Targets expressed on tumour initiating cells

EGFRvIIIAlbert 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
BrachyuryClaudia 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/NeuBrian 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
EZH2Elaine 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