| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1 x 106) resulted in
nearly the complete regression of 3-day established lung metastases.
Furthermore, mice that rejected CMS4 following a single adoptive
transfer of CTL displayed antitumor activity to a rechallenge 45 days
later, not only in the lung, but also at a s.c. distal site. Lastly,
the adoptive transfer of CTL to mice harboring extensive pulmonary
metastases (>150 nodules) led to a substantial reduction in tumor
burden. Overall, these data suggest that the adoptive transfer of
tumor-specific CTL may have therapeutic potential for malignancies that
proliferate in or metastasize to the lung. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The requirement for more selective cancer therapies, along with the molecular identification of tumor-specific Ags (TSA)2 and tumor-associated Ags, has led to the development of immune-based strategies for the treatment of metastatic disease, which are being tested in both animal models and clinical trials (1, 2, 3, 4, 5). Adoptive cellular immunotherapy of cancer involving the reinfusion of patient-derived effector cells that have been generated, propagated, and expanded in vitro is an example of one such promising experimental therapy. However, adoptive immunotherapy in clinical studies has achieved success only in limited patient populations, the exact reasons for which remain unclear (1, 2, 6).
The principles for developing adoptive immunotherapy for human disease
can be guided by insights derived from experimental animal models. In
fact, a number of animal studies have been performed that show the
effectiveness of adoptive cellular immunotherapy against several
different tumor types (7, 8, 9, 10). However, the vast majority
of those models have not generally reflected what is seen in human
disease. For example, tumor cell lines used in animal studies are often
transfected with surrogate rejection Ag (7, 8, 9), which
would not necessarily reflect expression or tissue distribution of an
endogenously derived, relevant tumor Ag. The level of expression of
these transfected Ags may also be higher than what is seen with an
endogenously derived TSA. Because a surrogate Ag, such as OVA or
-galactosidase, would represent a foreign Ag in a TCR nontransgenic
mouse, the T cells specific for those model Ags may also have an
affinity different from that of T cells specific for naturally
occurring tumor rejection Ags. Additionally, the adoptive transfer of
resting CD8+ T cells derived from TCR transgenic
animals is highly effective (7, 10), yet large numbers of
T cells with the same phenotype are not typically found in a host or
individual with a normal, heterogeneous T cell repertoire. Moreover, in
an effort to collect adequate numbers of Ag-specific T cells in
clinical situations, it would be necessary to propagate immune effector
cells in vitro before the initiation of adoptive immunotherapy. Taken
collectively, these models do not accurately parallel what would be
faced in a clinical paradigm of adoptive immunotherapy.
We sought to develop a mouse model for adoptive immunotherapy that would more closely mimic the nature of the biologic components (e.g., cancer cells and T cells) confronted in a clinical setting. For example, we used a tumor cell line expressing a naturally occurring tumor rejection Ag and established an Ag-specific CD8+ T cell line against that tumor from TCR nontransgenic mice. Using this T cell-tumor cell model, we examined several fundamental principles of adoptive immunotherapy in a pulmonary metastases setting that have remained largely uncharacterized. Specifically, we explored 1) the potency of Ag-specific CTL, both in vitro and in vivo; 2) the maintenance of an antitumor response following adoptive transfer, not only at the site of primary tumor rejection, but also at a s.c. distal site based on rechallenge experiments; and 3) the antitumor activity of Ag-specific CTL in mice with extensive disease.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Female BALB/c mice were obtained from the Frederick Cancer Research Animal Facility (Frederick, MD) and were used at >6 wk of age.
Tumor cells
The CMS4 sarcoma (11) was provided by Dr. A. DeLeo (University of Pittsburgh, Pittsburgh, PA). The CT26 carcinoma was provided by Dr. N. Restifo (National Institutes of Health, Bethesda, MD). The P815 mastocytoma and BALB/3T3 fibroblast lines were obtained from the American Type Culture Collection (Manassas, VA).
Production of CMS4-specific CD8+ CTL
A CD8+ CTL line reactive with the CMS4 (H-2d) sarcoma was established from BALB/c mice using an immunization strategy consisting of a viable tumor challenge (5 x 105 cells given s.c. in one flank) coadministered with anti-CTLA4 mAb (affinity-purified hamster anti-mouse clone UC10-4F10-11 (12); hybridoma line provided by Dr. J. Bluestone, University of California, San Francisco, CA) at 100 µg/inoculation/mouse given i.p. on days 0, 3, and 6 posttumor transplant in a manner similar to that described in Ref. (13). Mice exposed to this regimen that failed to display evidence of primary tumor growth were rendered "tumor-immune" based on resistance to a subsequent live rechallenge on the contralateral flank (given in the absence of anti-CTLA4 mAb). Rejection of the primary and/or secondary CMS4 tumor challenge correlated with the induction of a tumor-specific CD8+ CTL response demonstrable from immune splenocytes. A spleen-derived CD8+ CTL line (1–2 x 105/well) was propagated in vitro in 24-well plates (Costar, Cambridge, MA) by weekly stimulation with irradiated (20 Gy) syngeneic BALB/c splenocytes (5 x 106/well) as APC, irradiated (200 Gy) CMS4 tumor cells (1 x 105/well) as a source of cognate Ag, and IL-2 (60 IU/ml, Tecin; Hoffman-LaRoche, Nutley, NJ).
Peptides
The AH1 peptide (SPSYVYHQF) (14) and other experimental peptides were synthesized in our laboratory using an Applied Biosystems 432A peptide synthesizer (Foster City, CA) by F-moc chemistry. Peptides were purified and analyzed by reversed-phase HPLC using a C18 column (>90% purity). The peptides were dissolved in distilled water at 2 mg/ml, filter-sterilized, and stored in aliquots at -80°C.
s.c. tumor growth
CMS4 tumor cells were washed three times with HBSS before injection. Mice were given an injection of 5 x 105 tumor cells s.c. in the flank. Tumor growth was measured weekly in two dimensions, using a digital caliper. Tumor volume was calculated as previously described (15).
Cytotoxicity assays
CTL activity was assessed using a standard 4-h 51Cr-release assay. Target cells were labeled with 250 µCi of Na2[51Cr]O4 (Amersham, Arlington Heights, IL). CTL were recovered from culture by centrifugation over a Ficoll-Hypaque gradient (LSM; ICN Biomedicals, Aurora, OH). CTL and radiolabeled target cells were then coincubated in 96-well, U-bottom plates (Costar), either at a constant E:T ratio with/without differing concentrations of peptide or with/without a constant peptide concentration at graded E:T ratios. For recovery of CTL following adoptive transfer, lungs from mice receiving CTL (adoptively transferred, AT, lungs) or control mice (control lungs) were enzymatically digested for 4–6 h at room temperature with a sterile enzyme mixture consisting of hyaluronidase (0.1 mg/ml), collagenase (1 mg/ml), and DNase (30 U/ml), all obtained from Sigma (St. Louis, MO). After incubation, the single cell suspension was collected, washed, and centrifuged over a Ficoll-Hypaque gradient to recover viable cells before in vitro stimulation, as described above. For cold target inhibition assays, Con A-induced lymphoblasts, precoated with 1 µg/ml peptide for 90 min, were used as cold targets. Peptide-coated cold targets were added in increasing numbers and incubated with CTL 40 min before the addition of 51Cr-labeled targets. Following a total incubation of 4 h, supernatants were collected using a Supernatant Collection System (Skatron, Sterling, VA). Radioactivity was quantitated using a gamma counter. Percent specific 51Cr release was calculated according to the following formula: percent specific lysis = [(experimental cpm - spontaneous cpm)/(total cpm - spontaneous cpm)] x 100. Total 51Cr release was obtained by adding 0.2% Triton X-100 (final concentration) to the wells.
Cytokine production
Ficoll-Hypaque-purified CTL were incubated with tumor cells at a
1:3 or 1:10 ratio for 24 h in a 24-well plate (1 ml final volume).
Supernatants were collected by centrifugation and maintained in
aliquots at -80°C until use. Cytokine analysis was performed by
ELISA using matched pairs of anticytokine-specific mAb (BD PharMingen,
San Diego, CA) for IL-4, IL-5, IL-10, GM-CSF, TNF-
, and IFN-
.
Recombinant murine cytokine standards for IL-4, IL-5, IL-10, and
TNF- were also purchased from BD PharMingen. Recombinant murine
IFN- was purchased from R&D Systems (Minneapolis, MN). Recombinant
GM-CSF was obtained from PeproTech (Rocky Hill, NJ). Limit of detection
in the assay for IL-4 was 50 pg/ml; IL-5 was 100 pg/ml; IL-10 was 500
pg/ml; TNF- was 750 pg/ml; GM-CSF was 200 pg/ml; and IFN-
was 200 pg/ml.
Adoptive transfer experiments
CMS4 tumor cells, previously selected by one in vivo passage in the lungs of normal, nonimmunized mice, were washed three times, resuspended in HBSS, and injected i.v. into the lateral tail vein (26-gauge needle, 1–1.5 x 105 cells in 100-µl total volume). Three or 10 days later, CTL (4–5 days following in vitro stimulation) were prepared by centrifugation over a Ficoll-Hypaque gradient, washed three times, and resuspended in HBSS. Cells or HBSS alone were injected i.v. into the tail vein (26-gauge needle, varying numbers of cells in a 100-µl total volume). Mice were sacrificed at the indicated times following T cell transfer. For enumeration of lung metastases, lungs were inflated with a 15% solution of India ink, resected, and fixed in Fekete’s solution as described (16).
Statistical analysis
The exact Wilcoxon rank sum test was used to compare tumor growth in the naive control vs rechallenged mice. In the case of the lung metastasis setting, a two-sided p value was shown. In the case of the s.c. setting, two-sided p values were adjusted at each time point using the Hochberg method (17).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The s.c. growth of CMS4 tumor cells is shown in Fig. 1
A. Ten BALB/c mice received
an inoculation of 5 x 105 CMS4 tumor cells
and all of these 10 control mice exhibited s.c. tumor growth. In
contrast, of 15 mice injected with 5 x 105
CMS4 tumor cells in combination with a course of anti-CTLA4 mAb
(13), only one grew a tumor (Fig. 1B). Five
immune and another set of five control (naive) mice were given a
subsequent injection of 5 x 105 CMS4 tumor
cells and monitored for tumor growth. All control mice developed
tumors, whereas 0/5 mice that had previously rejected a CMS4 tumor
challenge on the contralateral side developed tumors (Fig. 1C). To further confirm the establishment of systemic
immunity following treatment with anti-CTLA4 mAb, CMS4-immune mice
that had also rejected a second s.c. challenge with CMS4 tumor cells
were inoculated i.v. with 1.5 x 105 CMS4
tumor cells; their lungs were examined for tumor nodules 2 wk later. As
shown in Fig. 1D, control mice (3/3) developed tumors,
whereas there was limited tumor growth in the lungs of CMS4-immune mice
(average <2 nodules/lung).
|
Spleen cells from mice that had rejected both a primary challenge
with CMS4 tumor cells (following anti-CTLA4 mAb treatment) and a
secondary s.c. challenge with the same tumor cells were cultured in
vitro with irradiated CMS4 tumor cells as a source of cognate Ag, and
IL-2. When tested for cytolytic activity in a 4-h
51Cr-release assay, these splenocytes
demonstrated specific lysis against CMS4 tumor cells (Fig. 2A). They did not lyse P815 or
BALB/3T3 fibroblast cell lines. Interestingly, these cells were
cross-reactive with the CT26 colon carcinoma cell line (Fig. 2A). Continued restimulation of the CTL cultures resulted in
the establishment of a stable CD8+ CTL line,
termed CMS4-reactive CTL.
|
B,
the CMS4-reactive CTL line recognized and lysed P815 target cells or
Con A-stimulated lymphoblasts incubated in the presence of AH1 peptide.
Lysis of these targets in the absence of exogenous peptide was <10%.
The peptide specificity of the CTL line for AH1 was demonstrated by
cytotoxicity assays using a panel of peptides (Fig. 2C).
Lysis of P815 target cells was observed only when these targets were
incubated with the AH1 peptide and not a panel of peptides reflecting
other tumor Ags or viral epitopes. Dose-response experiments revealed
that half maximal lysis occurred at 
1 ng/ml exogenous AH1 peptide
(data not shown).
Cold target inhibition assays using peptide-coated lymphoblasts as cold
cells to compete for lysis of 51Cr-labeled CMS4
tumor cells confirmed that lysis of CMS4 targets by the CMS4-reactive
CTL line involved immune recognition of the AH1 epitope on these tumor
cells. Increasing numbers of AH1 peptide-coated lymphoblasts, but not
uncoated cells or cells coated with an irrelevant
H-2Ld peptide epitope (P1A), were capable of
inhibiting lysis of 51Cr-labeled CMS4 tumor cells
(Fig. 3). Eighty-four percent inhibition
of lysis was observed using 8 x 104 cold
AH1-coated lymphoblasts, compared with 11% inhibition using the same
number of P1A-coated lymphoblasts.
|
were detected in 24-h culture
supernatants when the CMS4-reactive CTL line was stimulated with CMS4
tumor cells, APC/AH1 peptide, or Con A, as a positive control (Table I). No detectable IFN- was produced if
the cell line was stimulated with P815 or APC presenting a control
H-2Ld peptide, P1A. GM-CSF was also detected in
the same culture supernatants (Table I), and although TNF- was not
detected in an ELISA, functional "TNF-like" activity (most likely
TNF-) was shown by a TNF bioassay using L929 cells (data not shown).
No detectable IL-4, IL-5, or IL-10 was found in any of the supernatants
tested.
|
To test the ability of the CMS4-reactive CTL line to mediate
antitumor activity in vivo, mice bearing 3-day CMS4 lung metastases
were treated with varying numbers of CTL. Two weeks following the
adoptive transfer, lungs were removed and processed for the enumeration
of lung metastases. As shown in Fig. 4, lungs of control mice had an average of 214 nodules. The adoptive
transfer of as few as 3 x 104 CMS4-reactive
CTL was able to reduce tumor burden in the lung by approximately half
(112 ± 17.2), and optimal reduction of tumor burden was seen
between 1 x 106 and 3 x
106 adoptively transferred CMS4-reactive CTL
(2–6 nodules/lung). As an additional negative control, no reduction of
tumor burden was observed when 1 x 106 Flu
peptide-specific CTL were transferred to mice bearing 3-day CMS4 lung
metastases. No evidence of overt toxicity was observed by adoptive
transfer of Ag-specific CTL (up to 3 x 106
cells per mouse) under these conditions. Furthermore, in an ongoing
long-term survival experiment, up to 4 mo post adoptive transfer of
3 x 106 CTL per mouse, no apparent evidence
of toxicity caused by the immunotherapy protocol is noted
(n = 6 mice); on the contrary, these mice still appear
to be active and thriving as well as naive control mice (data not
shown).
|
, no detectable lysis of CMS4 tumor
cells was observed with cells recovered from control lungs. However,
cells digested from the lungs of mice that rejected CMS4 cells lysed
40% CMS4 tumor cells at an E:T ratio of 18:1. The CMS4-reactive CTL
line taken directly from culture was used as a positive control for the
assay.
|
A),
whereas the other group was rechallenged with CMS4 tumor cells s.c.
(Fig. 6C), 45 days following the original adoptive transfer.
In the first i.v. experiment, control mice challenged with CMS4 tumor
cells developed an average of 161 ± 38 pulmonary nodules compared
with 3 ± 2 nodules in the rechallenged mice (Fig. 6A).
When the experiment was repeated, control mice developed tumors that
were too numerous to count. However, the rechallenged mice developed an
average of 17 ± 7 pulmonary nodules. Overall, the difference
between tumor growth in naive control mice vs the rechallenged mice was
highly significant (p = 8.2 x
10-5). In the s.c. setting, in two independent
experiments, control (Fig. 6B) mice challenged with CMS4
tumor cells s.c. developed measurable tumors 11–14 days later. All
mice (10/10) developed tumors, the vast majority of which continued to
grow progressively. In the rechallenge group (Fig. 6C),
there was a significant difference in tumor size compared with control
mice at the earlier time points (p = 0.02 at
day 11 or 12). Although the average tumor size in the rechallenged
group remained smaller than that of the control group at later time
points, this was not statistically significant
(p = 0.08 at day 17 and p =
0.16 at day 23). Average tumor sizes are given in Fig. 6. However, it
is important to note that in the group of eight mice that were
rechallenged s.c., two remained tumor-free for the duration of the
experiment (Fig. 6C).
|
). Lungs were removed and the number of
metastases enumerated 7, 14, or 21 days following the adoptive
transfer. In the first experiment, the average number of pulmonary
nodules in control mice at the time of adoptive transfer on day 10 was
189 ± 26 (n = 5 mice). By day 17, the number of
metastases in control (HBSS) mice at day 17 was >250, whereas mice
receiving the CMS4-reactive CTL line had an average of 47 ± 8
(n = 5). This represented an 80% reduction of the
tumor burden in these animals (Fig. 7). To examine the efficacy of this
adoptive transfer paradigm in more detail, a second experiment was
performed and the number of pulmonary nodules enumerated at several
time points following the adoptive transfer. As shown by the open
circles in Fig. 7, the pulmonary nodules in the control mice at the
time of adoptive transfer on day 10 were too numerous to count and
increased in size by day 17. However, the mice that received the
CMS4-reactive CTL line had 117 ± 12 (n = 5)
nodules per lung on day 17. By day 24 the number of pulmonary nodules
in mice receiving the CMS4-reactive CTL line was further reduced to
35 ± 8 (n = 4). This number remained steady at
day 31 (n = 4); however, the size of the nodules on day
31 was larger than on day 24 (data not shown).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
An Ag-specific CD8+ CTL line was produced from
normal BALB/c mice challenged with a syngeneic tumor (CMS4 sarcoma)
coinjected with anti-CTLA4 mAb, which has previously been reported
to facilitate the induction of Ag-specific T cell responses in vivo
(13). Anti-CTLA4 mAb presumably functions by disallowing
or disengaging the transduction of inhibitory signals triggered during
the process of T cell costimulation (12, 21). Importantly,
these T cells were derived from a donor host with a normal,
unmanipulated TCR repertoire. An H-2Ld-restricted
peptide derived from an endogenous ectopic murine leukemia provirus,
previously described as a dominant rejection epitope for the CT26 colon
carcinoma cell line (14), was shown to be recognized by
the CMS4-reactive CTL line (Fig. 2). This is the first description of
this peptide (AH1) as an epitope expressed by the CMS4 sarcoma cell
line. Cold target inhibition assays confirmed that AH1 was a dominant
CD8+ T cell epitope presented endogenously by the
CMS4 sarcoma cell line (Fig. 3). Furthermore, these CTL could be stably
maintained, both phenotypically and functionally, in vitro by culture
with autologous tumor cells or AH1 peptide (data not shown) as a source
of cognate Ag and expanded proficiently to large numbers. These are
both important prerequisites for the production of immune effector
cells for adoptive immunotherapy in clinical settings. The Ag
specificity of the CMS4-reactive CD8+ CTL
reflected CTL-mediated lysis of, or cytokine production in response to,
syngeneic CMS4 tumor cells endogenously expressing the TSA. The notion
that AH1 was involved in the rejection response in this T cell tumor
model was further supported by the observation that immunization of
BALB/c mice with AH1 peptide in adjuvant led to the production of a
peptide-specific CD8+ CTL line, which also
efficiently lysed CMS4 sarcoma cells in vitro and expressed antitumor
activity in vivo by adoptive transfer (data not shown). Thus, the
biological components of this model resemble more closely what would be
available in a clinical setting. Using this model system, we then
examined 1) the potency and efficacy of CMS4-reactive
CD8+ CTL in adoptive therapy of pulmonary
metastases; 2) the maintenance of this antitumor response following
adoptive transfer, based on tumor rechallenge at the original or distal
sites of neoplastic growth; and 3) the effectiveness of antitumor
activity of Ag-specific CTL in mice with extensive disease.
The potency of the antitumor response mediated by the
CD8+ CMS4-reactive CTL line in vivo was shown in
the titration experiments (Fig. 4). As few as 0.3–1 x
105 CMS4-reactive CTL resulted in a reduction of
tumor burden in mice with 3-day established pulmonary metastases. One
million CMS4-reactive CTL resulted in the nearly complete elimination
of detectable metastases, whereas the adoptive transfer of the same
number of a control, influenza peptide-reactive CTL had no effect on
tumor burden. CTL activity was recovered from the lungs of mice, which
rejected tumor growth by adoptive transfer, suggesting that the
antitumor response in vivo correlated with the presence of functional
effectors in the lung (Fig. 5). Previous work from our laboratory has
shown that Ag-specific CD4+ or
CD8+ T cells can be recovered from spleen and
lung up to 10 wk following adoptive transfer in nontumor-bearing mice,
provided that these cells are exposed to Ag in vivo subsequent to the
adoptive transfer (22). In the present model, Ag
stimulation of the adoptively transferred cells was likely provided
through recognition of tumor cells in vivo.
The efficacy of adoptive transfer for therapy of mice with more
extensive pulmonary metastases was also examined. The CMS4-reactive CTL
was efficient at causing tumor regression in mice with this large tumor
burden (Fig. 7). Although regression was not complete and residual
metastatic lesions eventually began to grow in size (data not shown),
the mice survived at least 3 wk longer than control animals, which were
moribund by day 17.
Hansen et al. (10) examined the effectiveness of adoptive
transfer of uncultured, resting CD8+ T cells for
therapy of s.c. tumors expressing an endogenous tumor rejection Ag.
They were able to show that adoptive transfer was effective in mice
with 3-day (early), but not 5-day (late), s.c. established tumors. In
our model, therapeutic efficacy by adoptive transfer against 3-day
established s.c. tumors could not be demonstrated (data not shown).
However, it is important to point out that there was at least partial
immunity against a s.c. tumor cell challenge in mice that had
previously rejected tumor growth in the lung by adoptive transfer (Fig. 6C). In addition, the CMS4-reactive CTL line was highly
effective in the treatment of both early (day 3) and late (day 10)
visceral tumors (Figs. 4 and 7). Although both models use Ag-specific T
cells against tumors expressing endogenous tumor Ag, Hansen et al.
(10) used resting CD8+ splenocytes
from a TCR transgenic mouse. However, in a clinical setting,
patient-derived T cells would need to be expanded in vitro to generate
adequate numbers of Ag-specific T cells for adoptive transfer. Thus, it
is important to study the in vivo properties of T cells cultured under
those conditions.
It is also important to note that the adoptive transfer
experiments described here were conducted without exogenous cytokines
(e.g., IL-2), Ag or peptide boosting, or immunosuppressive drugs (e.g.,
cyclophosphamide), and with only one cycle of adoptive transfer. The
addition of these reagents or multiple cycles of adoptive transfer may
potentially improve therapeutic responses in cases of more aggressive
tumor-bearing conditions, such as an extensive or systemic tumor burden
(Figs. 6 and 7). Although the exact mechanisms of tumor rejection in
the lung, as well as at the s.c. distal site, require further
elucidation, the adoptive transfer of Ag-specific
CD8+ CTL can play an important regulatory and/or
effector role in the eradication of pulmonary metastases. In our model,
the initial rejection response also renders these mice tumor-immune,
based on the rejection of new tumor transplants given several weeks
later (Fig. 6). This was evident not only in the lungs of these animals
(Fig. 6A), but also at distal (s.c.) sites (Fig. 6C), albeit to a lesser extent. This finding may have
implications for the control of tumor growth in the event of disease
recurrence at systemic sites. The fact that these CTL produce copious
amounts of immunoregulatory cytokines in response to Ag stimulation,
such as IFN- and GM-CSF, suggests that these, as well as other
lymphokines, may be involved in the tumor rejection response.
Overall, we have described a model of adoptive immunotherapy for advanced pulmonary metastases using Ag-specific CTL and a tumor expressing an endogenous tumor rejection Ag. Highly potent, Ag-specific CTL were generated from tumor-immune mice and were stably propagated in vitro. Using this T cell-tumor model, we have shown that 1) tumor-reactive CD8+ CTL are highly effective in the adoptive therapy of pulmonary metastases; 2) adoptively transferred CTL are important for promoting or eliciting antitumor responses, not only at the initial site of tumor burden, but also at a s.c. distal site; and 3) tumor-reactive CD8+ CTL can mediate antitumor activity in mice with extensive pulmonary disease (day 10 metastases). Overall, these data suggest that the adoptive transfer of tumor-specific CTL may have therapeutic potential for immunotherapy of certain types of malignancies, such as those that might metastasize to the lung.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Abbreviation used in this paper: TSA, tumor-specific Ag.
Received for publication May 23, 2001. Accepted for publication August 15, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  D. Yang, N. ud Din, D. D. Browning, S. I. Abrams, and K. Liu Targeting Lymphotoxin {beta} Receptor with Tumor-Specific T Lymphocytes for Tumor Regression Clin. Cancer Res., September 1, 2007; 13(17): 5202 - 5210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Yang, M. Thangaraju, K. Greeneltch, D. D. Browning, P. V. Schoenlein, T. Tamura, K. Ozato, V. Ganapathy, S. I. Abrams, and K. Liu Repression of IFN Regulatory Factor 8 by DNA Methylation Is a Molecular Determinant of Apoptotic Resistance and Metastatic Phenotype in Metastatic Tumor Cells Cancer Res., April 1, 2007; 67(7): 3301 - 3309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, A. Dutuor, L. Tao, X. Fu, and X. Zhang Virotherapy with a Type 2 Herpes Simplex Virus-Derived Oncolytic Virus Induces Potent Antitumor Immunity against Neuroblastoma Clin. Cancer Res., January 1, 2007; 13(1): 316 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ohta, E. Gorelik, S. J. Prasad, F. Ronchese, D. Lukashev, M. K. K. Wong, X. Huang, S. Caldwell, K. Liu, P. Smith, et al. A2A adenosine receptor protects tumors from antitumor T cells PNAS, August 29, 2006; 103(35): 13132 - 13137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Liu, S. A. Caldwell, K. M. Greeneltch, D. Yang, and S. I. Abrams CTL Adoptive Immunotherapy Concurrently Mediates Tumor Regression and Tumor Escape J. Immunol., March 15, 2006; 176(6): 3374 - 3382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. N. Hwang, Z. Yu, D. C. Palmer, and N. P. Restifo The In vivo Expansion Rate of Properly Stimulated Transferred CD8+ T Cells Exceeds That of an Aggressively Growing Mouse Tumor Cancer Res., January 15, 2006; 66(2): 1132 - 1138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. W. J. Schreurs, M. A. J. A. Hermsen, R. I. K. Geltink, K. B. J. Scholten, A. A. T. P. Brink, E. W. M. Kueter, M. Tijssen, C. J. L. M. Meijer, B. Ylstra, G. A. Meijer, et al. Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes Blood, October 15, 2005; 106(8): 2663 - 2670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Liu, S. A. Caldwell, and S. I. Abrams Immune Selection and Emergence of Aggressive Tumor Variants as Negative Consequences of Fas-Mediated Cytotoxicity and Altered IFN-{gamma}-Regulated Gene Expression Cancer Res., May 15, 2005; 65(10): 4376 - 4388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Liu, S. A. Caldwell, and S. I. Abrams Cooperative Disengagement of Fas and Intercellular Adhesion Molecule-1 Function in Neoplastic Cells Confers Enhanced Colonization Efficiency Cancer Res., February 1, 2005; 65(3): 1045 - 1054. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Chakraborty, S. I. Abrams, C. N. Coleman, K. Camphausen, J. Schlom, and J. W. Hodge External Beam Radiation of Tumors Alters Phenotype of Tumor Cells to Render Them Susceptible to Vaccine-Mediated T-Cell Killing Cancer Res., June 15, 2004; 64(12): 4328 - 4337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. O'Mara and P. M. Allen Pulmonary Tumors Inefficiently Prime Tumor-Specific T Cells J. Immunol., January 1, 2004; 172(1): 310 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Caldwell, M. H. Ryan, E. McDuffie, and S. I. Abrams The Fas/Fas Ligand Pathway Is Important for Optimal Tumor Regression in a Mouse Model of CTL Adoptive Immunotherapy of Experimental CMS4 Lung Metastases J. Immunol., September 1, 2003; 171(5): 2402 - 2412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Liu and S. I. Abrams Alterations in Fas Expression Are Characteristic of, But Not Solely Responsible for, Enhanced Metastatic Competence J. Immunol., June 15, 2003; 170(12): 5973 - 5980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rosato, S. D. Santa, A. Zoso, S. Giacomelli, G. Milan, B. Macino, V. Tosello, P. Dellabona, P.-L. Lollini, C. De Giovanni, et al. The Cytotoxic T-Lymphocyte Response against a Poorly Immunogenic Mammary Adenocarcinoma Is Focused on a Single Immunodominant Class I Epitope Derived from the gp70 Env Product of an Endogenous Retrovirus Cancer Res., May 1, 2003; 63(9): 2158 - 2163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Meidenbauer, J. Marienhagen, M. Laumer, S. Vogl, J. Heymann, R. Andreesen, and A. Mackensen Survival and Tumor Localization of Adoptively Transferred Melan-A-Specific T Cells in Melanoma Patients J. Immunol., February 15, 2003; 170(4): 2161 - 2169. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||
