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Table 1 Targets expressed on tumour initiating cells

From: Stem cells and cancer immunotherapy: Arrowhead’s 2nd annual cancer immunotherapy conference

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 A1
Wilms 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