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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1184-1190
Anti-Idiotype Antibodies Can Induce Long-Term Complete Remissions
in Non-Hodgkin's Lymphoma Without Eradicating the Malignant Clone
By
Thomas A. Davis,
David G. Maloney,
Debra K. Czerwinski,
Tina-Marie Liles, and
Ronald Levy
From the Division of Medical Oncology, Stanford University School of
Medicine, Stanford, CA; and the Fred Hutchinson Cancer Center,
University of Washington, Seattle, WA.
 |
ABSTRACT |
The immunoglobulin on the surface of B-cell lymphomas can be a
tumor-specific target for monoclonal antibody therapy. Between 1981 and
1993, 45 individuals with low grade B-cell lymphoma were treated with
52 courses of custom-made anti-idiotype antibodies. The antibodies were
used either alone or in combination with  -interferon, chlorambucil,
or interleukin-2 (IL-2). The majority of these patients responded to
treatment, with a 66% overall and 18% complete response rate. Six
patients (13%) experienced prolonged complete remissions, five of
which are ongoing from 4 to 10 years after therapy and are the subject
of this report. We asked whether residual lymphoma could be found in
these patients with prolonged remissions. We performed enzyme-linked
immunosorbent assay (ELISA) assays for idiotype protein or
anti-idiotype antibodies in serum. Blood and bone marrow samples were
examined by flow cytometry for idiotype positive cells, and by
polymerase chain reaction (PCR) for clonal gene rearrangements of
immunoglobulin CDR3 sequences or t(14;18) translocations. Using these
sensitive and specific tests it was possible to detect very low levels
of residual lymphoma in five of these patients who had been in clinical
remission for 3 to 8 years before this evaluation. These five have
continued without recurrence for up to 3 years since. Thus, we have
found a pattern of residual inactive disease in patients treated with
anti-idiotype antibodies. The biology of follicular lymphoma evidently
includes the potential for tumor dormancy after therapies with varied
mechanisms of action, resulting in clinical inactivity for many years.
Thus, long-term control of the disease is possible at a clinical level despite persistence of the malignant clone.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
MOST HUMAN LYMPHOMAS are derived from B
lymphocytes, which express a cell surface immunoglobulin
molecule.1 The immunoglobulin of each B cell is unique,
containing two variable regions that normally serve as recognition
sites for foreign antigens. These variable regions are formed by the
rearrangement of the germ line immunoglobulin genes. This genetic
rearrangement allows for the tremendous diversity of human
immunoglobulins, a critical feature of the immune system. When a B cell
undergoes malignant transformation, it creates a clonal population of
cells, each of which expresses the same unique receptor,2
or "idiotype". Antibodies can be produced, which target the
unique idiotype of each malignant clone (anti-idiotype
antibodies).3 Soon after the introduction of hybridoma
technology, we developed mouse monoclonal antibodies against the
idiotypes expressed by B-cell lymphomas and used these antibodies in
therapeutic trials. We have previously reported the results of these
trials, where such monoclonal anti-idiotype antibodies were used alone
or in combination with -interferon, chlorambucil, or interleukin-2
(IL-2) as therapy for patients with B-cell lymphoma.1,4-7
In four different trials, 45 patients were treated with 52 courses of
anti-idiotype monoclonal antibodies. Eight patients experienced
complete tumor regression after therapy, and in six patients, these
complete responses have lasted for prolonged periods. Because advanced
stage low grade lymphomas are considered incurable, we wondered whether
these patients with long-term remissions had detectable disease despite
prolonged disease inactivity. Both the original tumor and idiotype
specific monoclonal antibodies were available, and we developed assays
for persistent disease using several different methodologies: (1)
enzyme-linked immunosorbent assay (ELISA) for detection of circulating
idiotype proteins or anti-idiotype antibodies; (2) flow cytometric
analysis to identify clonal or idiotype expressing B cells; and (3)
polymerase chain reaction (PCR) detection of either a t(14,18)
translocation (where the bcl-2 proto-oncogene is juxtaposed with the
immunoglobulin heavy chain) or a tumor-specific DNA sequence for the
immunoglobulin receptor hypervariable region of the malignant clone
(the third complementarity determining region, or CDR3). Over a span of
2 years, all six patients were seen and in five their complete
responses were ongoing, confirmed repeatedly with radiographic
scanning. All patients agreed to undergo bone marrow biopsy and
aspiration and peripheral blood was collected.
In this report, we present an overview of the clinical trials and
present our data on persistence of the malignant clone in the long-term
responding patients. Our results suggest that these patients harbor low
numbers of tumor cells identical to the original malignant clone,
presumably persisting in a dormant state.
| |
MATERIALS AND METHODS |
Anti-Idiotype Monoclonal Antibody Therapy
Anti-idiotype antibodies were produced by methods previously described
involving "rescue fusion" of malignant cells with a nonsecreting
heterohybridoma (K6H6-B5), isolation of the rescued tumor-derived
immunoglobulin, and production of rodent monoclonal antibodies.3,8 Therapeutic doses of these anti-idiotype
antibodies were infused three times weekly over 2 to 6 weeks. Patients
were treated with varying doses of antibody (ranging from 400 to 15,500 mg) dependent on availability of the therapeutic agents and clinical circumstances. In different trials patients received either
anti-idiotypic antibody as a single agent or therapeutic combinations
of antibody and immunomodulatory or chemotherapeutic agents.
Interferon.
Patients received -interferon (12 × 106
U/m2 intramuscularly) 2 hours before each antibody
infusion. Dosing three times weekly continued after
completion of all antibody infusions for a total of 8 weeks.4
Chlorambucil.
Patients received two courses of anti-idiotype antibody separated by 4 weeks. A single 5-day course of chemotherapy with chlorambucil (16 mg/m2/day) was given at the start of the second course of
antibody.6
IL-2.
A continuous intravenous (IV) infusion of IL-2 (6 × 106 IU/m2/day) was given during the third week
of a single course of anti-idiotype antibody.
Patients were followed for toxicity and tumor response as previously
described.1,3-5,7,9,10
Tumor Detection
Before evaluation for this study, all six patients who had experienced
durable complete remissions as defined by radiologic procedures and
marrow biopsies underwent repeat staging to confirm their remission
status. To collect samples for this analysis, peripheral blood and bone
marrow was collected at a single time point ranging from 3 to 14 years
postantibody therapy for the following analyses. Further peripheral
blood samples were collected and analyzed on subsequent visits, but
bone marrow biopsies were not repeated. Sensitivities for each
detection method were determined using sequential dilutions of
malignant cells into normal lymphocytes from spleen or blood.
ELISA
Serum was assayed by ELISA both for tumor idiotype protein and
anti-idiotype antibodies.5 For the detection of circulating idiotype, a sandwich ELISA was designed. Microtiter plates were coated
with the available anti-idiotype antibodies. These were the same
antibodies that had been used therapeutically. Sequential pretreatment
and posttreatment serum samples were serially diluted into the
precoated wells. Biotin-conjugated anti-idiotype antibodies were added
after washing, and detection was performed using
streptavidin-horseradish peroxidase (HRP) and
2,2 -Azino-di-[3-äthyl-benzthiazolinsulfonat (6)]
(ABTS; Boehringer Mannheim, Indianapolis,
IN). To assay for anti-idiotype antibodies, plates were coated with
idiotype protein and sequential pretreatment and posttreatment serum
samples were serially diluted into the precoated wells. For idiotype
proteins with IgM constant regions, detection was performed with
HRP-labeled goat antihuman IgG F(ab')2 fragments (Southern
Biotechnology Associates, Birmingham, AL). For IgG isotype
idiotype proteins, detection was performed with both HRP-labeled goat
antihuman IgM F(ab')2 fragments (Southern Biotechnology
Associates) and HRP-labeled goat antihuman kappa or lambda
F(ab')2 fragments (Biosource International, Inc,
Camarillo, CA), specific for the alternate light chain from that
present in the tumor idiotype. Plates were read on a Kinetic Microplate
Reader (Molecular Devices, Menlo Park, CA) and an
increase over baseline of at least two dilutions was required for
positivity.
Mononuclear cells were isolated from peripheral blood and bone marrow
aspirates by ficoll/hypaque centrifugation and the following analyses
were performed.
Flow Cytometry
Cells from both peripheral blood and marrow were stained in two colors
with the following fluorochrome conjugated reagents; goat antimouse
gamma1 and gamma2 (negative controls), anti-LeuM3 and anti-LeuM9
(monocytes, macrophages, eosinophils, and granulocytes), anti-CD45 (total leukocytes), anti-CD3(T cells),
anti-CD20 (B cells), anti-CD4 and CD8 (T cell subtypes), (all from
Becton Dickinson Immunocytometry Systems, San Jose, CA);
and antilambda and kappa Fab'2 fragments (Southern
Biotechnology Associates). A two-step stain was performed with the
anti-idiotype antibodies specific for each patient or an irrelevant
anti-idiotype antibody, followed by phycoerythrin
(PE)-labeled goat antimouse IgG (Southern Biotechnology Associates), and a second stain with fluorescein isothiocyanate (FITC)-labeled B1 (anti-CD20; Coulter Corp, Miami, FL).
Samples were analyzed using the Becton-Dickinson FACScan. Lymphocyte
populations were characterized, including assessment for any possible
clonality of B-cell immunoglobulins. Separate duplicate samples were
analyzed gating for CD-20 positive cells (B cells), and 20 to 50,000 gated events were collected. These were then analyzed for anti-idiotype
positivity, defined as a 1% increase over background binding of an
irrelevent anti-idiotype antibody.
Chromosomal t(14,18) Translocation
Genomic DNA was extracted from 1 × 107 cells using
phenol/chloroform extraction and ethanol precipitation. DNA aliquots of 0.5 µg were used in a seminested PCR amplification using taq
polymerase (Gibco BRL, Gaithersburg, MD) and the
following buffering conditions; 0.2 mmol/L deoxynucleotide
triphosphates (dNTP), 1.5 mmol/L MgCl2, 20 mmol/L Tris-HCl (pH 8.4), and 50 mmol/L KCl. The first stage incorporated outer bcl-2 5 primers from both major and minor breakpoint regions11,12 and a consensus J region 3
primer amplified for 50 cycles (94°C for 45 seconds,
56°C for 45 seconds, and 72°C for 1 minute). A volume of 2.5 µL of the product was then subjected to a
second 30 cycle amplification using the same cycling conditions and
inner bcl-2 5 primers from both major and minor breakpoint
regions and the same consensus J region 3 primer.11,12 Amplification products were identified after
electrophoretic separation in 2% agarose containing ethidium bromide.
DNA samples from the original malignant lymph node and normal
peripheral blood lymphocytes were run as simultaneous controls. Clonal
bands were sequenced to confirm the bcl-2 component. Each sample was
run in six separate reactions to confirm results.
CDR3-Primed PCR Amplification
By sequencing cDNA of the immunoglobulin heavy chain gene from the six
patients' original tumor biopsies, the specific CDR3 sequence in the
tumor immunoglobulin heavy chain gene was identified. A specific
antisense CDR3 primer was synthesized. cDNA was made from 1 × 107 cells using RNAzol total RNA purification (TEL test
"B", Inc, Friendswood, TX), random hexamer priming
and reverse transcriptase (Superscript II; Gibco BRL), and 5% by
volume was taken for a seminested amplification using taq
polymerase (Gibco BRL) with buffering conditions optimized for each
reaction (Opti-Prime, Stratagene, La Jolla, CA). VH
leader and constant region primers were selected to recognize the
immunoglobulin heavy chain gene from the malignant clone in the
original lymph node biopsy. An initial 40-cycle amplification was
performed using these primers and thermocycling conditions of 94°C,
56°C, and 72°C for 30 seconds each. A volume of
2.5 µL of the product was then subjected to a second 40-cycle
amplification using the same VH leader 5 primer and the specific
CDR3 3 primer. Buffer and annealing conditions for each set of
primers were optimized for best amplification. Amplification products
were identified after electrophoretic separation in 2% agarose
containing ethidium bromide. DNA samples from the original malignant
lymph node, blood mononuclear cells from normal subjects, and
class-matched control tumors were run as simultaneous controls. Clonal
bands were sequenced to confirm identity of the hypervariable regions.
Each sample was run in six separate reactions to confirm
results.13-15 A simultaneous amplification with
 2-microglobulin primers was performed to confirm the quality of the
cDNA preparation, and the reagent solution was amplified separately
without template to detect possible contamination.
| |
RESULTS |
Anti-Idiotype Antibody Therapy and Clinical Outcome
Rodent monoclonal antibodies were custom-made against the idiotype
expressed by each patient's tumor. These antibodies were exquisitely
specific, each of them failing to react with the idiotypes of several
hundred unrelated lymphomas. The antibodies were infused intravenously,
generally on a three times weekly schedule, in doses that were
escalated within each patient to achieve sustained levels in serum of
greater than 25 µg/mL. At this level of antibody, tissue penetration
was documented to occur within lymph node and splenic sites. The
cumulative doses ranged between 400 and 15,500 mg.
Several different trials were performed including: (1) antibody given
alone3,7; (2) antibody together with
-interferon4; (3) antibody together with a single, short
course of chlorambucil6; and (4) antibody together with
IL-2 (unpublished results). All patients had progressive and evaluable
disease at the time of antibody therapy. The initial clinical results
of most of these trials have been described previously.4-6
The treatments were well tolerated and no secondary or long-term
toxicities have been identified.
The long-term results of these trials are summarized in
Table 1. The different treatment
regimens produced an overall response rate of 66% with 18% complete
responses. The median survival from the time of treatment for all
patients was 4.5 years. The average time from diagnosis to the
beginning of antibody treatment was 5.6 years. The median survival from
the time of original diagnosis is 11 years. Eight of the 52 treatments
resulted in complete remissions after anti-idiotype antibody therapy.
These complete remissions were documented by radiographic studies and
bone marrow biopsies. Six of these eight responses have been durable
(lasting more than 4 years), five are ongoing, and three patients have
been in continuous remission for over 8 years. The clinical
characteristics of all patients achieving complete remissions are
described in Table 2. Patients are
identified in chronological order of treatment. Tumor histologies cross
a spectrum of low grade follicular lymphomas. All subjects had advanced
stage disease, some with B symptoms. Durable responses occured after
treatment with all treatment combinations.
Several of the case histories are particularly interesting.
Patient no. 1 was initially treated with anti-idiotype antibodies in
1981 for stage IV disease.3 He experienced complete regression of all tumor, even though pretreatment disease included bone
marrow involvement, extensive lymphadenopathy, and hepatosplenomegaly with individual retroperitoneal masses measuring up to 4 cm. He continued without evidence of disease for 7 years, at which time he
required coronary artery bypass grafting for atherosclerotic heart
disease. A localized skin recurrence of his lymphoma was identified
after an infection at the saphenous vein harvest site. A small field,
which included his ankle and distal lower leg, was treated with local
irradiation and no systemic therapy was given. He has been in
continuous remission for an additional 9 years.
Patient no. 14 was treated with a monoclonal anti-idiotype antibody
that bound to 100% of malignant cells in the original lymph node
biopsy. He had a good initial response to treatment, but developed
tumor regrowth after 3 months. The relapsed malignant cells were no
longer recognized by the primary antibody. A second anti-idiotype
antibody bound to 85% of the relapsed tumor and was given in a second
therapeutic course. He responded with complete regression of all
lymphoma and has been in continuous remission for over 10 years.
Tumor Detection in Patients With Long-Term Remissions
We performed an analysis for residual disease in the patients who have
experienced long-term complete remissions. Several different tests were
performed to detect the presence of tumor cells. The tests and their
sensitivities are shown in Table 3. PCR
analysis is known to be exquisitely sensitive. We performed two
different seminested PCR amplification assays to determine whether
tumor-specific DNA sequences were present in the collected samples. The
seminested strategy is described in
Fig 1. The bcl-2 assay, which is
performed on genomic DNA, can detect 1 rearranged genome in
105 normal cells.11,16,17 The CDR3 assay we
performed uses cDNA as its initial template. Thus, multiple copies of
the targeted message may be present in each malignant cell, allowing
for even greater sensitivity.18 Results of the CDR3-primed
amplification performed on serially diluted samples of tumor cells in
normal peripheral blood lymphocytes are shown in
Fig 2, lanes 7, 8, and 9 and represent
three separate cDNA preparations at the greatest dilution (one
malignant cell in 107 lymphocytes). One
sample shows amplification, indicating the limit of detection. Separate
dilution curves were performed for the other patients' tumors with
similar results, suggesting that with multiple sample runs we could
reliably detect one malignant cell in 107 normal cells. It
should be noted that in this assay, identity of residual tumor with the
pretreatment biopsy is confirmed by binding of the CDR3 primer and by
sequencing of the remaining heavy chain variable region. The sequence
of the CDR3 region in the amplified residual tumor is defined by the
primers used in the amplification and not by the actual CDR3 sequence
of the residual lymphoma.
View larger version (35K):
[in this window]
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| Fig 2.
An agarose gel showing the calibration of sensitivity for
the seminested CDR3 PCR amplification. The amplification product has a
length of approximately 350 bp. Cells from the malignant lymph node
(which contained 80% tumor cells) were serially diluted into normal
spleen cells down to 1 abnormal cell in 107 splenocytes.
Three separate dilutions of 1 in 107 were tested. Normal
spleen and no DNA controls are included. At the bottom are shown the
same cDNA preparations amplified with beta-2 microglobulin primers as a
control for quality of the cDNA and for gel loading.
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|
The combined results of the tumor detection assays are summarized in
Table 4. None of the patients had tumor
detectable by ELISA or flow cytometry. Patient no. 34 was the only
patient with a complete response to antibody therapy who relapsed
during the course of this analysis. The bone marrow biopsy performed
for this analysis contained lymphoid aggregates suspicious for
lymphoma. A bone marrow biopsy performed 4 years before, at the initial confirmation of complete response, had been negative. The PCR analyses
of both blood and bone marrow from this patient had detectable tumor-specific sequences. This patient has subsequently developed progressive but indolent lymphadenopathy at 4.5 years postantibody treatment.
Patient no. 1, the patient furthest out from anti-idiotypic antibody
treatment, had residual tumor detectable by PCR analysis, in marrow by
bcl-2, and both marrow and peripheral blood by CDR3 amplification.
Patient no. 13 also had disease detectable by molecular methods in both
peripheral blood and marrow. Patient no. 14 had disease detectable in
both marrow and blood only by the most sensitive CDR3 assay. Patient
no. 17 had PCR detectable disease in bone marrow by bcl-2 and
peripheral blood by CDR3. We were unable to identify residual disease
by any tests in patient no. 44. However, this patient's original tumor
did not contain an amplifiable bcl-2 translocation, making this PCR
assay inapplicable. All PCR products, which implied residual disease,
were subjected to nucleic acid sequencing and confirmed to have
identity with the original tumor (either containing an identical
breakpoint for the bcl-2 rearrangement or expressing the same variable
region in the immunoglobulin heavy chain gene).
All together, five of the six patients had detectable residual tumor
sequences using the sensitive and specific PCR tests. In all five
cases, the tumor was found in both peripheral blood and bone marrow.
These patients have all been followed for over 2 years since
identification of residual disease and, with the exception of patient
no. 34, all have continued in remission without any further therapy.
| |
DISCUSSION |
Throughout the 14-year time span during which these clinical trials
were performed, it was apparent that a significant subpopulation of
patients achieved marked reduction in tumor burden after infusions of
anti-idiotype antibodies. Some of these responses were quite dramatic.
The mechanism of this effect most likely involves the ability of
anti-idiotypic antibodies to cross-link tumor immunoglobulin receptors.
It has been shown that this cross-linking results in increased tyrosine
phosphorylation,19 a preliminary step in a cascade of
events that leads to cell death.20-23 This form of activation-induced cell death can also be triggered by cross-linking surface immunoglobulin molecules by multivalent surrogate peptide antigens.24 The ability of the anti-idiotype antibodies to
stimulate tyrosine phosphorylation within tumor samples was shown to
correlate with their ability to induce tumor regression.6
In six of the 45 patients treated on these protocols, a durable
disease-free remission was precipitated by the antibody therapy. All
had experienced significant disease growth before the antibody treatments. The duration of these six responses remains unexplained. A
cascade of signal transduction leading to apoptosis may explain their
initial responses, but remissions lasting for years after this
induction event require other explanations. For patients who
experienced complete tumor regression, the time until they achieved a
disease-free status ranged from 3 to 23 months. This slow tumor
involution is not consistent with simultaneous apoptosis of all
malignant cells. Dormancy of lymphomas has been described in animal
models after immune therapy. Uhr et al25 have documented that idiotypic vaccines can halt tumor cell cycling, possibly through
an autologous anti-idiotypic antibody mechanism.26-29 Their model suggests that this is mediated through surface immunoglobulin cross-linking,26,27,30 the same mechanism of action
implicated in our clinical results. However, in their model, the
continued presence of anti-idiotype antibodies is required for the
maintenance of tumor dormancy. Early relapses may occur because the
tumor becomes resistant to the effects of the antibody, but once the antibodies are cleared from the animal, the tumor recurs in most of
their animals.29 Clearly, this mechanism cannot fully
explain the continuing remissions in our patients, which can last over 10 years, long after all of the xenotypic antibodies were cleared from
their bodies. Moreover, we were unable to identify any endogenous humoral anti-idiotype response in these six patients.
Several discrepancies in our results are revealing with respect to the
accuracy of the molecular tests. In patient no. 17, the most sensitive
test, the CDR3-primed PCR amplification, was positive only in
peripheral blood and not in the bone marrow. It might have been
expected that marrow samples would always be positive if the blood were
positive, considering that low grade lymphoma is often identified
microscopically in marrow without identifiable malignant cells
circulating in peripheral blood, and that marrow aspirates often
contain peripheral blood cells.17 This may represent the
sampling error inherent in bone marrow biopsy and aspiration, as the
disease is present in a patchy distribution. The analysis of patient
no. 34 showed histologic evidence of lymphoma in bone marrow, but it is
notable that his marrow did not have tumor cells detectable by
fluorescence-activated cell sorting (FACS) analysis with
fluorescent-labeled anti-idiotype antibodies. He did have tumor
recognized by the specific CDR3 cDNA primer in his peripheral blood,
but it is possible that the tumor in his marrow had mutated its
idiotype to such a degree that it was no longer recognized by the
anti-idiotype antibodies used in the FACS assay or our CDR3 primer.
Tumor cells circulating in peripheral blood still contained a CDR3
region that annealed with our specific primer. His case exemplifies the
fact that detectable residual disease can be followed by disease
progression.
The different analyses defined in Table 3 serve to provide a
quantitative analysis for residual disease in each patient. With the
exception of patient no. 34, who had microscopic disease, no patient
had detectable tumor by tests with sensitivities of up to 1 malignant
cell in 104 normal cells. Four of the remaining five
patients did have disease detectable by assays with sensitivities of up
to 1 in 107 normal cells, confirming that the tumor burden
in these patients is extremely low.
Four of five patients with ongoing complete remissions had molecular
evidence of residual disease despite having shown no sign of clinical
disease activity for up to 10 years. Within this time frame one would
expect some sign of progressive disease if the tumor clone were
proliferating. Other investigators have been able to correlate
persistent disease, as identified by molecular detection, with poorer
prognosis and worse treatment outcomes after standard and aggressive
interventions including high-dose therapy requiring stem cell
rescue.31 A correlation between more intensive intervention
and higher molecular remission rates has been found.32 By
contrast, other studies have shown that persistent tumor-related DNA
sequences from indolent low grade lymphomas and aggressive acute
leukemias may be detectable for prolonged periods without evidence of
clinical relapse after a variety of therapies including chemotherapy,
local and total lymphatic irradiation, and high-dose therapy with stem
cell rescue.16,33-35 The prognostic relevence of the PCR
assay for bcl-2 rearrangements has further been questioned by the
finding that normal subjects have rare cells harboring such
rearrangements in tonsil36 or in peripheral
blood.37,38
The immunoglobulin heavy chain variable region cDNA sequences obtained
from our CDR3 assay showed clonal relatedness with the
parental tumors, but also reflected the expected point mutations that
are seen over time in B-cell malignancies.39 The average point mutation rate was 2.7% in variable region fragments comparing pretreatment and residual posttreatment sequences. This is consistent with the expected mutation rate and argues against assay contamination of residual tumor cDNA by pretreatment tumor immunoglobulin cDNA.
It must be noted that the PCR-based tests are actually detecting
tumor-related DNA sequences, and it is possible that the assays
identify a "premalignant" cell that contains the genomic rearrangements present in the fully malignant lymphoma. The exact point
at which a B cell becomes malignant has not been defined, and it is
quite possible that cells containing a specific bcl-2 rearrangement or
CDR3 sequence could persist, but do not have the ability to form
tumors.
Because it is difficult to find accurate and timely endpoints in
studies evaluating new therapies for low grade lymphoma, there is
currently an interest in the use of these extremely sensitive PCR tests
as surrogate endpoints in clinical trials. Conversion to molecular
negativity may certainly support a profound reduction in tumor burden,
but as others have shown and we confirm here, persistent positivity may
still be followed by prolonged remission. We conclude, therefore, that
such highly sensitive tests cannot replace clinical outcome in the
analysis of new therapies for low grade B-cell lymphomas.
The tenuous nature of dormancy in low grade lymphomas is well
documented in the disease course described for patient no. 1. Seven years after systemic therapy with anti-idiotypic antibodies, he
experienced a localized disease recurrence precipitated by cardiac
surgery and a localized infection. With control of this infection and
localized therapy, his disease regressed completely and has been
dormant since. The growth of lymphoma can be affected by infection, or
cytokines released as a consequence of infection. The underlying
mechanism is not understood.
The overall results from the anti-idiotypic antibody trials remain
positive on long-term follow-up, but the practical limitations of
producing individual therapeutic monoclonal anti-idiotype antibodies for each patient using hybridoma technology are prohibitive. It is
conceivable that newer technologies such as phage display antibody or
peptide libraries would make this therapy feasible. As an alternative approach, which still targets the unique receptor on each tumor, we
have immunized patients against their own receptors.40-42
One advantage is that smaller quantities of material are adequate to
stimulate an active immune response, which may similarly result in
dormant tumor or eliminate the malignant clone. Moreover, this vaccine
approach results in the stimulation of an immune response against
multiple epitopes of the idiotype molecule, therefore reducing the
chance of mutational escape. Once an immune response is triggered,
prolonged immunity may be achieved. The advantage of using a target
which is absolutely tumor specific remains appealing, even though the
approach requires a customized product for each patient. We anticipate
that the beneficial effects in patients41,42 will motivate
further innovations in technology.
| |
FOOTNOTES |
Submitted September 24, 1997;
accepted April 14, 1998.
Supported in part by Grant No. CA33399 from the National Institutes of
Health, Bethesda, MD. T.A.D. was a Lymphoma Research Foundation Award recipient and is supported by a Clinical Associate Physician Award from the General Clinical Research Centers of the
National Institutes of Health. R.L. is an American Cancer Society
Clinical Research Professor.
Address reprint requests to Ronald Levy, MD, Stanford
University, Department of Medicine, Division of Oncology, SUMC M207, Stanford, CA 94305-5306.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract
