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1 Collaborations with Dr. PI Terasaki 1.Natural anti-human lymphocyte cytotoxic antibodies in mammalian sera (Ferrone S….., Terasaki PI: i) Transplantation. 1973;16:287-94. ii) Tissue Antigens. 1973;3:88-94). 2.Characterization of serum HLA antigens Ferrone S….., Terasaki PI: i) Tissue Antigens: 1975;5:41-7. ii) Immunol Commun. 1972;1:77-91). 3.HLA phenotyping of cultured B lymphoid cells (Ferrone S….., Terasaki PI: i) J Clin Invest. 1975;55:388-94. ii) Transplantation. 1976;22:61-8)
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( HLA class I antigens in tumor cells Clinical applications 1991-20111978-19902012- Hybridoma methodology Many HLA class I- specific mAbs Renaissance phase Indifferent phase Enthusiasm phase Anti-CTLA4 Anti-PD-1 Anti-PD-L1
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Information in the literature 1.Defects in HLA class I antigens found in most if not all malignancies analyzed 2.Characterization of the multiple molecular mechanisms underlying HLA class I antigen defects in malignant cells 3.Assessment of the clinical significance of the HLA class I antigen defects found in malignant cells
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( HLA class I antigens in tumor cells Clinical applications 1991-20111978-19902012- Hybridoma methodology Many HLA class I- specific mAbs Renaissance phase Indifferent phase Enthusiasm phase Anti-CTLA4 Anti-PD-1 Anti-PD-L1
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HLA Class I Antigen Processing in Tumors
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6 ERK1/2 activation in melanoma cells with a constitutively active BRAF-mutated
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HLA Class I antigen up-regulation by BRAF-I and IFNα-2b on melanoma cells with an active BRAF-mutated SK-MEL-37 IFNα-2b BRAF-I HLA Class I mAb TP25.99HLA B/C mAb B1.23.2
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8 HLA Class I APM component up-regulation by EGFR-specific mAb cetuximab in the head and neck squamous cancer cell line JHU-029
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9 HLA-A2-MAGE-3 peptide complex up-regulation by EGFR-specific mAb cetuximab in the head and neck squamous cancer cell line JHU-029
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10 HLA Class I APM component up-regulation by docetaxel in human cancer cell lines
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11 Increased sensitivity to cognate CTL of human cancer cell lines treated with docetaxel
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12 HLA Class I APM component up-regulation by radiation in human cancer cell lines
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13 HLA class I antigen expression by malignant cells is modulated by signaling transduction pathways, chemotherapy and radiotherapy. These changes are associated with an increased T cell recognition and destruction of cancer cells. Conclusions
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( HLA class I antigens in tumor cells Clinical applications 1991-20111978-19902012- Hybridoma methodology Many HLA class I- specific mAbs Renaissance phase Indifferent phase Enthusiasm phase Anti-CTLA4 Anti-PD-1 Anti-PD-L1
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Targeting Immunoregulatory Molecules in Cancer 15 Figure adapted from A. Ribas, NEJM, 2012
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16 Immunotherapy with check point molecule-specific mAb induces dramatic and long lasting responses, but only in up to 30% of patients. These findings emphasize the need to identify biomarkers to select patients who may benefit from this therapy HLA class I antigen expression by malignant cells may be a useful biomarker since defects in HLA class I antigen expression may protect tumor cells. Conclusions
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Soldano Ferrone, MD, PhD Departments of Surgey and Orthopedic Surgery Massachusetts General Hospital, Harvard Medical School, Boston, MA (USA) HLA class I antigen defects in malignant cells
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19 Acknowledgements Francesco Sabbatino, MD, PhD Cristina R. Ferrone, MD James Hodge, PhD (NCI, Bethesda, MD) Robert L. Ferris, MD, PhD (University of Pittsburgh, Pittsburgh, PA)
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20 Model of HLA Class I APM component up-regulation by docetaxel in human cancer cell lines
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21 HLA Class I antigen up-regulation by EGFR-specific mAb cetuximab on the head and neck squamous cancer cell line JHU-029
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