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DEVELOPMENT OF CELLULAR IMMUNOLOGY ________________________________________________ 1880’s : Antibodies described (dominated studies of immunology until 1960’s) 1958 : Journal of Immunology (137 papers) “lymphocyte” not listed in index Two papers on transfer of lymph node cells were the only papers dealing with lymphocytes 1960’s : Importance of cellular immunology recognized as mediator of: allograft rejection protection against transfer of mouse tumors 1970’s : No convincing evidence for human lymphocytes reactive with cancer or the existence of human cancer antigens No successful immunotherapies for cancer in humans
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DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

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Page 1: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

DEVELOPMENT OF CELLULAR IMMUNOLOGY________________________________________________1880’s: Antibodies described

(dominated studies of immunology until 1960’s)

1958: Journal of Immunology (137 papers)“lymphocyte” not listed in indexTwo papers on transfer of lymph node cells were the

only papers dealing with lymphocytes

1960’s: Importance of cellular immunology recognized as mediator of: allograft rejection

protection against transfer of mouse tumors

1970’s: No convincing evidence for human lymphocytes reactive with cancer or the existence of human cancer antigens

No successful immunotherapies for cancer in humans

Page 2: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

“It would be as difficult to reject the right ear and leave the left ear intact as it is to immunize against cancer.”

W. H. WoglumCancer Research

Page 3: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

ADVANTAGES OF CELL TRANSFER THERAPY

1. Administer large numbers of highly selectedcells with high avidity for tumor antigens.

2. Administer cells activated ex-vivo to exhibitanti-tumor effector function.

3. Manipulate host prior to cell transfer to provide altered environment for transferredcells.

Page 4: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Adoptive transfer of tumor infiltrating lymphocytes (TIL)

+

+

-

-

-

-

Excise tumor

Reinfuse post-lymphodepletion

Plate fragments

Culture with 6000 IU/ml IL-2

Assay for specific tumor

recognition

Select and expand to 1010 cells

Page 5: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

INITIAL RESULTS WITH CELL TRANSFER THERAPY FOLLOWING LYMPHODEPLETING

CHEMOTHERAPY

Six of 13 (46%) patients with metastatic melanoma experienced objective cancer regression.

Four patients had mixed or minor responses.

All had previously been refractory to IL-2 administration and eight had prior chemotherapy.

(Science 298:850-854, 2002)

Page 6: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Cell Transfer Therapy(10/1/09)

________________________________________________________Treatment Total PR CR OR (%)No TBI 43 16 5 21 (49%)

(84, 36, 29, 28 (85+, 79+, 69+,14, 13, 11, 8 68+, 54+)

8, 7, 4, 3, 3, 2, 2, 2)

Page 7: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Preparative Regimens for Cell Transfer______________________________________________

Days-7 -6 -5 -4 -3 -2 -1 0 1 2 3

_____________________________________________________________________Non-myeloablative Cy Cy Flu Flu Flu Flu Flu

Cells IL-2 IL-2 IL-2

_____________________________________________________________________Ablative Cy Cy

Flu Flu Flu Flu FluTBI

Cells IL-2 IL-2 IL-2CD34+

_____________________________________________________________________

Cy: Cyclophosphamide 60 μg/kgFlu: Fludarabine 25 mg/m2

IL-2: 720,000 IU/kg q8hCells: Autologous TIL (1-5 x 1010)CD34+: >2 x 106/kgTBI: 200 cGy total body irradiation

Page 8: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Cell Transfer Therapy(10/1/09)

________________________________________________________Treatment Total PR CR OR (%)No TBI 43 16 5 21 (49%)

(84, 36, 29, 28, (85+, 79+, 69+,14, 13, 11, 8, 68+, 54+)

8, 7, 4, 3, 3, 2, 2, 2)

200 TBI 25 11 2 13 (52%)(54+, 50, 44+, 14, (58+, 47+)10, 6, 5, 5,

4, 3, 3)

Page 9: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Preparative Regimens for Cell Transfer______________________________________________

Days-7 -6 -5 -4 -3 -2 -1 0 1 2 3

_____________________________________________________________________Non-myeloablative Cy Cy Flu Flu Flu Flu Flu

Cells IL-2 IL-2 IL-2

_____________________________________________________________________Ablative Cy Cy

(200cGy) Flu Flu Flu Flu FluTBI

Cells IL-2 IL-2 IL-2

CD34+_____________________________________________________________________Ablative Cy Cy

(1200cGy) Flu Flu Flu Flu FluTBI TBI TBI

CellsIL-2 IL-2 IL-2 IL-2

CD34+

Page 10: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Cell Transfer Therapy(10/1/09)

________________________________________________________Treatment Total PR CR OR (%)No TBI 43 16 5 21 (49%)

(84, 36, 29, 28, (85+, 79+, 69+,14, 13, 11, 8, 68+, 54+)

8, 7, 4, 3, 3, 2, 2, 2)

200 TBI 25 11 2 13 (52%)(54+, 50, 44+, 14, (58+, 47+)10, 6, 5, 5,

4, 3, 3)

1200TBI 25 10 8 18(72%)(35+, 28+, 21, 13, (38+, 19, 34+, 34+,

7, 6, 6, 5, 29+, 28+, 28+, 27+) 4 , 3)

(52 responding patients: 42 had prior IL-2, 21 had prior IL-2 + chemotherapy)

Page 11: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

0

10

20

30

40

50

60

70

80

Vaccines IL-2 Anti-CTLA-4 ACT ACT +NMA

ACT +NMA +TBI

% o

bjec

tive

resp

onse

(REC

IST)

n = 541

n = 684n = 139

n = 86

n = 43

n = 25

Objective response rates (RECIST) in metastatic melanoma patients treated in the Surgery Branch, NCI

Page 12: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

R.K. (NMA)

Page 13: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

J.B.

1200 TBI

Page 14: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Pt. M.H.

Page 15: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Pt. M.H.

Page 16: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Pt. R.B.

Page 17: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Pt. R.B.

Page 18: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

C.K. (200cGy) Pre 12 days

Page 19: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

A.H.: N-M cell transfer

Page 20: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Pt. A.H. NMA

Page 21: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

P.T.

Young TILCD8

Page 22: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

P.T.Young TIL

CD8

Page 23: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology
Page 24: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Hypothesis of Mechanism of Cancer Regression Following Cell Transfer

The lymphophenic environment

1) eliminates T regulatory (suppressor) cells

2) eliminates competition for homeostaticcytokines (IL-7, IL-15) vital forT cell survival

In the lymphopenic host, anti-tumor T cells proliferate, persist, infiltrate organs, recognize cancer antigens and destroy cancer cells.

Page 25: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

pg/m

l IL-

15

0

20

40

60

80

No TBI 200 TBI 1200 TBI

Impact of Lymphodepletion on Serum Levels Of IL-15 and IL-7

pg/m

l IL-

7

0

20

40

60

80

PrePrePre Day 0Day 0Day 0

Page 26: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Three Factors that Correlate with Cancer Regression Following Cell Transfer Therapy

_______________________________________________

Non-Responders Responders

_______________________________________________________________(mean)

Persistence in PBMC at 18.5 1.0 p<0.0011-2 months (% CD3)

Telomere length in infusion 6.5 5.4 p<0.01TIL (kb)

CD27+CD8+ cells infused 1.5 0.46 p<0.0001(x10-10)

Page 27: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Simplification of adoptive immunotherapy to make it more widely applicable

_______________________________________________________________

Administer “Young TIL” (new method of cell preparation)

single cell suspension of the entire tumor, grow for 2 weeks REP for 2 weeks and administerno in vitro testing

Advantages:

short time in culture cells are less differentiated with shorter telomeres heterogeneous tumor antigen recognitionless labor intensive (no multiple cultures and no functional tests)more patients qualify for treatment

Page 28: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Cell Transfer Therapy(10/1/09)

_______________________________________________Treatment Total PR CR OR (%)

________________________________________________________________number of patients (duration in months)

Young TIL 24 4 1(25+,10,5,2) (16+) 5 (21%)

Page 29: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Cell Transfer Therapy(10/1/09)

_______________________________________________Treatment Total PR CR OR (%)

________________________________________________________________number of patients (duration in months)

Young TIL 24 4 1(25+,10,5,2) (16+) 5 (21%)

CD8 Young TIL 33 15 3 18 (55%)(12+,11+,10+,9+, (10+,8+,6+)9+,8+,6+,6+,4+,9,8,6,5,3,2)

Page 30: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

CONCLUSION

T cell based immunotherapy is capable of mediating the regression of large vascularized, invasive metastatic melanoma in humans

(The widely-held belief that immunotherapy can only affect minimal disease in the adjuvant setting is not the case.)

CHALLENGEDetermine ways to extend this approach to:

1) additional melanoma patients

2) patients with common epithelial cancers

Page 31: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Antigen recognition by CD4+ and CD8+ T lymphocytes

Page 32: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

IRESAIB LTR

MSGV1martAIB

anti-Mart-1 retroviral vector

TCR TCR

LTR

(Science 314:126,2006)

Page 33: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Treatment with MART-1 TCR transducedautologous lymphocytes

• Stimulate circulating PBL with OKT-3

• On day 2 and 3 transduce PBL with MART-1 TCR retroviral vector and culture in IL-2

• Infuse transduced cells following lymphodepletion of the host and administer IL-2

(Science 314:126, 2006)

Page 34: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

First Trial of Cell Transfer Therapy using TCR Gene‐Modified Cells

________________________________________________________

17 patients with metastatic melanoma      (Science, 314:126, 2006)

2 (12%) with objective regressions  

(both disease free over three years later)

14 additional patients treated

2 further objective regressions

Overall:  4/31 (13%) objective regressions

(Science 314:126, 2006)

Page 35: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

DMF4 and DMF5 MART1 andgp100(154) TCR retroviral constructs

gp100(154 ) (high-affinity murine TCR)

5’ LTR TCR IRES TCR 3’ LTR

5’ LTR TCR IRES TCR 3’ LTR

5’ LTR TCR 2A TCR 3’ LTR

DMF4 (previous MART1 clinical trial)

DMF5

Page 36: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Gene Therapy Using the DMF5 Receptor in Patients with Metastatic Melanoma

________________________________________________________

Cohort Cell# IL-2 ResponseTotal OR

________________________________________________________1 1-3x1010 limited 6 2

2 ~3x109 to tolerance 6 2

3 1-8x1010 to tolerance 8 2

Total 20 6(30%)

(All patients were refractory to prior treatment with IL-2.)

(Blood 114:535-546, 2009)

Page 37: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

D.T. DMF5 TCR

Page 38: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

J.K. F5 TCR

Page 39: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

T.D. F5 TCR

Page 40: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

S.S. 154 TCR

Page 41: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

D.Th. F5 TCR Pretreatment

Page 42: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Day 0 Day 6

Day 11 Day 20

Sequential tumor biopsies (D.Th.): MART TCR

Page 43: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

day 0 day 5 day 6 day 9

12 day day 16 day 19 day 26

Sequential tumor biopsies (D.Th.): MART TCR (CD8, 40x)

Page 44: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Two methods to improve the effectiveness of transduced T cell receptors

Reduce mispairing of the transduced alpha and beta chains

Modify the CDR2 and CDR3 regions of the TCR to improve antigen recognition

Page 45: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Optimizing Expression of the TCR Vector Constructs

Protein engineering of TCR chains

VDJ EX

EX TM CYVDJ

TM CY

SS

TCR Constant Region

SS

originalnew

Substitution of murine for human constant regions enhances pairing of the introduce TCR chains

Introduction of a secondCys disulfide bridge.

Page 46: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Human Constant Regions

F5-HH

Constant Regions: H

Page 47: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Human CR+ Cysteines

F5-HH-Cys

Constant Regions: H<H-Cys

Page 48: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Mouse Constant Regions

F5-HM

Constant Regions: H<H-Cys<M

Page 49: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Mouse CR + Cysteines

F5-HM-Cys

Constant Regions: H<H-Cys<M<M-Cys

Page 50: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

Method for increasing the affinity of T cell receptors_______________________________________________

CDR2 and CDR3 regions of the T cell receptor are responsible for binding to the peptide/MHC complex.

Selective substitution of individual amino acids in the CDR2 and CDR3 regions can increase the affinity of the TCR.

(J. Immunol. 180:6116-6131, 2008.)

Page 51: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

1G4 CDR395

WT TS

95:L L-

96:L -L

95:LL LL

95:LY LY

GFP

A2 NY-ESO-1+ +

+ +

+ +

+ +

+ -

+ -

1G4 CDR395

WT TS

95:L L-

96:L -L

95:LL LL

95:LY LY

GFP

CD4+ T cells CD8+ T cells

0 2000 4000 6000 8000

3 9 7 A 26 2 4 .3 81 3 0 0M D A 4 3 5 S -A 25 2 68 8 8 A 2

0 5 0 00 1 0 0 00 1 5 0 00 2 0 0 00 2 5 0 0 0IFN- (pg/ml)

Reactivity of Wild-type and Substituted Anti-ESO T Cell Receptor

Page 52: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

CONCLUSION

T cell based immunotherapy is capable of mediating the regression of large vascularized, invasive metastatic melanoma in humans

(The widely-held belief that immunotherapy can only affect minimal disease in the adjuvant setting is not the case.)

CHALLENGEDetermine ways to extend this approach to:

1) additional melanoma patients

2) patients with common epithelial cancers

Page 53: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

T-Cell Receptor Cell Transfer Gene Therapy for Cancers Other than Melanoma

_______________________________________________

NY-ESO-1 Cancer-testes antigen expressed on about one-third of common cancers

CEA Overexpressed on selected colorectal and other G-I cancers

CD19 Expressed on B-cell lymphomas and leukemias and normal B cells

Page 54: DEVELOPMENT OF CELLULAR IMMUNOLOGY · DEVELOPMENT OF CELLULAR IMMUNOLOGY _____ 1880’s: Antibodies described (dominated studies of immunology until 1960’s) 1958: Journal of Immunology

NY-ESO-1 CANCER ANTIGEN____________________________________________

No expression on adult human tissues except for testis

Expressed on about 25% of common epithelial cancers such as lung, breast, prostate