| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Immunology |
Cancer Research Laboratory [A. A. H., T. T., E. M. C., J. P. A.] and Howard Hughes Medical Institute [T. T., E. M. C., J. P. A.], University of California, Berkeley, California 94720; Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77027 [B. A. F., N. M. G.]; Department of Urology and Cardinal Bernardin Cancer Center, Loyola University School of Medicine, Maywood, Illinois 60153 [E. D. K.]; and Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892 [E. D. K., M. B. B.]
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
More recently, costimulation has been shown to be more complex than previously thought; CTLA-4 is a second T-cell counter-receptor for B7 (14) that plays a critical role in attenuating T-cell responses. CTLA-4 engagement may inhibit the initiation of T-cell responses by raising the threshold of signals needed for full activation, or may also play a role in terminating ongoing T-cell responses (15 , 16) . Anti-CTLA-4 antibodies that block CTLA-4/B7 interactions enhance in vivo T-cell responses to peptides, superantigens, and parasites, and can exacerbate experimental autoimmune encephalomyelitis (for review, see Ref. 15 ). Administration of anti-CTLA-4 antibodies is sufficient to induce the rejection of newly implanted, and in some cases, well established tumors in several transplantable murine tumor systems (17, 18, 19, 20) . The effectiveness of CTLA-4 blockade in these systems seems to be dependent on the inherent immunogenicity of the tumor. Whereas CTLA-4 blockade by itself is not effective in the treatment of poorly immunogenic transplantable tumors such as the mammary carcinoma SM1 (21) or the melanoma B16 (22) , eradication of these tumors can be achieved when anti-CTLA-4 is administered together with an irradiated tumor cell vaccine expressing GM-CSF. In the case of the B16 melanoma, tumor rejection is regularly accompanied by a progressive depigmentation that resembles the vitiligo accompanying immunotherapy in many human melanoma patients (23, 24, 25) . This result suggests that in mice, as in man, the antimelanoma response is, in part, directed to normal melanocyte-specific antigens (22 , 23) .
In contrast to the considerable literature documenting immunological responses to melanoma in humans and in mouse models, there is a paucity of data concerning immunological responses to prostate tumors. We have shown that CTLA-4 blockade is sufficient to obtain partial or complete regression of s.c. implants of tumor cell lines (26) derived from the TRAMP mice in syngeneic, nontransgenic C57BL/6 male mice (18) . In the current study, we examined the potential of CTLA-4 blockade in the treatment of primary cancer in TRAMP mice. We found that CTLA-4 blockade in combination with irradiated tumor cell vaccines was effective at reducing tumor incidence and the severity of prostatic lesions. We also noted significant accumulation of inflammatory cells in the prostates of some TRAMP mice that received vaccinations. Finally, we show that the antitumor response is directed, in part, against antigens expressed by normal prostate, because immunization of nontransgenic mice with GM-CSF-expressing tumor cell vaccines under conditions of CTLA-4 blockade can result in marked prostatitis. This work demonstrates for the first time the effectiveness of this immunotherapeutic regimen in primary cancer and indicates that prostatic tumors may express tissue-specific antigens that provide targets for immunotherapy.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Mice received s.c. vaccinations of 1 x 106 cells each of irradiated (12,000 rads) TRAMP-C1 and TRAMP-C2 or their GM-CSF-transduced derivatives, GMTRAMP-C1/C2. To maximize antigenic challenge, this treatment was repeated two additional times, 3 days apart. Seven days after the initiation of vaccination, mice received i.p. injections of 100 µg of anti-CTLA-4 (clone 9H10; Ref. 28 ) or with purified hamster IgG (Jackson Immunoresearch Corp., West Grove, PA). Additional doses of antibody were administered 3 and 6 days after the first treatment. Mice were euthanized at the indicated age, and the prostatic complex was microdissected under a stereomicroscope. Tumor incidence was initially assessed at necropsy and confirmed by histopathological examination, using a score of 4.0 (see below, invasive adenocarcinoma) as the defining criterion.
Histopathological Analyses.
The prostatic complex was microdissected into the individual lobes and
fixed in 10% neutral buffered formalin. Tissues were processed and
stained with H&E for routine histopathological analyses. TRAMP tissues
were graded blindly by two individuals using the following criteria
(29)
: (a) normal epithelium was assigned a
score of 1.0; (b) early signs of prostatic intraepithelial
neoplasia with tufting of the epithelium and increased
nucleus:cytoplasm ratio were scored as 2.0; (c) more
advanced prostatic intraepithelial neoplasia with noted cribiform
structures and an increase in mitotic and/or apoptotic figures was
scored as 3.0; (d) the loss of interductal spaces and the
invasion of basement membranes was scored as 4.0; (e) total
loss of ductal lumens with evidence of adenocarcinoma was scored as
5.0; and (f) sheets of anaplastic cells were scored as 6.0.
Each arbitrarily numbered sample was scanned for the peak severity at
x4 and graded at a magnification of x10. To generate a mean peak
score, the maximum histological score for the ventral, dorsal, or
lateral prostate lobes for each animal was used to calculate a mean for
the treatment group. The predominant peak score for all TRAMP animals
was 4.0, with few histological scores below 3.0.
Cell Culture.
TRAMP-C cells are early passage (10–15 passages in vitro),
nonclonal epithelioid tumor cells independently derived from a TRAMP
mouse and were propagated as described (26)
. To obtain
GM-CSF-expressing lines, cells were infected with a retrovirus
containing the mouse gm-csf gene driven by the Maloney
murine leukemia virus LTR, using the 
CRIP producer line (Somatix,
Inc., Alameda, CA), as described (21)
. GM-CSF production
was assayed by ELISA (PharMingen, San Diego, CA). Both GMTRAMP-C1 and
GMTRAMP-C2 secreted GM-CSF at 150–200 ng/ml/1 x 106 cells/24 h. Cells used for injection were
released from tissue culture dishes with trypsin (BioWhittaker) and
washed three times in HBSS (BioWhittaker). Cells were resuspended at a
density of 1 x 107 cells/ml,
irradiated with 12,000 rads using a Cs-source irradiator, and injected
s.c. in a volume of 0.1 ml.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
At 3 weeks after treatment, the tumors in the control antibody-treated
mice were sufficiently large to warrant concern about survival of the
remaining mice. Therefore, the remaining 25 mice in each group were
euthanized 5 weeks later to allow assessment of tumor incidence and
tumor grade. Similar to the analysis at 3 weeks after treatment, there
was no significant difference in animal weight or prostate weight
between any of the treatment groups. However, there were significant
differences in tumor incidence (Fig. 1A)
. A significantly lower tumor incidence was observed in
mice treated with anti-CTLA-4 and either the TRAMP-C1/C2 vaccine (43%,
P = 0.05) or the GMTRAMP-C1/C2 vaccine (33%,
P = 0.009) than in mice treated with control
antibody alone (69%). Treatment with anti-CTLA-4 alone had no
significant effect on tumor incidence (64%), and there was no
significant reduction in tumor incidence in mice receiving the control
antibody treatment and either vaccine (55%-TRAMP-C1/C2 and
75%-GMTRAMPC1/C2). Thus, neither CTLA-4 blockade nor vaccination alone
was effective at treating primary tumors in TRAMP mice. However, the
combination of anti-CTLA-4 and either vaccine synergized to decrease
tumor incidence. The expression of GM-CSF by the vaccine may further
enhance the antitumor response because the tumor incidence was slightly
lower in mice that received vaccinations of GMTRAMP-C1/C2 (33%
anti-CTLA-4+GMTRAMP-C1/C2 versus
43%-anti-CTLA-4+TRAMP-C1/C2).
|
, for mice that
received vaccinations of GMTRAMP-C1/C2 there was significant reduction
in tumor incidence in the mice treated at 14 weeks of age
(P = 0.003), but not in the group treated at
16 weeks of age (P = 0.1). This suggests that
the stage of tumor development at the time of immunotherapy of TRAMP
mice influenced the efficacy of treatment. Tumor incidence in mice
treated with TRAMP-C1/C2 and anti-CTLA-4 at 14 and 16 weeks of age was
equivalent.
Reduction of Tumor Grade in TRAMP Mice Treated with
Combination Immunotherapy.
To assess the severity of prostate lesions in TRAMP mice, the
individual lobes of the prostate were prepared for routine
histopathological analysis and scored as described in "Materials and
Methods." As shown in Fig. 2A
, there was a significant reduction in the severity of
lesions in mice treated with anti-CTLA-4 and either vaccine.
Specifically, TRAMP mice treated with TRAMP-C1/C2 and anti-CTLA-4 had a
significantly lower score (mean peak score, 4.6) than control
immunoglobulin-treated mice (mean peak score, 5.5;
P = 0.03). Even more striking was the finding
that mice treated with GMTRAMP-C1/C2 and anti-CTLA-4 had a
significantly lower tumor grade (mean peak score, 3.9) than all three
control groups: control immunoglobulin/no vaccine (mean peak score,
5.5; P = 0.0009), control
immunoglobulin/GMTRAMP-C1/C2 (mean peak score, 5.5;
P = 0.0002), and anti-CTLA-4 treatment alone
(mean peak score, 4.8; P = 0.04). Treatment
with anti-CTLA-4 alone or either vaccine without CTLA-4 blockade had no
significant effect on tumor grade. These findings demonstrate that in
addition to reducing the incidence of primary tumors, vaccination
reduced the severity of prostatic lesions in TRAMP mice.
|
). Interestingly, when treated at 16
weeks of age, TRAMP mice receiving the GMTRAMP-C1/C2 vaccine and
anti-CTLA-4 (mean peak score, 4.5) only had a slightly lower mean peak
score than mice treated with GMTRAMP-C1/C2 and control immunoglobulin
(mean peak score, 5.6; P = 0.03). Tumor grade
in mice treated TRAMP-C1/C2 at 14 and 16 weeks of age was equivalent.
Perhaps the most striking histological feature of these analyses
was observed in mice treated with GMTRAMP-C1/C2 and anti-CTLA-4, where
there was an accumulation of inflammatory cells in the interductal
spaces (Fig. 3, C and D)
. In these mice, inflammatory
cells were closely associated with the vasculature of the stroma. In
contrast, there was no significant accumulation of inflammatory cells
in any of the control immunoglobulin-treated mice (Fig. 3B)
.
In TRAMP mice treated with a GM-CSF-expressing vaccine alone, there
were occasional areas where inflammatory cells were detected, but these
sites were not nearly as extensive as those observed in mice also
treated with anti-CTLA-4 (data not shown). The morphological features
of the infiltrating cells suggested that the perivascular inflammation
was comprised of lymphoid and myeloid cells.
|
. There was no evidence of significant inflammation or
tissue damage in the dorsolateral or ventral lobes of the prostates of
mice vaccinated with the GMTRAMP-C1/C2 vaccine only. However, there was
mononuclear cell infiltration and destruction of glandular epithelium
of the male reproductive tract (including the dorsolateral prostate) in
some mice vaccinated with GMTRAMP-C1/C2 and treated with anti-CTLA-4.
These results demonstrate that the response elicited by the vaccination
regimen is directed, in part, to antigens expressed by normal prostate
cells. |
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The reduction of both tumor incidence and histological tumor grade indicates that the combination of a cell-based vaccine together with anti-CTLA-4 was sufficient to slow the progression of primary prostatic tumors. Because the TAg transgene is under the transcriptional control of an androgen-regulated promoter and is, therefore, constitutively active in prostatic lumenal epithelial cells after sexual maturation, over time, a transformed phenotype will be observed in nearly all prostatic epithelium. It is not surprising that the immune system is unable to completely eliminate tumors in this aggressive model, but rather is remarkable that an antitumor immune response can have a significant impact on disease progression in a situation where an entire organ is undergoing transformation.
Our data in this primary tumor model indicate a synergy between CTLA-4 blockade and a tumor cell-based vaccine. TRAMP mice treated with either the vaccine or antibody alone had no reduction in tumor incidence or tumor grade, whereas the combination of both resulted in a significant reduction in both criteria. This suggests that an additional source of antigen from the cell-based vaccine contributes to T-cell priming, which is enhanced by blockade of CTLA-4/B7 interactions. The fact that tumor incidence and tumor grade were lower in mice that received the GMTRAMP-C1/C2 vaccine than those receiving the TRAMP-C1/C2 vaccine suggests that the effect is enhanced by the recruitment and activation of APCs by GM-CSF expression.
The basis for the age dependence on the effectiveness of treatment is not clear. The accessibility of the tumor to the immune system may change with the progression of neoplasia due to alterations in vasculature or intratumoral pressure. Tumor growth during this time period may begin to exceed the ability of the immune system to have a significant impact on controlling tumorigenesis. However, at 14 and 16 weeks of age, there do not appear to be any histopathological differences that might suggest that the antigenic profile might differ between these two ages.
Vaccination of nontransgenic mice with the same therapeutic strategy demonstrated to be effective for treatment of TRAMP mice led to autoimmune prostatitis and destruction of some prostatic epithelium. This finding suggests that the vaccination approach is capable of inducing an autoimmune response against normal prostate antigens. We have also observed development of autoimmune depigmentation following rejection of a pigmented melanoma using a combination of CTLA-4 blockade and melanoma cells expressing GM-CSF (22) that is similar to the vitiligo that has been observed in patients showing clinical responses to immunotherapy of melanoma (23) . The results reported here add support to the idea that effective tumor immunity is, in fact, closely tied to autoimmunity. Rather than being viewed as a troublesome side effect, an emerging concept is that intentional induction of autoimmunity to defined tissue-specific antigens may be a practical strategy for generation of effective antitumor responses (25 , 31) . The findings presented in this study support this approach for immunological treatment of tumors arising from nonvital tissues.
The work presented here clearly demonstrates that CTLA-4 blockade, in combination with a tumor cell-based vaccine, can elicit responses that can decrease the incidence of primary tumors in the TRAMP mice. We have previously shown that CTLA-4 blockade can synergize with tumor cell vaccines engineered to express GM-CSF and can be quite effective against murine melanoma (22) and mammary carcinoma (21) . Recent clinical trials have shown that autologous melanoma cells transduced to express GM-CSF can elicit potent, although not curative (32) , antitumor responses. Similarly, a recent report of a clinical trial using GM-CSF-secreting tumor cell vaccines has documented the induction of immune responses, including Th1, Th2, and antibody, in prostate cancer (33) . Together, these findings make a compelling case for the use of a combination of GM-CSF-secreting tumor cell vaccines and anti-CTLA-4 in clinical trials. We are currently examining the effectiveness of CTLA-4 blockade in combination with more conventional therapies, such as androgen ablation or chemotherapy, that might induce sufficient tumor cell death to achieve priming of tumor-reactive T cells in the absence of a cell-based vaccine. Recent data provide compelling support for the therapeutic potential of the blockade of CTLA-4-mediated inhibitory signals of T-cell activation as a strategy for enhancing immunological responses to tumors. The demonstrated link between tumor immunity and autoimmunity underscore the power of this approach. A greater understanding of the role of CTLA-4 and other costimulatory molecules in the regulation of tolerance to self-antigens will facilitate the design of even more effective immunotherapies for cancer and other diseases with immune components.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 Supported in part by grants from the CaP CURE
Foundation (to A. A. H., N. M. G., and J. P. A.), the NIH, the
National Cancer Institute (to E. D. K., N. M. G., M. B. B, and
J. P. A.), and the American Foundation for Urological Diseases [to
B. A. F. (Wyland F. Leadbetter Fellow) and E. D. K. (Pfizer
Fellow)]. A. A. H. was a fellow of the Department of Defense Breast
Cancer Research Program and a CaP CURE Young Investigator. J. P. A.
is an Investigator of the Howard Hughes Medical Institute. 
2 To whom requests for reprints should be
addressed, Department of Microbiology and Immunology and Department of
Urology, SUNY Upstate Medical University, 766 Irving Avenue, Syracuse,
New York 13210. Phone: (315) 464-7690; Fax: (315) 464-5869; E-mail: hurwitza{at}mail.upstate.edu
3 To whom requests for reprints should be
addressed, at Howard Hughes Medical Institute, 401 LSA, University of
California, Berkeley, CA 94270. E-mail: jallison{at}uclink4.berkeley.edu
4 The abbreviations used are: APC,
antigen-presenting cell; GM-CSF, granulocyte-macrophage
colony-stimulating factor; TRAMP, transgenic adenocarcinoma of mouse
prostate; GM-TRAMPC, GM-CSF-transduced prostatic carcinoma cells
derived from TRAMP mice.
5 S. Tevethian and L. Mylin, personal
communication.
Received 11/17/99. Accepted 3/21/00.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  C. Fonseca, R. Soiffer, V. Ho, M. Vanneman, M. Jinushi, J. Ritz, D. Neuberg, R. Stone, D. DeAngelo, and G. Dranoff Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction Blood, February 19, 2009; 113(8): 1681 - 1688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ribas, B. Comin-Anduix, J. S. Economou, T. R. Donahue, P. de la Rocha, L. F. Morris, J. Jalil, V. B. Dissette, I. P. Shintaku, J. A. Glaspy, et al. Intratumoral Immune Cell Infiltrates, FoxP3, and Indoleamine 2,3-Dioxygenase in Patients with Melanoma Undergoing CTLA4 Blockade Clin. Cancer Res., January 1, 2009; 15(1): 390 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Fong and E. J. Small Anti-Cytotoxic T-Lymphocyte Antigen-4 Antibody: The First in an Emerging Class of Immunomodulatory Antibodies for Cancer Treatment J. Clin. Oncol., November 10, 2008; 26(32): 5275 - 5283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Q. Phan, J. S. Weber, and V. K. Sondak CTLA-4 Blockade with Monoclonal Antibodies in Patients with Metastatic Cancer: Surgical Issues Ann. Surg. Oncol., November 1, 2008; 15(11): 3014 - 3021. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Wolchok and Y. Saenger The Mechanism of Anti-CTLA-4 Activity and the Negative Regulation of T-Cell Activation Oncologist, October 1, 2008; 13(suppl_4): 2 - 9. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Kirkwood, A. A. Tarhini, M. C. Panelli, S. J. Moschos, H. M. Zarour, L. H. Butterfield, and H. J. Gogas Next Generation of Immunotherapy for Melanoma J. Clin. Oncol., July 10, 2008; 26(20): 3445 - 3455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Liu, I.-E. A. Eltoum, B. Guo, B. H. Beck, G. A. Cloud, and R. D. Lopez Protective Immunosurveillance and Therapeutic Antitumor Activity of {gamma}{delta} T Cells Demonstrated in a Mouse Model of Prostate Cancer J. Immunol., May 1, 2008; 180(9): 6044 - 6053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fasso, R. Waitz, Y. Hou, T. Rim, N. M. Greenberg, N. Shastri, L. Fong, and J. P. Allison SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade PNAS, March 4, 2008; 105(9): 3509 - 3514. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. S. Hodi, M. Butler, D. A. Oble, M. V. Seiden, F. G. Haluska, A. Kruse, S. MacRae, M. Nelson, C. Canning, I. Lowy, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients PNAS, February 26, 2008; 105(8): 3005 - 3010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Raina, M.-J. Blouin, R. P. Singh, N. Majeed, G. Deep, L. Varghese, L. M. Glode, N. M. Greenberg, D. Hwang, P. Cohen, et al. Dietary Feeding of Silibinin Inhibits Prostate Tumor Growth and Progression in Transgenic Adenocarcinoma of the Mouse Prostate Model Cancer Res., November 15, 2007; 67(22): 11083 - 11091. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. S. Hodi Cytotoxic T-Lymphocyte Associated Antigen-4 Clin. Cancer Res., September 15, 2007; 13(18): 5238 - 5242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Stewart and S. I. Abrams Altered Immune Function during Long-Term Host-Tumor Interactions Can Be Modulated to Retard Autochthonous Neoplastic Growth J. Immunol., September 1, 2007; 179(5): 2851 - 2859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Roth, Y. Sheinin, C. M. Lohse, S. M. Kuntz, X. Frigola, B. A. Inman, A. E. Krambeck, M. E. Mckenney, R. J. Karnes, M. L. Blute, et al. B7-H3 Ligand Expression by Prostate Cancer: A Novel Marker of Prognosis and Potential Target for Therapy Cancer Res., August 15, 2007; 67(16): 7893 - 7900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. F. Valenzuela, K. E. Pace, P. V. Cabrera, R. White, K. Porvari, H. Kaija, P. Vihko, and L. G. Baum O-Glycosylation Regulates LNCaP Prostate Cancer Cell Susceptibility to Apoptosis Induced by Galectin-1 Cancer Res., July 1, 2007; 67(13): 6155 - 6162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ribas, D. C. Hanson, D. A. Noe, R. Millham, D. J. Guyot, S. H. Bernstein, P. C. Canniff, A. Sharma, and J. Gomez-Navarro Tremelimumab (CP-675,206), a Cytotoxic T Lymphocyte Associated Antigen 4 Blocking Monoclonal Antibody in Clinical Development for Patients with Cancer Oncologist, July 1, 2007; 12(7): 873 - 883. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tuve, B.-M. Chen, Y. Liu, T.-L. Cheng, P. Toure, P. S. Sow, Q. Feng, N. Kiviat, R. Strauss, S. Ni, et al. Combination of Tumor Site-Located CTL-Associated Antigen-4 Blockade and Systemic Regulatory T-Cell Depletion Induces Tumor-Destructive Immune Responses Cancer Res., June 15, 2007; 67(12): 5929 - 5939. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-H. Su, T.-Y. Chang, Y.-J. Lee, C.-K. Chen, H.-F. Liu, C.-C. Chu, M. Lin, P.-T. Wang, W.-C. Huang, T.-C. Chen, et al. CTLA-4 gene and susceptibility to human papillomavirus-16-associated cervical squamous cell carcinoma in Taiwanese women Carcinogenesis, June 1, 2007; 28(6): 1237 - 1240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. O'Mahony, J. C. Morris, C. Quinn, W. Gao, W. H. Wilson, B. Gause, S. Pittaluga, S. Neelapu, M. Brown, T. A. Fleisher, et al. A Pilot Study of CTLA-4 Blockade after Cancer Vaccine Failure in Patients with Advanced Malignancy Clin. Cancer Res., February 1, 2007; 13(3): 958 - 964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Vieweg, Z. Su, P. Dahm, and S. Kusmartsev Reversal of Tumor-Mediated Immunosuppression Clin. Cancer Res., January 15, 2007; 13(2): 727s - 732s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Kocak, K. Lute, X. Chang, K. F. May Jr., K. R. Exten, H. Zhang, S. F. Abdessalam, A. M. Lehman, D. Jarjoura, P. Zheng, et al. Combination Therapy with Anti-CTL Antigen-4 and Anti-4-1BB Antibodies Enhances Cancer Immunity and Reduces Autoimmunity. Cancer Res., July 15, 2006; 66(14): 7276 - 7284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tartz, J. Kamanova, M. Simsova, P. Sebo, S. Bolte, V. Heussler, B. Fleischer, and T. Jacobs Immunization with a Circumsporozoite Epitope Fused to Bordetella pertussis Adenylate Cyclase in Conjunction with Cytotoxic T-Lymphocyte-Associated Antigen 4 Blockade Confers Protection against Plasmodium berghei Liver-Stage Malaria Infect. Immun., April 1, 2006; 74(4): 2277 - 2285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kapadia and L. Fong CTLA-4 Blockade: Autoimmunity As Treatment J. Clin. Oncol., December 10, 2005; 23(35): 8926 - 8928. [Full Text] [PDF]
|
|
|
|
|
|
A. V. Maker, G. Q. Phan, P. Attia, J. C. Yang, R. M. Sherry, S. L. Topalian, U. S. Kammula, R. E. Royal, L. R. Haworth, C. Levy, et al. Tumor Regression and Autoimmunity in Patients Treated With Cytotoxic T Lymphocyte-Associated Antigen 4 Blockade and Interleukin 2: A Phase I/II Study Ann. Surg. Oncol., December 1, 2005; 12(12): 1005 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Webster, E. J. Small, B. I. Rini, and E. D. Kwon Prostate Cancer Immunology: Biology, Therapeutics, and Challenges J. Clin. Oncol., November 10, 2005; 23(32): 8262 - 8269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Lute, K. F. May Jr, P. Lu, H. Zhang, E. Kocak, B. Mosinger, C. Wolford, G. Phillips, M. A. Caligiuri, P. Zheng, et al. Human CTLA4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies Blood, November 1, 2005; 106(9): 3127 - 3133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Ji, D. Gondek, and A. A. Hurwitz Provision of Granulocyte-Macrophage Colony-Stimulating Factor Converts an Autoimmune Response to a Self-Antigen into an Antitumor Response J. Immunol., August 1, 2005; 175(3): 1456 - 1463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Palapattu, S. Sutcliffe, P. J. Bastian, E. A. Platz, A. M. De Marzo, W. B. Isaacs, and W. G. Nelson Prostate carcinogenesis and inflammation: emerging insights Carcinogenesis, July 1, 2005; 26(7): 1170 - 1181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Yu. Nikitina, S. A. Desai, X. Zhao, W. Song, A. Z. Luo, R. D. Gangula, K. M. Slawin, and D. M. Spencer Versatile Prostate Cancer Treatment with Inducible Caspase and Interleukin-12 Cancer Res., May 15, 2005; 65(10): 4309 - 4319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Hodge, M. Chakraborty, C. Kudo-Saito, C. T. Garnett, and J. Schlom Multiple Costimulatory Modalities Enhance CTL Avidity J. Immunol., May 15, 2005; 174(10): 5994 - 6004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Y. Tsang, C. Palena, J. Yokokawa, P. M. Arlen, J. L. Gulley, G. P. Mazzara, L. Gritz, A. Gomez Yafal, S. Ogueta, P. Greenhalgh, et al. Analyses of Recombinant Vaccinia and Fowlpox Vaccine Vectors Expressing Transgenes for Two Human Tumor Antigens and Three Human Costimulatory Molecules Clin. Cancer Res., February 15, 2005; 11(4): 1597 - 1607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sanderson, R. Scotland, P. Lee, D. Liu, S. Groshen, J. Snively, S. Sian, G. Nichol, T. Davis, T. Keler, et al. Autoimmunity in a Phase I Trial of a Fully Human Anti-Cytotoxic T-Lymphocyte Antigen-4 Monoclonal Antibody With Multiple Melanoma Peptides and Montanide ISA 51 for Patients With Resected Stages III and IV Melanoma J. Clin. Oncol., February 1, 2005; 23(4): 741 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. F. May Jr, S. Roychowdhury, D. Bhatt, E. Kocak, X.-F. Bai, J.-Q. Liu, A. K. Ferketich, E. W. Martin Jr, M. A. Caligiuri, P. Zheng, et al. Anti-human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies Blood, February 1, 2005; 105(3): 1114 - 1120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Demaria, N. Kawashima, A. M. Yang, M. L. Devitt, J. S. Babb, J. P. Allison, and S. C. Formenti Immune-Mediated Inhibition of Metastases after Treatment with Local Radiation and CTLA-4 Blockade in a Mouse Model of Breast Cancer Clin. Cancer Res., January 15, 2005; 11(2): 728 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Roden, M. T. Moser, S. D. Tri, M. Mercader, S. M. Kuntz, H. Dong, A. A. Hurwitz, D. J. McKean, E. Celis, B. C. Leibovich, et al. Augmentation of T Cell Levels and Responses Induced by Androgen Deprivation J. Immunol., November 15, 2004; 173(10): 6098 - 6108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Daftarian, G.-Y. Song, S. Ali, M. Faynsod, J. Longmate, D. J. Diamond, and J. D. I. Ellenhorn Two Distinct Pathways of Immuno-Modulation Improve Potency of p53 Immunization in Rejecting Established Tumors Cancer Res., August 1, 2004; 64(15): 5407 - 5414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Madrenas, L. A. Chau, W. A. Teft, P. W. Wu, J. Jussif, M. Kasaian, B. M. Carreno, and V. Ling Conversion of CTLA-4 from Inhibitor to Activator of T Cells with a Bispecific Tandem Single-Chain Fv Ligand J. Immunol., May 15, 2004; 172(10): 5948 - 5956. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Prud'homme Altering immune tolerance therapeutically: the power of negative thinking J. Leukoc. Biol., April 1, 2004; 75(4): 586 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Y. Mapara and M. Sykes Tolerance and Cancer: Mechanisms of Tumor Evasion and Strategies for Breaking Tolerance J. Clin. Oncol., March 15, 2004; 22(6): 1136 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lane, J. Leitch, X. Tan, J. Hadjati, J. L. Bramson, and Y. Wan Vaccination-Induced Autoimmune Vitiligo Is a Consequence of Secondary Trauma to the Skin Cancer Res., February 15, 2004; 64(4): 1509 - 1514. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Peng, M. J. Townsend, J. L. Hecht, I. A. White, and L. H. Glimcher T-bet Regulates Metastasis Rate in a Murine Model of Primary Prostate Cancer Cancer Res., January 15, 2004; 64(2): 452 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Santulli-Marotto, S. K. Nair, C. Rusconi, B. Sullenger, and E. Gilboa Multivalent RNA Aptamers That Inhibit CTLA-4 and Enhance Tumor Immunity Cancer Res., November 1, 2003; 63(21): 7483 - 7489. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Q. Phan, J. C. Yang, R. M. Sherry, P. Hwu, S. L. Topalian, D. J. Schwartzentruber, N. P. Restifo, L. R. Haworth, C. A. Seipp, L. J. Freezer, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma PNAS, July 8, 2003; 100(14): 8372 - 8377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Hodge, D. W. Grosenbach, W. M. Aarts, D. J. Poole, and J. Schlom Vaccine Therapy of Established Tumors in the Absence of Autoimmunity Clin. Cancer Res., May 1, 2003; 9(5): 1837 - 1849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Daniel, N. Meyer-Morse, E. K. Bergsland, K. Dehne, L. M. Coussens, and D. Hanahan Immune Enhancement of Skin Carcinogenesis by CD4+ T Cells J. Exp. Med., April 21, 2003; 197(8): 1017 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. S. Hodi, M. C. Mihm, R. J. Soiffer, F. G. Haluska, M. Butler, M. V. Seiden, T. Davis, R. Henry-Spires, S. MacRae, A. Willman, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients PNAS, April 15, 2003; 100(8): 4712 - 4717. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Espenschied, J. Lamont, J. Longmate, S. Pendas, Z. Wang, D. J. Diamond, and J. D. I. Ellenhorn CTLA-4 Blockade Enhances the Therapeutic Effect of an Attenuated Poxvirus Vaccine Targeting p53 in an Established Murine Tumor Model J. Immunol., March 15, 2003; 170(6): 3401 - 3407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Parmiani, C. Castelli, P. Dalerba, R. Mortarini, L. Rivoltini, F. M. Marincola, and A. Anichini Cancer Immunotherapy With Peptide-Based Vaccines: What Have We Achieved? Where Are We Going? J Natl Cancer Inst, June 5, 2002; 94(11): 805 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mercader, B. K. Bodner, M. T. Moser, P. S. Kwon, E. S. Y. Park, R. G. Manecke, T. M. Ellis, E. M. Wojcik, D. Yang, R. C. Flanigan, et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer PNAS, December 4, 2001; 98(25): 14565 - 14570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. van Elsas, R. P.M. Sutmuller, A. A. Hurwitz, J. Ziskin, J. Villasenor, J.-P. Medema, W. W. Overwijk, N. P. Restifo, C. J.M. Melief, R. Offringa, et al. Elucidating the Autoimmune and Antitumor Effector Mechanisms of a Treatment Based on Cytotoxic T Lymphocyte Antigen-4 Blockade in Combination with a B16 Melanoma Vaccine: Comparison of Prophylaxis and Therapy J. Exp. Med., August 20, 2001; 194(4): 481 - 490. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
2 versus ctrl Ig/no vaccine.
B, reanalysis of data presented in A for
tumor incidence as a function of age at the time of treatment revealed
that the significant reduction in tumor incidence was from the mice
treated at 14 weeks of age. In contrast, there was no significant
reduction in tumor incidence in mice treated at 16 weeks of age. *,
