Bild 1

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CCK CancerCenterKarolinska
Individual Idiotype Vaccines in Hematological
Malignancies
Håkan Mellstedt M.D., Ph.D.Professor of
Oncologic Biotherapy at the Karolinska
Institute Managing Director, CancerCenterKarolinsk
a Karolinska University HospitalStockholm, Sweden
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B cell malignancies are clonal expansions of B
lymphocytes at various stages of maturation
expressing a unique immunoglobulin, the idiotype.
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Idiotype as a Tumor Specific Antigen
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The Idiotype is a Tumor Specific Antigen, which
can be Exploited as A Target for Vaccine
Treatment (I)

• The individual idiotype is expressed as a
  complete surface bound immunoglobulin molecule.
• Idiotype vaccination induced antibodies(B cell
  response) should be of therapeutic benefit.

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The Idiotype is a Tumor Specific Antigen, which
can be Exploited as A Target for Vaccine
Treatment (II)

• Peptide fragments of the idiotype V-region (CDR
  and FR) can be exhibited by MHC class I and II
  molecules on the tumor cells.
• Idiotype vaccination induced CD4 and CD8 T cell
  responses should be of therapeutic benefit.

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Idiotype Vaccine Development in Progress for B
cell Malignancies

• Non-Hodgkin lymphoma (mainly follicular
  lymphoma)
• CLL
• Multiple myeloma

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Spontaneous Idiotype Immunity
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Naturally occurring type I (IFN-?) T cells
(ELISPOT) recognizing 8- to 10-aa long peptides
from the CDR regions of the tumor-derived
idiotypic immunoglobulin
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Naturally occurring type I (IFN- ?) T
cells(ELISPOT) recognizing 15- to 20-aa long
peptides from the CDR regions of tumor-derived
idiotypicimmunoglobulin
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Schematic presentation of natural occuring
idiotype reactive T cells in patients with MM at
different stages of the disease
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Idiotype vaccination in pre-clinical models
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Kwak et al PNAS9310972-10977, 1996
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Kwak et al PNAS9310972-10977, 1996
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Kwak et al PNAS9310972-10977, 1996
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The role of Id humoral and cellular responses in
eradication of myeloma cells.
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Schematic diagram showing production of
Id-vaccines using the hybridoma technology.
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Published clinical trials of Id vaccination in
lymphoma
Neelapu et al Expert Review Vaccine 5381-394,
2006
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Comparison of idiotype vaccine therapies for
follicular lymphoma
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Lymphoma Id vaccines in Phase III clinical trials
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Induction of Complete Response Following
Vaccination
Neelapu et al, 2006
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A humoral response was associated with a
significantly longer time to tumor progression
(TTP), whereas a cellular immune response was not.
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Vaccination with Idiotype-KLH Adjuvant in
Follicular Lymphoma Immune Responders vs.
Non-Responders
Progression-free Survival
Overall Survival
Alive ()
Alive ()
100
100
p 0.04
Responder (n14)
80
80
60
p lt 0.0001
60
40
40
Responder (n14)
Non-Responder (n18)
Non-Responder (n18)
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Historical Controls (n260)
0
0
0
2
4
6
8
10
12
14
16
18
0
2
4
6
8
10
Years after last chemotherapy
Years after diagnosis
Hsu et al., Blood 1997
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Vaccination with Idiotype-KLH Adjuvant in
Follicular Lymphoma PFS in Humoral Immune
Responders and FcgRIII Genotype
Weng et al., JCO 2004
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Idiotype Vaccination in NHLClinical Response
Assessment
Redfern et al, JCO 243107, 2006
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Idiotype Vaccination in NHL
Redfern et al, JCO 243107, 2006
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Idiotype Vaccination in NHL Immune Responses in
Patients with Objective Responses
Abbreviations KLH, keyhole limpet hemocyanin
Id, Idiotype , positive -, negative PR,
partial response CR, complete response
Redfern et al, JCO 243107, 2006
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Idiotype vaccination in first relapse and
achieving CR after chemotherapy
Inoges et al JNCI 981292-1300, 2006
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Clinical Benefit Associated With Idiotypic
Vaccination in Patients With Follicular Lymphoma
Relapse-free survival curves
A) Relapse-free survival after the first and
second clinical complete responses (CR) of all 25
vaccinated patients. B) Relapse-free survival
after the first and second CR of vaccinated
patients after stratification for immune
responsiveness to the vaccine. There were 20
responders and five nonresponders. C)
Relapse-free survival after the first and second
complete response of the 18 immune responders
who, at first relapse, had received a prevaccine
treatment that would not be considered superior
to the up-front therapy received shortly after
diagnosis (that is, all immune responders but UPN
1 and UPN 23). P values are from adjusted
log-rank tests, computed and matched by patient
to take into account the paired nature of
survival times. P value of (B) refers to the sole
comparison between cumulative relapse-free
survival of the 20 immune responders after
achieving first and second complete response,
respectively.
Inoges et al JNCI 1292/1300 2006
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Idiotype Vaccination in Multiple Myeloma Stages
I/II
I. Idiotype alone vaccination. In 2/5 a transient
T cell response. No clinical response. II. Idiotyp
e GM-CSF. A T cell response in 5/7 patients.
Both MHC class I and II restricted type I T cell
responses. 1/7 had a partial remission (gt 50
M-comp. reduction). III. Idiotype IL-12 GM-CSF
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Idiotype Vaccination with IL-12 or IL-12 Plus
GM-CSF

• Twenty-eight IgG myeloma patients, clinical stage
  I-IIA were included.
• Autologous idiotypic Ig (M-component) in alum was
  given i.c. during induction phase (14 weeks) and
  the maintenance phase (96 weeks).
• Adjuvant cytokines
• IL-12 was given s.c. on day one (IL-12 group)
  (n15)
• IL-12 s.c. on day one GM-CSF s.c., days 1-4
  (IL-12/
• GM-CSF group) (n13)
• Read out systems
• Proliferation assay (3H-thymidine)
• ELISPOT assay
• DTH
• Real-time PCR for cytokines

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Frequency of Patients Mounting an Idiotype
Specific T Cell Response
Adjuvant Frequency cytokines IL-12/GM-CSF 11
(85) (n13) IL-12 4 (27) (n15)

p0.01
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Characterization of the Cellular Immune Response
Based on the Cytokine Pattern (Real-Time PCR)
Adjuvant Th1 Th2 Mixed
Neg cytokine IL-12 6 0 3
0 (n 9) IL-12/GM-CSF 2
4 2 1 (n9) The difference
comparing a Th1 and Th2 response is statistically
significant (plt0.05) 2 patients positive in
proliferation assay/ELISPOT 7 patients
positive in proliferation assay/ELISPOT
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Relation Between Induction of Idiotype-specific
T Cell Response and Tumor Volume (M-Component
Conc.)
Patients with an M-component conc. gt50 g/L did
not mount an immune response
Clin Cancer Res 200713(5)1503-10.
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Relative Change in Treg Cells (CD4 CD25 Foxp3)
over Time in Immune Responders (n12) and
Non-responders (n8)
P lt 0.001
The difference was statistically significant
(plt0.01).
Clin Cancer Res 200713(5)1503-10.
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Median Time to Progression (TTP) in Myeloma
Patients Vaccinated with the Idiotype Comparing
Immune Responders (N16) (?) and Non-Immune
Responders (N12) (- - - -) (p0.03)
Clin Cancer Res 200713(5)1503-10.
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RT-ASO-PCR for Circulating Myeloma B Cells (CMC)
(Patient No. 3)
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Declining Circulating Myeloma B Cells (CMC)
During Idiotype Vaccination
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Idiotype Vaccination in Patientswith Multiple
Myeloma

• Total no. of patients 188
• Freq. () of idiotype spec. 65 (58-72) immune
  responses (mean CI95 )
• Clinical effects OR (CR, PR, MR) () 24 (19-29)
  (mean CI95 )

best response in any test ab, in vitro
cellular, DTH
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Summary of idiotype vaccination

• In lymphoma both a humoral and cellular immune
  response seems to be of therapeutic value.
• In multiple myeloma, only a cellular immune
  response might be of therapeutic value.
• In both diseases adjuvant vaccination might be of
  preference.
• Results of phase III clinical trials in
  follicular lymphoma might be expected in 2009.
• Is the idiotype the optimal tumor antigen in B
  cell malignancies?