Collaborations with Dr. PI Terasaki

1. Collaborations with Dr. PI Terasaki 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). Characterization of serum HLA antigens Ferrone S….., Terasaki PI: i) Tissue Antigens: 1975;5:41-7. ii) ImmunolCommun. 1972;1:77-91). HLA phenotypingofcultured B lymphoidcells(Ferrone S….., Terasaki PI: i) J ClinInvest. 1975;55:388-94. ii) Transplantation. 1976;22:61-8)  

2. HLA class I antigens in tumor cells ( Enthusiasm phase Renaissance phase Indifferent phase Anti-CTLA4 Anti-PD-1 Anti-PD-L1 Hybridoma methodology Many HLA class I-specific mAbs Clinical applications 1978-1990 1991-2011 2012-

3. Information in the literature   Defects in HLA class I antigens found in most if not all malignancies analyzed Characterization of the multiple molecular mechanisms underlying HLA class I antigen defects in malignant cells Assessment of the clinical significance of the HLA class I antigen defects found in malignant cells

4. HLA class I antigens in tumor cells ( Indifferent phase Enthusiasm phase Renaissance phase Anti-CTLA4 Anti-PD-1 Anti-PD-L1 Hybridoma methodology Many HLA class I-specific mAbs Clinical applications 1978-1990 1991-2011 2012-

5. HLA Class I Antigen Processing in Tumors

6. ERK1/2 activation in melanoma cells with a constitutively active BRAF-mutated 6

7. HLA Class I antigen up-regulation by BRAF-I and IFNα-2b on melanoma cells with an active BRAF-mutated SK-MEL-37 HLA Class I mAb TP25.99 HLA B/C mAb B1.23.2 BRAF-I IFNα-2b

8. HLA Class I APM component up-regulation by EGFR-specific mAbcetuximab in the head and neck squamous cancer cell line JHU-029

9. HLA-A2-MAGE-3 peptide complex up-regulation by EGFR-specific mAbcetuximab in the head and neck squamous cancer cell line JHU-029

10. HLA Class I APM component up-regulation by docetaxel in human cancer cell lines

11. Increased sensitivity to cognate CTL of human cancer cell lines treated with docetaxel

12. HLA Class I APM component up-regulation by radiation in human cancer cell lines

13. Conclusions • 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.

14. HLA class I antigens in tumor cells ( Renaissance phase Indifferent phase Enthusiasm phase Anti-CTLA4 Anti-PD-1 Anti-PD-L1 Hybridoma methodology Many HLA class I-specific mAbs Clinical applications 1978-1990 1991-2011 2012-

15. Targeting Immunoregulatory Molecules in Cancer Figure adapted from A. Ribas, NEJM, 2012

16. Conclusions • 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.

18. HLA class I antigen defects in malignant cells Soldano Ferrone, MD, PhD Departments of Surgey and Orthopedic Surgery Massachusetts General Hospital, Harvard Medical School, Boston, MA (USA)

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)

20. Model of HLA Class I APM component up-regulation by docetaxel in human cancer cell lines

21. HLA Class I antigen up-regulation by EGFR-specific mAbcetuximab on the head and neck squamous cancer cell line JHU-029