Targets expressed on tumour initiating cells
| Targets | Speaker | Highlights |
|---|---|---|
| EGFRvIII | Albert Wong, Stanford University Medical Center | • Truncated version of EGFR, with autonomous signalling and pro-tumorigenic capabilities |
| • Expressed by CSCs in glioblastoma: the cells with the highest tumorigenic properties are CD133 EGFRvIII double-positive cells | ||
| • Neither homogenously expressed within tumors, nor indispensable to tumor cells; its expression could vary during tumor progression | ||
| • EGFRvIII is being pursued through vaccination, monoclonal antibodies and adoptive T cell therapy with CARs | ||
| Cyclin A1Wilms Tumor antigen -1 (WT-1) | Philip Greenberg, University of Washington, Fred Hutchinson Cancer Research Center | • Cyclin A1 and WT-1 are expressed in Acute Myeloid Leukemia (AML) CSCs |
| • Cyclin A1 is a new target: its expression encoded by CCNA1 is largely restricted to the meiotic phase in normal germinal cells but appears to be co-opted by many malignancies, including ~60% of cases of AML | ||
| • T cells against Cyclin A1 and WT-1 epitopes were generated and tested in preclinical models | ||
| • Clinical evaluation of TCR-engineered adoptive T cell therapy is ongoing in AML patients with antigen+ leukemia and the appropriate HLA restricting element | ||
| Chondroitin sulfate proteoglycan 4 (CSPG4) | Soldano Ferrone, Massachusetts General Hospital and Harvard Medical School | • Complex and extensively glycosylated tumor antigen expressed on the cell membrane |
| • Amenable to immune interventions such as antibody therapy and chimeric antigen receptor (CAR)-engineered T cells | ||
| • Expressed on normal cells and highly upregulated on tumor cells of various origin: ectodermic, endodermic and mesodermic | ||
| • Within tumors, CSPG4 could be also expressed on pericytes and other stromal cells, supporting a multi-pronged mechanism of action | ||
| • CSPG4 is also expressed on tumor initiating cells | ||
| • Its expression on some normal cells associated with vasculature and central nervous system could be of concern; yet antibody approaches directed to post-translational modifications could be a fertile area of new drug development | ||
| 5T4 -trophoblast glycoprotein (TPGB) | Kenneth Geles, Pfizer Inc | • Tumor-specific membrane expression, amenable to antibody therapy. Normal expression of is limited to placenta and embryonic stem cells |
| • 5T4 is over-expressed in colorectal, gastric and ovarian cancers and is associated with advanced disease and/or worse clinical outcome | ||
| • It can function as a pro-migratory factor in embryonic cells that have undergone an epithelial-to-mesenchymal (EMT) transition and can also modulate CXCR4 and Wnt signalling | ||
| • 5T4 is also enriched on cancer stem cells (tumor-initiating cells) in non-small cell lung carcinoma (NSCLC) | ||
| • In the H460 lung cancer cell line, the CD24low/CD44high subset is most tumorigenic and enriched for the 5T4 mRNA | ||
| • Sorting cells from a NSCLC patient derived xenograft (PDX) based on 5T4 expression confirmed that 5T4high cells were more tumorigenic | ||
| • High levels of 5T4 expression were associated with poorly differentiated NSCLC tumors and worse overall survival | ||
| • Treatment of preclinical lung and breast cancer models with an anti-5T4 antibody drug conjugate (A1-mcMMAF) resulted in long-term tumor regressions. This is the first proof-of-concept targeting a heterogeneous subpopulation of cells at the apex of a cellular hierarchy with an ADC | ||
| • This therapeutic candidate entered Phase 1 clinical trials | ||
| Brachyury | Claudia Palena, National Cancer Institute | • Brachyury is an embryonically relevant T-box protein required for the normal development of the mesoderm |
| • It is aberrantly expressed in various tumor types, including lung, breast, colon and prostate carcinomas• Primary tumors, metastatic lymph nodes | ||
| • and distant metastasis of breast cancer have been shown to be highly positive for Brachyury | ||
| • Expression of Brachyury in epithelial cancer cells drives EMT. Tumor cells undergoing EMT acquire features of stemness | ||
| • Expression of Brachyury in lung and | ||
| • breast carcinoma cells has been associated with resistance to conventional anti-cancer modalities | ||
| • As antibodies are not applicable and small molecules have been unsuccessful, T-cell mediated immunotherapeutic approaches against Brachyury are being developed | ||
| • Brachyury has been shown to be an immunogenic molecule; an HLA-A0201 epitope was identified (WLLPGTSTL) and used to efficiently expand Brachyury-specific CD8+ T cells from patients | ||
| • Brachyury-based cancer vaccine is in clinical development | ||
| HER-2/Neu | Brian Czerniecki, University of Pennsylvania | • Well characterized cell surface, cell growth receptor within the EGFR class of receptors, with amplified expression and prominent biology |
| • Expressed on CSC in luminal breast cancer | ||
| • When co-expressed with the estrogen receptor, HER-2 expression is up-regulated by mechanisms other than gene amplification | ||
| • CSC with dim Her-2 expression could have a role in tumor escape from targeted therapies, irrespectively of the Her-2 status of the primary tumor | ||
| • Her-2-directed antibody therapies are not applicable or not effective in patients with tumors that have modest levels of Her-2 expression | ||
| • Thus, alternate immune interventions to target such cells are needed, such as therapeutic vaccines, currently in development | ||
| EZH2 | Elaine Hurt, Medimmune | • Described an in vitro high throughput assay to discover novel targets associated with cancer stem cells |
| • These targets are amenable to antibody based immunotherapy and related approaches, as they are expressed on the cell membrane | ||
| • Described EZH2, a novel target associated with the Wnt/Notch pathway, and thus closely related to stemness | ||
| Cancer testes antigens (CTAs) | John Yu, Immunocellular Therapeutics | • Another source of cancer stem cell-associated targets is represented by glioblastoma, with convincing evidence in support of their existence |
| • These cells are largely chemorefractory and radioresistant, and responsible for tumor relapse | ||
| • As this cancer originates from the ectoderm, its shares antigens with melanoma. CTAs with restricted expression within normal vital organs, constitute a rich source of novel targets amenable to immunotherapy | ||
| • An approach has been designed to target such antigens by utilizing active immunotherapy (therapeutic cancer vaccination) to elicit multiple immune responses against glioblastoma cancer stem cells | ||
| Maurizio Chiriva-Internati, Texas Tech University | • Most CTAs characterized to date are expressed inside the cell and thus are targetable only through immunotherapies that are directed at MHC-restricted epitopes (therapeutic vaccines and TCR-engineered T cells) | |
| • There is emerging evidence that certain CTAs, associated with tumor initiating cells, can be also displayed onto the cell membrane | ||
| • Such targets are SP17, AKAP4, Ropporin, and PTTG1, expressed in a broad range of tumors of widely different histological origin: multiple myeloma, lung cancer, ovarian and prostate carcinoma | ||
| • AKAP4 in particular showed some promising evidence of membrane expression in multiple myeloma cells | ||
| • The possible expression of some CTAs onto the cell membrane, render these molecules promising targets for antibody and CAR-approaches |