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)  

(

HLA class I antigens in tumor cells

Clinical applications

1991-20111978-1990 2012-

Hybridoma methodology

Many HLA class I-specific mAbs

Renaissance phaseIndifferent phaseEnthusiasm phase

Anti-CTLA4

Anti-PD-1

Anti-PD-L1

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  

(

HLA class I antigens in tumor cells

Clinical applications

1991-20111978-1990 2012-

Hybridoma methodology

Many HLA class I-specific mAbs

Renaissance phaseIndifferent phaseEnthusiasm phase

Anti-CTLA4

Anti-PD-1

Anti-PD-L1

HLA Class I Antigen Processing in Tumors

6

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

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 TP25.99 HLA B/C mAb B1.23.2

8

HLA Class I APM component up-regulation by EGFR-specific mAb cetuximab in the head and neck

squamous cancer cell line JHU-029

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

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

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

(

HLA class I antigens in tumor cells

Clinical applications

1991-20111978-1990 2012-

Hybridoma methodology

Many HLA class I-specific mAbs

Renaissance phaseIndifferent phaseEnthusiasm phase

Anti-CTLA4

Anti-PD-1

Anti-PD-L1

Targeting Immunoregulatory Molecules in Cancer

15Figure adapted from A. Ribas, NEJM, 2012

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

17

Soldano Ferrone, MD, PhD

Departments of Surgey and Orthopedic SurgeryMassachusetts General Hospital,Harvard Medical School,Boston, MA (USA)

HLA class I antigen defects in malignant cells

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 mAb cetuximab on the head and

neck squamous cancer cell line JHU-029