Transcript A Better Immunotoxin Against Cancer - FLC Mid

A better
immunotoxin
against cancer
Monoclonal antibodies
VL
Ck
VH
C 1
H
CH1
Ck
IgG
VH
VL
Gets cancer cells to commit suicide
Get immune system to kill cancer cells
Examples: Rituximab, Alemtuzumab, Herceptin
Radiolabeled Monoclonal antibodies
VL
Ck
VH
C 1
H
CH1
Ck
IgG
VH
VL
Targets radiation to the cancer cell
Examples: Zevalin, Bexxar
Immunotoxins
VL
Ck
VH
C 1
H
CH1
Ck
IgG
VH
VL
Inhibition of protein synthesis
Cell death
TOXIN
RECOMBINANT IMMUNOTOXINS
VL
Ck
VH
C 1
H
CH1
Ck
RFB4
VH
VL
VL
VH
-s-s-
C
3
II
Ib
III
Ib
III
BL22
Ia
II
PE
CD22
BL22
III
II
REDL
II
III
S
III
S
II
Ia
VL
VH
-s-s-
II
III
RFB4(dsFv)-PE38 (BL22)
ENDOSOMES
REDL
III
II
REDL
III
Ia
II
SH H
S
II
COATED
PIT
III
PE38
III
III
III
SHUTTLE
II
PSEUDOMONAS EXOTOXIN
III
II
III
II
II
ER
II
Ia
GOLGI
III
II
II
EF2
KDEL
RECEPTOR
CYTOSOL
HAIRY CELL LEUKEMIA
B-cell leukemia
2% of all Leukemias
Low blood counts
Splenomegaly (large spleen)
Cytoplasmic projections
Treatment of HCL
Cladribine (CdA) and Pentostatin
(DCF) can induce long term CRs
but have not been shown to cure
the disease. They have
decreased efficacy with each
repeated course.
Phase I Trial of BL22 in CdA-Resistant HCL
Summary
• Response:
Total
CR
PR
CR+PR
31 19 (61%) 6 (19%) 25 (81%)
• CR rate 86% at high doses, 41% at low doses
• Most (11/19) CRs were after just 1 cycle
• Toxicity: Most commonly temporary fluid retention
Kreitman et al., NEJM, 345:241, 2001, Kreitman et al., JCO, 23:6719, 2005
Phase II Trial of BL22 in HCL
Results
Retreat 56%
CR:
HR:
PR:
SD:
Complete remission
Hematologic remission (good blood counts)
Partial remission (>50% improvement)
Stable disease PD: Progressive disease
Conclusions:
• One cycle highly active
• Retreatment improved best response
Disease-Free Survival (%)
Phase II Disease-free survival
100
80
|
|
| || | |
| |
| | |
60
40
n=17 (Patients achieving CR)
20
Median CR duration = 31+ (5-59+) mo
12/17 (71%) still in CR
0
0
10
20
30
40
50
Months from beginning BL22
60
/mm
3
g/dl
CELLS/mm
3
x10
-3
Complete remission with BL22
4
3
2
1
0
300 C1
250
200
150
100
50
0
18
16 C1
14
12
2000 C1
1500
1000
500
0
0
ANC
C2
C3
PLATELETS
Col 4 vs Col 10
C2
HGB
C3
HCL
50
PLATELETS
C3
HGB
C2
ANC
100
150
200
250
HCL
300 29003100
DAY OF BL22 PROTOCOL
Resolution of Splenomegaly with BL22
Pre
(Height = 250 mm)
C7D1
(Height = 125 mm)
CD4 counts in HCL Pre and Post BL22
CD4 count (cells/ul)
1000
800
600
400
200
0
Pre
Post
Conclusions:
• Hairy cell leukemia is a chronic leukemia which shows no
evidence of cure with standard chemotherapy, so
patients who are young may die of this disease without
alternative treatment.
• BL22 is highly active in HCL despite patients not
responding to standard HCL therapy.
• Compared to standard chemotherapy, BL22 is not toxic to
normal T-cells and does not even have prolonged
damage to normal B-cells.
• HA22 (CAT-8015), an improved version of BL22, is
completing Phase I testing in HCL.
COLLABORATORS: BL22
LMB:
IRA PASTAN
DAVID J.P. FITZGERALD
Q.C. WANG
MASANORI ONDA
G. SALVATORE
B.K. LEE
CLINICAL IMMUNOTHERAPY SECTION, LMB
INGER MARGULIES
EVGENY ARONS
KAKUSHI MATSUSHITA ROBERTA TRAINI
TARA SUNUM
RAJAT SINGH
rIMMUNOTOXIN CLINICAL TEAM (CCR)
LINDA ELLISON
ELIZABETH MAESTRI
RAFFIT HASSAN
RITA MINCEMOYER
BARBARA DEBORAH
SONYA DUKE
EMORY: HARRY FINDLEY
PATHOLOGY:
MARYALICE STETLER- STEVENSON
ELAINE S. JAFFE
MARK RAFFELD
MEDICINE / PED BRANCH:
WYNDHAM H. WILSON
ALAN WAYNE
MARP FACILITY (DTP):
STEVE GIARDINA
DANIEL COFFMAN
TOBY HECHT
MedImmune:
BOB LECHLEIDER
KATHERINE KAUCIC
PHARMACY:
GEORGE GRIMES
DAVID KOHLER
HEMATOLOGY: PIERRE NOEL, MARGARET RICK, JAY LOZIER
/mm
3
C1
3
2
1
0
300
200
100
0
g/dl
CELLS / mm3 x 10-3
BL22 PATIENT BH20
ANC (Neutrophils)
ANC (Neutrophils)
C1
PLATELETS
PLATELETS
C1
14
12
10
8
10
Hemoglobin (Red cells)
Hemoglobin (Red cells)
C1
Hairy cell count
Hairy cell count
5
0
-25
0
25
50
75
100
500
DAY OF BL22 PROTOCOL
1000