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Immunology |
The Johns Hopkins University School of Medicine, Department of Oncology, Graduate Program in Immunology, Baltimore, Maryland 21231
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Studies aimed at identifying tumor-associated T-cell antigens (12 , 13) and understanding antigen-specific T-cell regulation (14, 15, 16) have provided new insights into the mechanisms of immune tolerance that may limit the effectiveness of cancer vaccines (17, 18, 19, 20) . For example, a number of nonmutated, tissue-specific proteins have been identified as T-cell targets recognized on human tumors (12, 13 , 21 , 22) . This implies that mechanisms are in place to delete or suppress high avidity T cells specific for these antigens that would otherwise be capable of inducing autoimmunity. This also implies that T cells with lower avidity for these same antigens may have escaped tolerance and are capable of being activated. This would explain reports describing the existence of ineffective antibody and T-cell responses directed at specific antigens expressed by simultaneously progressing cancers in patients (11 , 23) .
Several groups have observed that some chemotherapeutic agents can modulate the immune response (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) . A number of reports have demonstrated that some chemotherapeutic agents can enhance the antitumor activity of adoptively transferred T cells (25 , 26) , tumor vaccines (29 , 31) , and macrophages (30) . For example, it has been known for a long time that pretreatment with agents such as CTX enhances the efficacy of adoptive transfer of antigen-specific lymphocytes and antitumor vaccines (25 , 26 , 31) . The immunopotentiation of T cell-mediated immune response by CTX has been suggested in various animal tumor models as well as in Phase I/II clinical trials (25 , 26 , 31, 32, 33) . Mokyr et al. (34) demonstrated that the timing between antigen injection and CTX administration is crucial to potentiate the antitumoral immune response. Other studies have revealed the synergistic effect of chemotherapy with passive immunotherapy using the HER-2/neu targeted antibody, trastuzumab (35 , 36) .
Mice transgenic for the nontransforming rat neu proto-oncogene expressed under the control of a mammary-specific promoter (neu transgenic mice) develop spontaneous focal mammary adenocarcinomas (37) . We described recently the immunological characterization of these mice and found that T-cell tolerance to neu exists in these mice relative to the parental nontransgenic mice (38) . Despite the existence of tolerance, it was possible to induce neu-targeted immunity potent enough to overcome this tolerance and significantly delay both transplantable and spontaneously arising tumors. In this report, we have used the neu transgenic mouse model to identify chemotherapeutic agents that, when given sequentially with a neu-expressing GM-CSF-secreting whole tumor vaccine, can enhance vaccine efficacy. Our findings show that pretreatment with PTX or CTX increases the vaccine efficacy, in particular the type I cytokine immune response. These results suggest that combined treatment with immune-modulating doses of chemotherapy and the GM-CSF-secreting neu vaccine can overcome immune tolerance and induce an antigen-specific immune response.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Lines and Media.
NT cells were derived from spontaneous mammary tumors of female neu transgenic mice as described previously (Ref. 38
; NT cells are from a neu-expressing tumor cell line derived from spontaneous tumor of neu transgenic mice; NT-B7 are NT cells that human the B7 costimulatory molecule). The NT cell line overexpresses the rat neu cDNA, and these levels remain stable (38)
. The NT cell line was grown in our defined Breast Media, which consists of RPMI 1640 (Life Technologies, Inc., Grand Island, NY) with 20% FBS (Hyclone, Logan, UT), 1% L-glutamine (JRH Biosciences, Lenexa, KS), 1% non-essential amino acids, 1% sodium pyruvate, 0.5% penicillin/streptomycin, 0.02% Gentamicin (Sigma Chemical Co., St. Louis, MO), and 0.2% insulin (Lilly, Indianapolis, IN), and maintained at 37°C in 5% CO2 atmosphere. The NT cell line was expanded to large numbers to produce master cell banks of each line to avoid extensive in vitro passage, thereby maintaining reproducibility of each in vivo study. Production was performed at the NIH cGMP facility (Frederick, MD). neu and MHC class I levels were tested by fluorescence-activated cell sorter and confirmed to be stable before and after freezing. NT-B7 cells were produced via retroviral transduction of NT cells with a human B7-1 encoding retrovirus as described previously (4)
. NT-B7 was maintained in our defined Breast Media supplemented with neomycin (Life Technologies, Inc.). NIH-3T3 cells (3T3; ATCC, Rockville, MD) were grown in DMEM (Life Technologies, Inc.) with 10% bovine calf serum (Hyclone) 1% L-glutamine, 1% non-essential amino acids, 1% sodium pyruvate, 0.5% penicillin/streptomycin at 37°C and 10% CO2 atmosphere. The NIH-3T3 derivative, ATCC CRL-1915 (3T3-neu; ATCC), which overexpresses the rat HER-2/neu proto-oncogene, was grown in 3T3 media + 0.3 µM methotrexate at 37°C in 10% CO2 atmosphere. NIH-3T3 cells and 3T3-neu were genetically modified to express the murine cytokine GM-CSF using the retroviral vector MFG as described previously (4)
, resulting in 3T3/GM and 3T3-neu/GM cell lines, respectively (3T3/GM are 3T3 cells that produce murine GM-CSF; 3T3-neu are NIH-3T3 cells that express rat HER-2/neu cDNA; 3T3-neu/GM are 3T3-neu cells that produce murine GM-CSF). Murine GM-CSF production was tested with a commercially available ELISA kit (Endogen, Woburn, MA) and was determined to be between 200 and 250 ng/106 cells/24 h for 3T3/GM and 3T3-neu/GM. GM-CSF bioactivity was confirmed using the GM-CSF-dependent cell line, NFS-60, as described previously (4)
. Production of GM-CSF by untransduced NT cell line is not detected as determined by ELISA.
Chemotherapeutic Agents.
PTX (Bristol-Myers Squibb, Princeton, NJ), DOX (Gensia, Irvine, CA), and CIS (Bristol-Myers Squibb) were diluted in HBSS before injection. CTX (Bristol-Myers Squibb) was diluted in sterile water before injection. PTX, CTX, and CIS were injected i.p.; DOX was injected i.v.
Vaccination and Tumor Challenge.
On the day of vaccination, vaccine cells grown in vitro were trypsinized, washed three times in HBSS (pH 7.4; Life Technologies, Inc.), and counted. The cells were resuspended in HBSS at 107 cells/ml and irradiated with 50 Gy from a 137Cs source (Nordion, Toronto, Ontario, Canada), discharging 1400 rad/min. Eight-week-old neu transgenic or FVB/N mice were given three simultaneous 100-µl s.c. injections (right and left hind limbs and left arm) using a 1-ml tuberculin syringe with a 27-gauge needle (39)
. The mice in the vaccine group received three simultaneous injections of 106 3T3-neu/GM cells. To insure that the effect observed was neu specific, all control mice as well as the mice in the chemotherapy group alone received a mock vaccination consisting of three s.c. injections of 106 3T3/GM cells. 3T3/GM mock vaccination did not delay the occurrence of tumor growth compared with mice injected only with HBSS (data not shown). On the day of the tumor challenge, NT cells thawed from frozen bank stores and grown in vitro for 1 or 2 weeks were trypsinized, washed three times in HBSS, and injected into the right upper mammary fat pad. Mice were challenged with 5 x 104 (neu transgenic) or 5 x 106 (FVB/N) NT tumor cells. In treatment experiments, mice were challenged with NT cells on day 0 and vaccinated on day 3 unless otherwise specified. In prevention experiments, mice were challenged with NT cells 2 weeks after vaccination. Tumor occurrence (shown as the tumor-free probability) or changes in tumor growth were monitored twice a week. Changes in tumor growth (mm2) were determined by multiplying the two perpendicular diameters.
T-Cell Assays.
neu-specific, IFN-
- or IL-4-producing T cells were quantified by ELISPOT analysis. neu transgenic mice were given a s.c. challenge with NT cells, followed 3 days later by vaccination with 3T3-neu/GM or 3T3/GM with or without chemotherapy. On day 12 after vaccine, T cells were isolated from splenocytes by Ficoll (Amersham, Uppsala, Sweden) separation and passed over a nylon wool column to remove B cells and macrophages. CD4+ cells were positively selected with Dynabeads and Detachbead mouse CD4, according to the manufacturer‘s instructions (Dynal, Lake Success, NY). After one round of CD4+-positive selection, >98% of cells were shown to be CD4+ by fluorescence-activated cell sorter. neu-specific IFN- or IL-4 production was determined by a standard ELISPOT protocol and as described previously (38
, 40)
. IFN--treated NT-B7 cells (104 per well) were used as stimulators, and serial dilutions of unfractionated lymphocytes or CD4+ T cells were added to the wells for an 18-h incubation at 37°C. Each condition was tested in triplicate. Reagents and materials used in the assay were the following: 96-well filtration plate (MA1PS4510, Millipore, Molsheim, France), rat antimouse IFN- at 10 µg/ml (PharMingen, San Diego, CA), rat antimouse biotin IFN- (Biosource International, Camarillo, CA), rat antimouse IL-4 at 10 µg/ml (PharMingen), rat antimouse biotin IL-4 (Biosource International), avidin-alkaline phosphatase at 2 µg/ml (Sigma Chemical Co., St. Louis, MO), and 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium (Sigma Chemical Co.).
Statistical Analysis.
Unpaired Student‘s t tests were performed to analyze tumor size and ELISPOT data. Kaplan-Meier analyses were used to analyze tumor-free survival, and the log-rank test was used for comparisons. P < 0.05 was considered as statistically significant.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. neu transgenic mice given the same vaccine demonstrated a small but significant and reproducible delay in transplantable tumor growth when the tumor challenge was given 2 weeks after the vaccine (Fig. 1C)
. However, in treatment experiments, a statistical difference in the rate of tumor growth between the control and the vaccine groups was not detected in neu transgenic mice, even if the vaccine was administered as early as 1 day after the tumor challenge (Fig. 1D)
. These results provide further evidence that the neu transgenic mice demonstrate an immune tolerance to neu.
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show that our vaccine approach is potent enough to eradicate large established tumor burdens in a host that does not exhibit antigen-specific immune tolerance to tumor. In contrast, the same vaccine is not potent enough to prevent tumor development in the neu transgenic mice (38
, 41) . Therefore, immune-modulating agents that can overcome the mechanisms of tolerance may enhance the effectiveness of neu-specific immunization. One immune-modulating approach is to test selected chemotherapeutic agents at non-immune-suppressing doses for their ability to enhance the potency of the vaccine. We therefore tested four chemotherapeutic agents (CTX, DOX, PTX, and CIS) in combination with the 3T3-neu/GM vaccine. These four drugs were chosen for evaluation for three reasons: (a) these agents are commonly used for the treatment of human cancers; (b) each drug represents a different class of chemotherapeutic agents and would be expected to interact with the vaccine by distinctly different mechanisms; and (c) there are data in the literature suggesting that each of these agents have immune-modulating effects (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 , 42 , 43) .
Initially, feasibility studies were performed in FVB/N mice to identify a dose range and optimal sequence of administration for each chemotherapeutic agent when combined with the vaccine. Mice were given 5 x 106 NT cells inoculated into the right upper mammary fat pad on day 0 and vaccinated 3 days later with three simultaneous s.c. injections of 1 x 106 irradiated 3T3-neu/GM cells given into the left and right hind limbs and the left upper limb. Each of the four chemotherapeutic agents were given either 1 day prior to vaccination (at the time of immune priming) or 7 days after vaccination (at the time of initial T-cell activation and expansion). Table 1
summarizes the dose range for each agent used as well as the type of effect observed.
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. However, when these two chemotherapeutic agents were given at the same doses 7 days after vaccination, the combination chemotherapy/vaccine was not superior to chemotherapy alone. In contrast, DOX (dose <10 mg/kg) and CIS (dose <5 mg/kg) neither inhibited nor significantly enhanced the potency of the vaccine when given either 1 day before or 1 week after vaccination.
CTX, PTX, and DOX Enhance the Antitumor Effects of the Vaccine and Significantly Delay Transplantable Tumor Progression in neu-Transgenic Mice.
Next, we tested the dose and schedule of each chemotherapeutic agent found to be effective in the nontolerized mice for the ability to enhance the potency of the vaccine in the neu transgenic mice. Mice were inoculated with 5 x 104 NT cells in the right upper mammary fat pad on day 0 and vaccinated 3 days later. As shown in Fig. 2
, when either CTX or PTX was given 1 day before vaccination, they enhanced the potential of the vaccine to delay tumor growth. In contrast, DOX had no effect when administered prior to vaccination but could enhance the antitumor effect when administered 1 week after the vaccination. CIS was the only drug of the four that did not appear to enhance the antitumor immune response of the vaccine at all at the dose range and schedules studied (data not shown).
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, the association of CTX/DOX and vaccine was significantly more effective at controlling the tumor occurrence than either treatment modality alone. This polychemotherapy/vaccine regimen cured 20% of the neu transgenic mice in two similar experiments and was better to control tumor growth than CTX/vaccine or DOX/vaccine (data not shown).
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, CTX and vaccine combination induced a more potent antitumor response than either vaccine or chemotherapy alone. Similar results were obtained with PTX and DOX (data not shown). These data therefore support the hypothesis that these chemotherapeutic agents increase the potency of the vaccine via mechanisms that are distinct from direct tumor lysis.
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ELISPOT analysis was used to quantitate neu-specific T-cell induction in neu transgenic mice after 3T3-neu/GM vaccine with and without chemotherapy. Mice were challenged with NT cells, followed 3 days later with either a 3T3-neu/GM vaccine or a mock vaccination (3T3/GM). CTX, PTX, and DOX were given either 1 day before the vaccine or 1 week after the vaccine. The mice were sacrificed 12 days after vaccine administration, and unfractioned T cells were isolated from the spleen as described in "Materials and Methods." As shown in Fig. 5
, CTX and PTX administered 1 day before the vaccine increased the number of neu-specific T cells when compared with mice that received 3T3-neu/GM vaccine alone. PTX and CTX injected after the vaccine significantly decreased the number of neu-specific T cells when compared with the mice that received vaccine alone. In contrast, DOX given 1 day before the vaccine or 1 week after the vaccine did not decrease or increase the number of neu-specific T cells. This supports the hypothesis that the DOX given after the vaccine increased its efficacy through a different mechanism than PTX or CTX.
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and IL-4 ELISPOT analyses were performed on CD4+ T cells isolated and purified from spleen 12 days after vaccination. As shown in Fig. 6
, the Th1 but not the Th2 response was increased when PTX or CTX were given before a 3T3-neu/GM vaccine compared with the group that received the vaccine only. In contrast, DOX given after the vaccine did not increase or decrease the Th1 or Th2 response (data not shown). These data therefore suggest that CTX and PTX, when given prior to the vaccine, enhance the Th1 T-cell response.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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neu transgenic mice offer the opportunity to test vaccine strategies in the context of tumor-specific immune tolerance (38) . Our previous studies have demonstrated that neu transgenic mice exhibit a neu-specific immune tolerance similar to what is observed in patients with breast cancers that overexpress HER-2/neu (38) . Although neu-targeted vaccination was able to eradicate large burdens of preestablished tumors in the nontolerized parental mice in this study, these same vaccines could only significantly delay the development of transplantable neu-expressing tumors in a prevention model in the neu transgenic mice (38) . Furthermore, we did not observe a significant difference in tumor growth between the control and vaccine groups in the treatment experiments. This reinforces data reported previously demonstrating that tumor vaccines alone have a limited potential for the treatment of measurable tumor burdens and highlights the importance of identifying more potent vaccine strategies for clinical testing.
We evaluated the possible integration of chemotherapy and vaccine to treat transplantable mammary tumors in neu transgenic mice. We found that, when given in the proper sequence and at immune-modulating doses, systemic administration of CTX, PTX, and DOX can enhance rather than inhibit the antitumor immunity generated by the vaccine. The fact that this finding is also observed in prevention experiments in which the tumor challenge is given 7 days after the last dose of chemotherapy suggests that the antitumor effect cannot be explained only by a direct chemotherapy-induced cytolytic effect on the tumor cells. Rather, CTX, PTX, and DOX appear to also have a direct immune augmenting effect. This immune-enhancing effect appears to be attributable in part to an augmentation of the number and activity of antigen-specific T cells. Furthermore, the data suggest that PTX and CTX may amplify the Th1 T-cell response. In contrast to CTX and PTX, DOX does not appear to significantly enhance the number of neu-specific T cells in our model. It is still possible that it acts by enhancing T-cell function. However, alternative mechanisms, including recruitment and activation of professional antigen-presenting cells, and enhancement of innate immune responses also require consideration.
Previous studies have already demonstrated that pretreatment with CTX prior to T-cell adoptive transfer enhances T-cell efficacy (25, 26) . There are also reports suggesting that CTX can enhance the antitumor immune response of whole-cell vaccination in the clinic (31) and induce a Th1 immune response in tumor models (45) . Other studies have suggested that pretreatment with CTX can overcome tolerance (46 , 47) . Yoshiba et al. (46) successfully provoked significant delayed-type hypersensitivity footpad reactions against syngeneic and autologous testicular cells in mice pretreated with CTX. In addition, Polak et al. (47) demonstrated that acquired tolerance to 2,4-dinitrochlorobenzene can be reversed by a single treatment with CTX just prior to administration of the allergen. Our results are consistent with these earlier findings and confirm that CTX can break tolerance and augment the antigen-specific antitumor immune response induced by a GM-CSF-secreting whole-cell vaccine in a murine model that exhibits tumor-specific tolerance. However, an earlier study performed by our group failed to demonstrate a synergistic effect between pretreatment with CTX and immunization with a GM-CSF-secreting whole-cell vaccine in the murine CT26 colorectal carcinoma model (29) . The discrepancy between the results of the earlier study and this current study may be explained in part by the difference in the tumor models, because tolerance has not been demonstrated in the CT26 tumor system. In fact, the interactions of each chemotherapeutic agent with vaccine were more evident in the neu transgenic mice than in the parental FVB/N mice. The differences may also be explained by the timing and dose of CTX tested in the two studies (29) .
The exact mechanisms by which CTX enhances antitumor immunity are still undergoing debate. Many studies have reported that CTX may delete or inhibit tumor-induced suppressor or immunoregulatory T cells (48 , 49) . Others have suggested that CTX may release soluble factors, which may sustain the proliferation, survival, and activity of the transferred immune T cells (26) . Recently, Schiavoni and colleagues (50 , 51) demonstrated that CTX induces type 1 IFN secretion in vivo and enhances the number of T cells exhibiting the CD44hi memory phenotype.
To our knowledge, this is the first study to evaluate the potential synergy between PTX and an antigen-specific whole-cell vaccine for the ability to induce T-cell responses. As with CTX, we observed that PTX was synergistic with the vaccine only when given prior to vaccination. Multiple immunostimulatory functions have been previously attributed to PTX in vitro and in vivo (30
, 52
, 53)
. PTX can enhance the tumoricidal activity of murine macrophages by inducing nitric oxide production and secretion of TNF-
, IL-1ß, and superoxide anions (54)
. PTX has also been reported to enhance macrophage IL-12 production, a Th1-type cytokine (54)
. This finding provides one explanation for the observed PTX/vaccine induced increase in a number of neu-specific Th1 cells in our studies. The fact that PTX inhibited the in vivo activity of the vaccine when given after vaccination is not surprising because PTX has been shown to impair the proliferation of T cells by stabilization of the microtubules (55)
. Importantly, the observed abrogation of in vivo activity also correlated with a lack of Th1 induction when PTX was given after vaccination.
Among the chemotherapeutic drugs tested, DOX was the only one that enhanced the in vivo antitumor response when given after the vaccine. This observed in vivo response could not be correlated with an increase in the number of neu-specific T cells. Although an earlier report from our group suggested that DOX could enhance tumor-specific T-cell activity, this finding was only based on an observed increase in CTL activity in vitro (29) . Others have reported that splenic and tumor-infiltrating mature T cells were completely insensitive to DOX cytotoxicity and showed increased CTL activity when examined ex vivo (56) . However, CTL activity is not quantitative and has not been rigorously evaluated for its ability to correlate with in vivo antitumor activity. Other reports have suggested that DOX can modulate monocyte/macrophage activity in an antigen-independent manner (24) . Mihich and colleagues (57 , 58) have demonstrated a 2-fold increase in the number of splenic macrophages as early as 5 days after DOX administration. DOX has also been shown to increase macrophage tumoricidal activity (59) . Early studies from our group have also defined a non-antigen-dependent role for macrophages induced by the GM-CSF whole-cell vaccine (4 , 44) . Macrophages have been shown to infiltrate the site of tumor challenge as early as 1 day after immunization (4) . These macrophages release nitric oxide and probably collaborate with other immune cells infiltrating the site to cause its destruction (44) . Further investigation of the effects of DOX on macrophages when given with the GM-CSF-secreting vaccine is under way.
We successfully combined immune-modulating doses of chemotherapy and an antigen-specific vaccine to treat neu-expressing tumors in neu transgenic mice. The doses of chemotherapy that appear to enhance the vaccine are clearly inferior as tumor lytic agents to the conventional cytoreductive doses currently used in the clinic. Further studies are needed to evaluate the impact of conventional chemotherapy doses on the potency of antigen-specific vaccines.
In conclusion, our data support a role for immune-modulating doses of chemotherapy in overcoming immune tolerance when combined with antigen-specific vaccination. These data provide the rationale for testing immune-modulating doses of chemotherapy in sequence with antigen-specific cancer vaccines in patients with cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by Department of Defense Grant DAMD17-96-6138 (to E. M. J.); National Cooperative Drug Discovery Group Grant U19CA72108 (to E. M. J.); NIH Grant T32AI07247 (to R. T. R. and A. M. E.); NIH Grant 5T32A107247 (to D. W.); the AACR Cancer Research Foundation of America Fellowship in Prevention (to R. T. R.); and National Cancer Institute Specialized Program of Research Excellence in Breast Cancer Grant CA88843 (to E. M. J.). J. P. M. is a Fulbright Scholar supported by a grant from Belgium Televie-FNRS (credit 7.4568.98) and Oeuvre Belge du Cancer. 
2 To whom requests for reprints should be addressed, at The Johns Hopkins University School of Medicine, Department of Oncology, Graduate Program in Immunology, 1650 Orleans Street, Blaustein-Bunting Building, Room 4 M07, Baltimore, MD 21231. Phone: (410) 614-4626; Fax: (410) 614-8216; E-mail: ejaffee{at}jhmi.edu
3 The abbreviations used are: GM-CSF, granulocyte/macrophage-colony stimulating factor; CTX, cyclophosphamide; ATCC, American Type Culture Collection; neu, HER-2/neu; DOX, doxorubicin; CIS, cisplatin; PTX, paclitaxel; IL, interleukin; ELISPOT, enzyme-linked immuno-spot assay; Th, T helper; 3T3, NIH-3T3.
Received 6/19/00. Accepted 3/ 2/01.
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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]
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 S. Brode, T. Raine, P. Zaccone, and A. Cooke Cyclophosphamide-Induced Type-1 Diabetes in the NOD Mouse Is Associated with a Reduction of CD4+CD25+Foxp3+ Regulatory T Cells J. Immunol., November 15, 2006; 177(10): 6603 - 6612. [Abstract] [Full Text] [PDF]
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 C. P. Tarassoff, P. M. Arlen, and J. L. Gulley Therapeutic vaccines for prostate cancer. Oncologist, May 1, 2006; 11(5): 451 - 462. [Abstract] [Full Text] [PDF]
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J. Taieb, N. Chaput, N. Schartz, S. Roux, S. Novault, C. Menard, F. Ghiringhelli, M. Terme, A. F. Carpentier, G. Darrasse-Jese, et al. Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines. J. Immunol., March 1, 2006; 176(5): 2722 - 2729. [Abstract] [Full Text] [PDF]
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P. M. Arlen, J. L. Gulley, C. Parker, L. Skarupa, M. Pazdur, D. Panicali, P. Beetham, K. Y. Tsang, D. W. Grosenbach, J. Feldman, et al. A Randomized Phase II Study of Concurrent Docetaxel Plus Vaccine Versus Vaccine Alone in Metastatic Androgen-Independent Prostate Cancer Clin. Cancer Res., February 15, 2006; 12(4): 1260 - 1269. [Abstract] [Full Text] [PDF]
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 C. Butts, N. Murray, A. Maksymiuk, G. Goss, E. Marshall, D. Soulieres, Y. Cormier, P. Ellis, A. Price, R. Sawhney, et al. Randomized Phase IIB Trial of BLP25 Liposome Vaccine in Stage IIIB and IV Non-Small-Cell Lung Cancer J. Clin. Oncol., September 20, 2005; 23(27): 6674 - 6681. [Abstract] [Full Text] [PDF]
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L. A. Emens and E. M. Jaffee Leveraging the Activity of Tumor Vaccines with Cytotoxic Chemotherapy Cancer Res., September 15, 2005; 65(18): 8059 - 8064. [Abstract] [Full Text] [PDF]
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A. J. Muller and G. C. Prendergast Marrying Immunotherapy with Chemotherapy: Why Say IDO? Cancer Res., September 15, 2005; 65(18): 8065 - 8068. [Abstract] [Full Text] [PDF]
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R. Singh, M. E. Dominiecki, E. M. Jaffee, and Y. Paterson Fusion to Listeriolysin O and Delivery by Listeria monocytogenes Enhances the Immunogenicity of HER-2/neu and Reveals Subdominant Epitopes in the FVB/N Mouse J. Immunol., September 15, 2005; 175(6): 3663 - 3673. [Abstract] [Full Text] [PDF]
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A. M. Ercolini, B. H. Ladle, E. A. Manning, L. W. Pfannenstiel, T. D. Armstrong, J.-P. H. Machiels, J. G. Bieler, L. A. Emens, R. T. Reilly, and E. M. Jaffee Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response J. Exp. Med., May 16, 2005; 201(10): 1591 - 1602. [Abstract] [Full Text] [PDF]
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 M. E. C. Lutsiak, R. T. Semnani, R. De Pascalis, S. V. S. Kashmiri, J. Schlom, and H. Sabzevari Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide Blood, April 1, 2005; 105(7): 2862 - 2868. [Abstract] [Full Text] [PDF]
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A. Casati, V. S. Zimmermann, F. Benigni, M. T. S. Bertilaccio, M. Bellone, and A. Mondino The Immunogenicity of Dendritic Cell-Based Vaccines Is Not Hampered by Doxorubicin and Melphalan Administration J. Immunol., March 15, 2005; 174(6): 3317 - 3325. [Abstract] [Full Text] [PDF]
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P. Yu, Y. Lee, W. Liu, T. Krausz, A. Chong, H. Schreiber, and Y.-X. Fu Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors J. Exp. Med., March 7, 2005; 201(5): 779 - 791. [Abstract] [Full Text] [PDF]
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 L A Emens, R T Reilly, and E M Jaffee Breast cancer vaccines: maximizing cancer treatment by tapping into host immunity Endocr. Relat. Cancer, March 1, 2005; 12(1): 1 - 17. [Abstract] [Full Text] [PDF]
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C. T. Garnett, C. Palena, M. Chakarborty, K.-Y. Tsang, J. Schlom, and J. W. Hodge Sublethal Irradiation of Human Tumor Cells Modulates Phenotype Resulting in Enhanced Killing by Cytotoxic T Lymphocytes Cancer Res., November 1, 2004; 64(21): 7985 - 7994. [Abstract] [Full Text] [PDF]
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M. R. Bishop, D. H. Fowler, D. Marchigiani, K. Castro, C. Kasten-Sportes, S. M. Steinberg, J. C. Gea-Banacloche, R. Dean, C. K. Chow, C. Carter, et al. Allogeneic Lymphocytes Induce Tumor Regression of Advanced Metastatic Breast Cancer J. Clin. Oncol., October 1, 2004; 22(19): 3886 - 3892. [Abstract] [Full Text] [PDF]
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 D. E. Spaner Amplifying cancer vaccine responses by modifying pathogenic gene programs in tumor cells J. Leukoc. Biol., August 1, 2004; 76(2): 338 - 351. [Abstract] [Full Text] [PDF]
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M. A. Mihalyo, A. D. H. Doody, J. P. McAleer, E. C. Nowak, M. Long, Y. Yang, and A. J. Adler In Vivo Cyclophosphamide and IL-2 Treatment Impedes Self-Antigen-Induced Effector CD4 Cell Tolerization: Implications for Adoptive Immunotherapy J. Immunol., May 1, 2004; 172(9): 5338 - 5345. [Abstract] [Full Text] [PDF]
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I. F. Hermans, T. W. Chong, M. J. Palmowski, A. L. Harris, and V. Cerundolo Synergistic Effect of Metronomic Dosing of Cyclophosphamide Combined with Specific Antitumor Immunotherapy in a Murine Melanoma Model Cancer Res., December 1, 2003; 63(23): 8408 - 8413. [Abstract] [Full Text] [PDF]
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M. E. Wolpoe, E. R. Lutz, A. M. Ercolini, S. Murata, S. E. Ivie, E. S. Garrett, L. A. Emens, E. M. Jaffee, and R. T. Reilly HER-2/neu-Specific Monoclonal Antibodies Collaborate with HER-2/neu-Targeted Granulocyte Macrophage Colony-Stimulating Factor Secreting Whole Cell Vaccination to Augment CD8+ T Cell Effector Function and Tumor-Free Survival in Her-2/neu-Transgenic Mice J. Immunol., August 15, 2003; 171(4): 2161 - 2169. [Abstract] [Full Text] [PDF]
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A. M. Ercolini, J.-P. H. Machiels, Y. C. Chen, J. E. Slansky, M. Giedlen, R. T. Reilly, and E. M. Jaffee Identification and Characterization of the Immunodominant Rat HER-2/neu MHC Class I Epitope Presented by Spontaneous Mammary Tumors from HER-2/neu-Transgenic Mice J. Immunol., April 15, 2003; 170(8): 4273 - 4280. [Abstract] [Full Text] [PDF]
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Y. Miyagi, N. Imai, T. Sasatomi, A. Yamada, T. Mine, K. Katagiri, M. Nakagawa, A. Muto, S. Okouchi, H. Isomoto, et al. Induction of Cellular Immune Responses to Tumor Cells and Peptides in Colorectal Cancer Patients by Vaccination with SART3 Peptides Clin. Cancer Res., December 1, 2001; 7(12): 3950 - 3962. [Abstract] [Full Text] [PDF]
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, controls 3T3/GM (mock vaccine); 
, vaccination 3T3-neu/GM. *, P < 0.05 as determined by unpaired Student‘s t test.
