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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 902-908
Interleukin-12 Therapy of Cutaneous T-Cell Lymphoma Induces Lesion
Regression and Cytotoxic T-Cell Responses
By
Alain H. Rook,
Gary S. Wood,
Elisa K. Yoo,
Rosalie Elenitsas,
David M.F. Kao,
Matthew L. Sherman,
William K. Witmer,
Kenneth A. Rockwell,
Ryan B. Shane,
Stuart R. Lessin, and
Eric C. Vonderheid
From the Department of Dermatology, University of Pennsylvania School
of Medicine, Philadelphia, PA; the Department of Dermatology, Case
Western Reserve School of Medicine, Cleveland, OH; Genetics Institute,
Inc, Cambridge, MA; Investigational Pharmacy, Hospital of the
University of Pennsylvania, Philadelphia, PA; and the Department of
Dermatology, Allegheny University School of Medicine, Philadelphia, PA.
 |
ABSTRACT |
Progression of cutaneous T-cell lymphoma (CTCL) is associated with
profound defects in cell-mediated immunity and depressed production of
cytokines, which support cell-mediated immunity. Because we have
observed marked defects in interleukin-12 (IL-12) production in CTCL
and because IL-12 is critical for antitumor cytotoxic T-cell responses,
we initiated a phase I dose escalation trial with recombinant human
IL-12 (rhIL-12) where patients received either 50, 100, or 300 ng/kg
rhIL-12 twice weekly subcutaneously or intralesionally for up to 24 weeks. Ten patients were entered: 5 with extensive plaque, 3 with
Sezary syndrome, and 2 with extensive tumors with large cell
transformation. One patient with Sezary syndrome dropped out after 1 week for personal reasons. Subcutaneous dosing resulted in complete
responses (CR) in 2 of 5 plaque and partial responses (PR) in 2 of 5 plaque, and 1 of 2 Sezary syndrome (overall response rate
CR+PR 5 of 9, 56%). A minor response also occurred in 1 of 5 plaque patients. Intralesional dosing resulted in individual tumor
regression in 2 of 2 patients. Biopsy of regressing lesions showed a
significant decrease in the density of the infiltrate in all cases and
complete resolution of the infiltrate among those with clinical lesion
resolution. An increase in numbers of CD8-positive and/or
TIA-1-positive T cells were observed on
immunohistochemical analysis of skin biopsy specimens obtained from
regressing skin lesions. Adverse effects of rhIL-12 on this regimen
were minor and limited and included low-grade fever and headache. One
patient discontinued rhIL-12 at week 6 because of depression. These
results suggest that rhIL-12 may augment antitumor cytotoxic T-cell
responses and may represent a potent and well-tolerated therapeutic
agent for CTCL.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
CUTANEOUS T-CELL lymphoma (CTCL) is a
clonally derived malignant proliferation of skin-invasive
CD4+ T lymphocytes.1,2 Clinical manifestations
of CTCL can encompass a broad spectrum of findings ranging from limited
cutaneous patches and plaques with no overt peripheral blood or lymph
node involvement to extensive skin involvement with tumors or
erythroderma with concomitant blood, node, or visceral
disease.3 Because CTCL is a malignancy that is responsive
at all stages to biological response modification,4-6 a
thorough understanding of the immunopathogenesis of this disease can
lead to the enhanced use of novel biologic agents, including
recombinant cytokines. In this regard, it is known that during disease
progression, a variety of immunologic abnormalities become evident
including prominent defects in cell-mediated immunity.7,8
These abnormalities are typically associated with the depressed ability
of peripheral blood cells to produce the T-helper type I cytokines
interferon- (IFN-) and interleukin-2 (IL-2).7,9 The
pathogenesis of these cytokine defects may be related to the excess
production of T-helper type 2 cytokines (IL-4, -5, and -10) by the
malignant clonal T-cell population, which can antagonize the function
and production of IFN- and IL-2.10,11
IL-12 is a recently identified cytokine, which is a powerful inducer of
IFN- production12 and which exerts potent Th1-inducing effects.12,13 Furthermore, IL-12 augments natural killer
cell cytotoxicity14 and cytotoxic T-cell proliferation and
function,15 activities that may be beneficial in regard to
the abnormal Th2 clonal proliferation observed in advanced CTCL. Recent
studies16 have demonstrated a deficiency in production of
IL-12 by peripheral blood cells from patients with advanced CTCL.
Notably, culture of these patients' cells with recombinant IL-12
(rIL-12) in vitro leads to a restoration of IFN- production and a
marked enhancement of cell-mediated cytotoxicity. Because lesional
infiltrating cytolytic T cells have been shown in early skin lesions of
CTCL17 and are believed to play a role in retarding the
progression of disease, the ability to enhance their generation via the
administration of exogenous IL-12 could be important for the therapy of
CTCL. Moreover, the restoration of IFN- production, as well as the enhancement of cell-mediated cytotoxicity, serve as primary rationale for the use of IL-12 as therapy for this T-cell malignancy.
For these reasons, a phase I trial using human recombinant IL-12
(rhIL-12) to treat patients diagnosed with CTCL was initiated. We
report here that rhIL-12 administered subcutaneously twice weekly was
well tolerated and induced significant clinical responses in 5 of 9 patients. Furthermore, serial immunohistochemical studies of involved
skin lesions before and during therapy indicated that lesion regression
was associated with tumor infiltrating cytotoxic T-cell responses.
| |
MATERIALS AND METHODS |
Patients.
Patients 18 years of age or older with the clinical and histological
diagnosis3 of CTCL with plaques, tumors, or erythroderma with an expected survival of at least 6 months were eligible for entry
into the study. Individuals with seropositivity against human
immunodeficiency virus (HIV), human T-cell lymphotrophic virus
(HTLV)-I, or hepatitis C were excluded, as were
individuals with a past history of gastrointestinal hemorrhage or
serious autoimmune, cardiac, or renal disease. CTCL patients with
documented visceral involvment, other than bone marrow involvment, were
also excluded. No more than 3 systemic therapies were permitted during the previous 12 months.
Study design.
This was an open-label, nonrandomized, single center, phase I trial to
test the safety and efficacy of rhIL-12. Dose levels of 50 ng/kg, 100 ng/kg, or 300 ng/kg were administered 2 times a week by subcutaneous
injection. In some cases, rhIL-12 was administered directly into
discrete plaques or tumors. Treatment was performed for up to 24 weeks.
An initial group of 2 patients was entered at 50 ng/kg. Safety at this
dose was evaluated at 4 weeks before entering patients at the 100 ng/kg
dosing level. Similarly, an initial group of 4 patients was entered at
the 100 ng/kg dose and safety was evaluated at 4 weeks before entering
patients at the 300 ng/kg dose range. Toxicity grading of adverse
experiences was in accordance with the modified National Cancer
Institute (NCI) Common Toxicity Criteria Scale. If after 4 weeks of therapy, adverse effects were mild and the level of disease
was stable or progressive, escalation of the dose to the next higher
level was possible at the discretion of the investigator. Before
initiating therapy with rhIL-12, all other topical and systemic
therapies, with the exclusion of 1% hydrocortisone cream or ointment,
which could be applied to less than 5% of the skin surface area daily, were to be discontinued for at least a 3-week period. Therapies other
than 1% hydrocortisone preparations were not permitted once rhIL-12
was started.
Patient evaluation.
Before initiation of rhIL-12, all patients had a complete history and
physical examination. In addition, a chest x-ray, electrocardiogram, complete skin photographs, skin biopsy of 1 or more lesions for hematoxylin and eosin (H&E) analysis and for
immunohistochemistry, complete blood count, serum chemistries,
urinalysis, serology for HIV, HTLV-I, hepatitis C, and
fluorescence-activated cell sorting (FACS) analysis of peripheral blood
were performed. Routine physical exams, blood counts, and chemistries
were repeated weekly during the first month of treatment, then monthly
thereafter. Repeat skin biopsies were obtained at the time of initial
lesion regression and on complete clinical regression. A Sezary cell preparation was performed on 1-µm sections of pelleted, fixed buffycoat specimens at baseline and at the final study visit for patients with no blood involvement at baseline or every 2 months for
patients with blood involvement at baseline. Blood was also obtained
for T-cell receptor gene rearrangement testing at baseline, at the time
of a complete response of skin disease, and at completion of the
study.18
Patients were evaluated for treatment efficacy by skin lesion
measurements after every 4 weeks during the period of drug
administration and at 1 month after completion of treatment and
photography at the conclusion of therapy. A complete clinical response
(CR) was defined as complete disappearance of all measurable and
evaluable lesions for at least 1 month. A CR was documented by rebiopsy of a previously involved skin site and by reevaluation of previously involved peripheral blood by gene rearrangement studies and Sezary count. A partial clinical response (PR) was defined as at least 50%
disappearance of all CTCL skin lesions or decrease in area of skin
involvement for at least 1 month. A minor response was defined as 25%
to 49% disappearance of all CTCL skin lesions for at least 1 month,
while stable disease was defined as less than 25% disappearance of all
measurable and evaluable lesions or stabilization of all existent
lesions for at least 1 month. Progressive disease was defined as
worsening on 2 consecutive visits 4 weeks apart with at least a 50%
increase in measured cutaneous disease burden from baseline.
Immunohistochemistry.
Representative portions of lesional skin biopsy specimens were
snap-frozen, stored at  70°C, cryostat-sectioned, and
acetone-fixed as described previously.19 Sections were
immunostained with a 3-stage monoclonal antibody/biotin/avidin method
with 3,3-diaminobenzidine chromagen and counterstained with methylene
blue as reported previously.19 The antibody panel included
T-cell subset markers (CD3, CD4, CD7, CD8), IL-2 receptor (CD25),
cytolytic granule marker (TIA-1), class II major histocompatibility
antigen (HLA-DR), and proliferating cell marker (Mib-1). Controls
included deletion of various immunostaining stages, replacement of
first stage monoclonal antibodies with irrelevant antibodies of similar
isotype, and staining of normal skin and reactive lymphoid tissues.
Stained sections were evaluated using a standard light microscope.
| |
RESULTS |
Patient characteristics.
Ten patients with the clinical and histological diagnosis of CTCL began
therapy with rhIL-12. The characteristics of the patients are shown in
Table 1. Three of 5 with plaque type
disease had more than 30% of their skin surface area involved with
typical plaques, while 1 of these patients (patient 7) had a detectable T-cell receptor gene rearrangement in the peripheral blood at baseline.
Patients 1 and 5 with evidence of numerous skin tumors each had
evidence of large cell transformation on histological analysis of
biopsy specimens from skin tumors.20 Patients 3, 4, and 10 had Sezary syndrome with 70%, 80%, and 85% of circulating mononuclear cells as Sezary cells. All patients with tumors and Sezary syndrome had received a mean of 3 previous therapies and thus could be considered as heavily pretreated before starting rhIL-12.
Clinical response to rhIL-12.
All patients with plaque disease had measurable clinical improvement
while receiving rhIL-12 (Table 1). Two patients experienced a CR at
weeks 7 and 8, respectively
(Fig 1A
through D). A PR was documented in each by 5 weeks of therapy. Both
received 100 ng/kg rhIL-12. Each CR was documented by histological
evidence of clearing of previously involved areas of the skin.
Furthermore, a previously detectable T-cell receptor gene rearrangement
in the blood of patient 7 became undetectable at the time of the
documented CR and remained undetectable at the conclusion of treatment.
This patient had more than 80% of her skin surface involved with
patches and plaques before initiating rhIL-12. She maintained the CR
for 8 weeks while on therapy (Fig 1A and B). Recurrence of skin lesions was characterized by the development of 2 faint patches each 2 cm in
diameter located on the lateral ankles, which persisted throughout the
conclusion of the 24 weeks of therapy. However, at follow-up 1 month
after concluding rhIL-12, all skin abnormalities had again resolved.
Recurrence of skin lesions in patient 6 was also associated with
minimal disease with several small patches observed, which were limited
to the thighs. One month after concluding rhIL-12, more extensive
patches had recurred on the body, but the extent of skin disease was
still significantly less than at the treatment initiation.
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| Fig 1.
CRs of 2 patients during treatment with rhIL-12. (A)
Patient 7 before starting rhIL-12. (B) Patient 7 at the conclusion of
treatment with rhIL-12 showing complete clearing of skin lesions on the
trunk. (C) Patient 6 before initiating rhIL-12. (D) The same patient at
week 10 of therapy with complete clearing of skin lesions.
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| Fig 2.
Intralesional injections of rhIL-12 result in tumor
regression. (A) Tumor of the right forearm at baseline in patient 5. (B) Complete flattening of the tumor at week 3 after 6 injections of
rhIL-12 at a dose of 100 ng/kg into the tumor. Histologic examination
of the flattened tumor showed complete resolution of the malignant
infiltrate.
|
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In addition to the 2 plaque patients with CRs, 2 plaque patients
experienced a PR, which was established at 12 weeks and 7 weeks of
therapy, respectively. The former received 300 ng/kg, while the other
received 100 ng/kg during 24 weeks of therapy. The PR were maintained
for the remainder of the 24 weeks of therapy. One plaque patient had a
minor response noted at week 12 while receiving 50 ng/kg, but she
elected to discontinue therapy at week 13 due to increasing pruritus.
The pruritus persisted after discontinuing rhIL-12 and was thus
attributed to her disease.
Among the 3 patients with Sezary syndrome, defined as such by the
presence of erythroderma and circulating malignant cells detected by
flow cytometry or morphological analysis of buffy coats, 1 elected to
discontinue therapy for personal reasons after only 2 injections of
rhIL-12, 1 discontinued therapy at week 10 with stable skin and blood
disease at a dose of 100 ng/kg, and 1 had a documented PR at week 13 with clearing of erythema from large areas of the trunk. This patient
started at 100 ng/kg and dose escalated at week 4 to 300 ng/kg.
Histological analysis of improving areas of the skin further confirmed
the response by showing a significant reduction in the cutaneous
lymphoid infiltrate compared with baseline. In addition, an
overall decrease in scaling was also observed. These improvements
in skin disease were maintained throughout the remainder of the
24 weeks of therapy. The total white blood count decreased from
18,000/µL at baseline to 9,000/µL at study completion,
and the relative percentage of circulating Sezary cells decreased from
80% to 50% during the treatment period. Moreover, the absolute
lymphocyte count dropped by one half, suggesting a significant decrease
in the total number of circulating Sezary cells.
Each of the 2 tumor-stage patients had rapidly progressive disease with
numerous skin tumors at the time of initiation of rhIL-12. Direct
intralesional therapy into tumors was undertaken with each patient.
Patient 1 began at a dose of 50 ng/kg and was dose escalated to 100 ng/kg at week 4, while patient 5 began rhIL-12 at 100 ng/kg and
escalated to 300 ng/kg at week 4. Although as shown in Fig 2, each
experienced flattening and complete resolution of several injected
tumors, new lesions continued to develop beyond the injection sites
and, thus, each had progressive disease. Patient 1 discontinued therapy
at week 6, while patient 5 discontinued treatment at week 8.
Immunohistochemistry.
The 5 patients with significant clinical responses had
immunohistological analysis of biopsy material from involved skin
lesions obtained at baseline and during lesion regression. All
pretreatment samples demonstrated epidermal hyperplasia and increased
keratinocyte HLA-DR expression. The epidermal and dermal lymphocytic
infiltrate contained a predominantly CD3+CD4+
T-cell infiltrate deficient in CD7 expression with a minority of
CD8+ cells admixed. Repeat biopsies were obtained within 1 to 2 weeks of initially noting lesion regression while on rhIL-12
treatment. In 5 of 5 patients analyzed, a number of alterations were
noted during lesion regression that were considered significant
differences from baseline. All cases showed a 2- to 3-fold reduction in
total CD3+ T cells
(Fig 3A and
B) associated with a 2- to 3-fold increase in the proportion of
CD8+ cells (cytotoxic T cells). A 2- to 3-fold increase in
the porportion of TIA-1+ cells (cytotoxic cell marker) in 2 of 3 evaluable cases was detected (Fig 4A and B). In addition, there
was a trend toward normalization of the epidermis with reduction in
epidermal hyperplasia, scale, and/or ulceration in each case,
associated with a reduction in epidermal HLA-DR expression in 2 of 3 evaluable cases. The other 2 cases were missing epidermis in some
specimens due to lesional ulceration or loss of epidermis during
subdivision of the biopsy specimen for various assays.
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| Fig 3.
CD3+ cells within involved skin lesions
decrease during lesion regression while receiving rhIL-12. (A) Biopsy
specimen of involved skin from patient 6 at baseline. (B) Biopsy
specimen of same lesion as in (A) when lesion was nearly completely
resolved during rIL-12 treatment.
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| Fig 4.
TIA-1+ cells increase significantly within
regressing skin lesions during rhIL-12 treatment. (A) Involved skin at
baseline from patient 8 with small numbers of TIA-1+
cells as indicated by the arrow. (B) A 2- to 3-fold increase in the
proportion of TIA-1+ cells as indicated by the arrows
within the same lesion during regression associated with rhIL-12
treatment.
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Adverse effects of rhIL-12.
The adverse effects associated with rhIL-12 treatment during this trial
are shown in Table 2. Most
adverse effects were mild and were short-lived with a duration of 24 to
36 hours after the initial injection. Constitutional symptoms
consisting of fatigue, headache, or myalgias typically did not recur
after subsequent doses of rhIL-12. Exceptions included patient 10 who
entered the trial at a dose of 300 ng/kg, but who experienced severe
fatigue lasting 1 week after the initial injection, which necessitated a dose decrease to 100 ng/kg. Similarly, patient 7 experienced severe
fatigue when she was dose escalated from 100 ng/kg to 300 ng/kg at week
4. Because of this, the dose was deescalated to the original level
after a single injection at 300 ng/kg. Subsequently, it was determined
that significant alcohol ingestion had occurred on the day of the dose
escalation.
Patients 9 and 10 each had elevations in serum hepatic enzyme levels
measured during week 2 of therapy on doses of 300 ng/kg. In each case,
alcohol ingestion occurred within 24 hours of the rhIL-12 dosing. Both
patients had 1 dose of rhIL-12 omitted and, within 1 week, serum levels
of hepatic enzymes returned to normal. No additional abnormalites in
these laboratory parameters were noted during the duration of rhIL-12
therapy for these 2 patients.
Patient 1 experienced depression at week 5 of therapy after dose
escalation from 50 ng/kg to 100 ng/kg at week 4. Because of the
severity of the depression, he elected to discontinue treatment with
rhIL-12 after 6 weeks of therapy. The depression resolved within 1 week
of discontinuation of the rhIL-12. It is noteworthy that this patient
also experienced severe depression during treatment with recombinant
IFN- , which also resolved on discontinuation of this cytokine, thus
suggesting that this apparent idiosyncratic adverse effect was not
unique to rhIL-12.
| |
DISCUSSION |
Our results with a small number of patients with mycosis fungoides and
Sezary syndrome suggest that rhIL-12, in the dosing schedule used, is
both efficacious and without serious adverse effects. Five of five
patch/plaque type patients had a clinical response, with 2 of the 5 experiencing a complete clinical response associated with
histological clearing. One of 2 Sezary syndrome patients who remained
on protocol for more than 2 months also experienced a significant
reduction in their disease burden. While the 2 tumor-stage patients
with large cell transformation did not experience a significant overall
response, intralesional injections of rhIL-12 resulted in regression of
the injected tumors, indicating that rhIL-12 can exert biological
activity even in aggressive forms of CTCL.
The observation that the plaque type patients more frequently responded
to rhIL-12 than patients with Sezary syndrome or multiple tumors may
relate to the overall degree of immunological integrity in each subset
of patients. Those with plaque type disease tend to have a more intact
cell-mediated immune response than do patients with multiple tumors or
with Sezary syndrome.21,22 Those with more advanced disease
will have a larger tumor burden consisting of CD4+
malignant T cells that produce the immunosuppressive cytokines IL-4 and
IL-10, which exhibit the capacity to blunt an antitumor cytolytic
T-cell response.23,24 In addition, the tumor stage patients
had been heavily pretreated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) chemotherapy and high dose
methotrexate, which may depress cell-mediated immunity and which might
be expected to counteract the immune enhancing effects of rhIL-12.
Although the numbers of patients participating in our study were small and definitive conclusions regarding response rates of different patient subtypes cannot be made, it is possible that a more substantial immunological substrate existed among patch/plaque stage patients, which presumably facilitated the response to rhIL-12 administration.
The findings of significantly increased numbers of CD8+ or
TIA-1+ cytotoxic cells within skin lesions undergoing
regression strongly suggest that clinical responses were a consequence
of the immunomodulatory effects of rhIL-12 to induce antitumor
cytolytic T cells. The reservoir for these tumor infiltrating T cells
is undoubtedly derived from circulating normal CD8+ T cells
with skin-homing potential. These observations are consistent with our
recent studies that indicate that rhIL-12 is not likely to be acting
directly on the Sezary T cells.25 We have shown that
peripheral blood Sezary T cells express the  1, but not the 2,
component of the IL-12 receptor.25 The 2 component
appears to be necessary for both high-affinity cell surface binding of IL-12, as well as for the intracellular transmission of the IL-12 signal.26,27 When high concentrations of rhIL-12 are added to cultures of Sezary patient-derived purified malignant
CD4+ T cells, it fails to result in activation of IL-12
responsive Jak and Stat pathways essential for mediating IL-12 effects
on lymphocytes.25 In contrast to the rIL-12 refractory
malignant T-cell population, Sezary patient CD8+ T cells,
as well as peripheral blood lymphocytes of patch/plaque patients, do
appear to possess the 2 component of the IL-12 receptor and do
exhibit activation of IL-12 responsive signal transduction pathways
when cultured with rhIL-12.25 These studies suggest that
rhIL-12 is most likely to exert its effects in CTCL by mediating activation of normal immune cells. Thus, the in vivo responses and our
in vitro data support the hypothesis that those patients with the most
intact cell-mediated immune response are most likely to display a
benefit from rIL-12.
Although previous studies of rhIL-12 administered intravenously have
been associated with a greater incidence of adverse
experiences,28 the current study has demonstrated that
rhIL-12 is well tolerated when administered subcutaneously twice weekly
in the doses used. The high response rate of patients with plaque stage
CTCL and the lack of serious toxicity of rhIL-12 in this patient
population has prompted the development of future phase II/III clinical
trials. These studies should delineate those categories of patients
most likely to benefit from the effects of rhIL-12. Another future goal
of these trials should be to determine whether the beneficial antitumor
effects of rhIL-12 can be synergistically enhanced by the concomitant
use of other cytokines, which augment cell-mediated immunity.
| |
ACKNOWLEDGMENT |
The authors thank Dr Giorgio Trinchieri for the inspiration for this study.
| |
FOOTNOTES |
Submitted January 13, 1999; accepted April 10, 1999.
Supported in part by grants from the Leukemia Society of America and by
Genetics Institute, Inc, and by a grant from the National Institutes of
Health to the General Clinical Research Center (5-MO1RR0040).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Alain H. Rook, MD, Department of
Dermatology, University of Pennsylvania, 3600 Spruce St, Philadelphia,
PA 19104; e-mail: arook{at}mail.med.upenn.edu.
| |
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ABSTRACT
INTRODUCTION