Tumor Antigen Immunization of
Human Allotransplant Donors
in Myeloma
Michael R. Bishop, Sattva Neelapu, Daniel Fowler, Claude Kasten-Sportes,
Ronald Gress, Michael Krumlauf, Kathleen Castro, and Larry W. Kwak
Experimental Transplantation and Immunology Branch
National Cancer Institute/National Institutes of Health
Bethesda, MD, USA
M.D. Anderson Cancer Center
Houston, TX, USA
Introduction
Progression and relapse are significant problems with
reduced-intensity allogeneic stem cell transplantation (RIST).
The idiotypic determinants (Id) of the surface and cytoplasmic
immunoglobulin (Ig) of myeloma cells provide tumor-specific
antigen, which is distinct from antigens on normal cells, to
serve as an ideal vaccine.
Idiotype vaccine can be given not only to myeloma patients,
but also to normal allogeneic donors to induce tumor-specific
immunity prior to stem cell donation.
Hypothesis: Vaccination in donors with patient-specific
idiotype would result in improved remission rates and
decrease relapse in myeloma patients undergoing RIST.
PBMC Responses to Myeloma Id
CD4+ T Cell Proliferation
DONOR
RECIPIENT +30
RECIPIENT +60
Lancet 345:1016, 1995
Active Immunization Of Donors Against Purified Myeloma Protein
Of The Recipient Undergoing An Immunoablative Allogeneic
Hematopoietic Stem Cell Transplantation (CC 00-C-0201)
Primary Objectives:
1) To induce cellular and humoral immunity in allogeneic stem
cell donors and recipients against the unique idiotype
expressed by the recipient's myeloma.
2) To determine whether antigen-specific immunity, induced in
the stem cell donor, can be passively transferred to the
allogeneic HSCT recipient in the setting of a reduced-intensity
conditioning regimen.
Patient Eligibility
Patients with IgG or IgA multiple myeloma.
The concentration of the M protein in harvested
plasma >70% of the total serum Ig of the
corresponding isotype.
At least a partial remission following
conventional therapy or after autologous stem
cell transplantation.
18 - 75 years of age.
Consenting first degree relative matched at 6/6 or
5/6 HLA antigens.
Vaccine Generation and Donor Vaccination
Plasmapheresis of recipient prior to initiation of therapy.
Ig is purified and conjugated to keyhole limpet hemocyanin (KLH) and
emulsification in adjuvant.
Vaccine requires 2-3 months for generation.
Donor receives 3 SQ injections of Id-KLH vaccine within 10 weeks before
stem cell collection:
First injection with Id-KLH + GM-CSF (week 0).
Second injection with with unconjugated Id + GM-CSF (week 2).
Third injection with unconjugated Id + GM-CSF (week 6) after study.
Stem cell collection (week 10) after mobilization with G-CSF.
Active Immunization Of Siblings Donors Against Purified
Myeloma Protein Of The Recipient Undergoing Allogeneic HSCT
(CC 00-C-0201)
RECIPIENT
DONOR
Plasma
Apheresis
Id-KLH vaccine generation
Induction chemo:
EPOCH-F
Vaccine x 3
I
Conditioning:
Fludara/CY
Stem cell mobilization and
GVHD: CsA +/- MTX
collection
Vaccine @ +3, +4, and +6
months post-transplant
Results - Donors
Vaccine successfully generated from all (N = 10) plasma
donations forwarded for vaccine production.
Seven matched siblings have undergone vaccination.
All donors completed vaccination series.
Single Grade 3 toxicity (NCI CTC) - lymphopenia (transient).
Grade 1 and 2 toxicities characterized reactions at the
injection sites (erythema, pain, induration, and pruritus) and
pain (arthralgias, bone pain, chest pain).
KLH-specific immunity was induced in all of the first 3 donors
tested and Id-specific immunity was induced in 2 of the first 3
donors tested.
Induction of Id-specific Immunity
DB (Donor)
3500
800
GM-CSF
IFNg
700
3000
PBMC alone
600
l 2500
PBMC alone
Id
l
/m
500
Id
g
/m
2000
p
Irrel. Id
g
Irrel. Id
-
p 400
F
-
S 1500
gN
-C
300
M
IF
G 1000
200
500
100
0
0
Prevaccine
1 mo Post 3rd vaccine
Prevaccine
1 mo Post 3rd vaccine
Time Point
Time Point
RIST Patient Characteristics
N = 7
Subtype: IgG = 5, IgA = 2
Ages: 50 - 60 years
M = 4/F = 3
Prior autologous HSCT = 3
Results - Recipients
N = 5 (evaluable > 6 months)
Median donor chimerism at day +28 = 100% (85 100%)
GVHD:
Grade II-IV acute GVHD = 1
Limited chronic GVHD = 3
Extensive chronic GVHD = 1
Treatment-related deaths = 2 (GVHD at day +67 and 1 year)
Response:
CR = 3 (2, 23+, 17+ months post-RIST)
PR = 2 (12, 6+ months post-RIST).
No disease progression observed.
Transfer of KLH-specific CD4+ and CD8+ T cell immunity
DB (Donor) - 1 mo. Post 3rd Vaccine
No Ag/CD4
KLH / CD4
No Ag / CD8
KLH / CD8
.02%
.29%
.01%
.16%
DA (Recipient) - Day 100 Post PBSCT
No Ag/CD4
KLH / CD4
No Ag / CD8
KLH / CD8
.71%
.10%
.06%
.22%
Id-specific Immunity
DA (Recipient)
GM-CSF
IFNg
250
90
80
200
l
70
PBMC alone
PBMC alone
/m
l 60
Id
g 150
Id
/m
p
g
-
50
Irrel. Id
F
Irrel. Id
p
S
-g 40
100
-C
N
M
IF 30
G
50
20
10
0
0
Day 60 Post SCT
Day 100 Post SCT
Day 60 Post SCT
Day 100 Post SCT
Time Point
Time Point
Blocking of Id-specific T cell Responses with HLA
Class I and Class II Antibodies
600
No Ag
500
Id
Irrelevant Id
Id + G1
l 400
Id + MHC class l
/m
Id + G2a
gp
Id + MHC Class ll
-e 300
ink
toyC 200
100
0
GM-CSF
TNFa
DA (Recipient) Day 100 Post HSCT
Observations and Conclusions
Id-KLH vaccines can be safely and effectively given
to normal stem cell donors.
Tumor specific immunity can be induced in donor
with Id vaccination.
There was evidence of possible transfer of tumor
specific immunity from donor to recipient.
Vaccination of donors with tumor-specific antigen
represents a tactic to potentially reduce progression
and relapse after allogeneic stem cell
transplantation.
Collaborators
National Cancer Institute
M.D. Anderson Cancer Center
Daniel Fowler, MD
Sattva Neelapu, MD
Claude Kasten-Sportes, MD
Larry W Kwak, MD, PhD
Ronald Gress, MD
Sergio Giralt, MD
Michael Krumlauf, RN
Kathleen Castro, MS, RN
Document Outline