCR. To meet this objective, immune cells of T, B and myeloid lineage will be analyzed. Phenotypic characterization of these cell subsets will be performed using standard immunological procedures such as immunofluorescence, immunohistochemistry, ELISA, ELISpot, qRT-PCR, analytic cytometry, CyTOF (cytometry time of flight), and in vitro stimulation. To relate immune responses to cancer cell intrinsic biology, RNA and DNA will be sequenced to identify cancer cell transcriptome and mutations, as well as T cell receptor unique sequences. Results from all laboratory analysis will be combined with relevant clinical data. Any confirmation of diagnosis, tissue types and other clinical data will be provided as available from the pathologists of the relevant disease site at UHN. An incomplete understanding of T cell responses to cancer impedes the development of more effective immunotherapeutics. Discovery using tumour specimens from cancer patients will clarify how the complexity of the tumour environment shapes T cell specificity to induce effective immune responses and facilitate our development of better immune modulating therapeutics.

View this trial on ClinicalTrials.gov