Clinical Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Infection and Cancer: Biology, Therapeutics, and Prevention
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
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Arlen, P. M.
Right arrow Articles by Dahut, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Arlen, P. M.
Right arrow Articles by Dahut, W.
Clinical Cancer Research Vol. 12, 1260-1269, February 2006
© 2006 American Association for Cancer Research

Cancer Therapy: Clinical

A Randomized Phase II Study of Concurrent Docetaxel Plus Vaccine Versus Vaccine Alone in Metastatic Androgen-Independent Prostate Cancer

Philip M. Arlen1, James L. Gulley1, Catherine Parker2, Lisa Skarupa1, Mary Pazdur1, Dennis Panicali5, Patricia Beetham1, Kwong Y. Tsang1, Douglas W. Grosenbach1, Jarett Feldman1, Seth M. Steinberg3, Elizabeth Jones4, Clara Chen4, Jennifer Marte1, Jeffrey Schlom1 and William Dahut2

Authors' Affiliations: 1 Laboratory of Tumor Immunology and Biology, 2 Medical Oncology Clinical Research Unit, 3 Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, and 4 Clinical Center, NIH, Bethesda, Maryland and 5 Therion Biologics Corporation, Cambridge, Massachusetts

Requests for reprints: Jeffrey Schlom, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, 10 Center Drive, Room 8B09, Bethesda, MD 20892-1750. Phone: 301-496-4343; Fax: 301-496-2756; E-mail: js141c{at}nih.gov.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: Docetaxel has activity against androgen-independent prostate cancer and preclinical studies have shown that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to the vaccine. Secondary end points were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen.

Experimental Design: The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF-PSA). Patients received granulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specific T cells.

Results: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer–associated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progression-free survival on docetaxel was 6.1 months after receiving vaccine compared with 3.7 months with the same regimen in a historical control.

Conclusion: This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.

Adenocarcinoma of the prostate is the most common noncutaneous malignancy diagnosed in American males and the second leading cause of cancer death. One of six men will develop clinically significant prostate cancer in his lifetime. During 2005, an estimated 232,900 men will be diagnosed with prostate cancer and 30,350 will die from the disease in the United States (1). Overall survival for patients with metastatic androgen-independent prostate cancer has been improved with a docetaxel-based regimen. The clinical benefit shown in these recent studies is an ~3-month increase in survival using an every-3-week regimen of docetaxel (2, 3). However, compared with the every-3-week schedule, weekly docetaxel is associated with significantly less grade 3 or 4 hematologic toxicity. Other studies have looked at combining weekly docetaxel with other agents (4, 5). A randomized phase II trial at the National Cancer Institute compared the addition of daily low-dose thalidomide (200 mg) to weekly docetaxel (30 mg/m2) versus docetaxel alone (6). Docetaxel was administered for 3 consecutive weeks of a 4-week cycle. Nine of 25 patients (37%) in the docetaxel alone arm and 25 of 50 patients (50%) in the combination arm had a prostate-specific antigen (PSA) decline of at least 50%. In a recent update, the overall survival of the combination arm was 25.9 months versus 14.7 months in the docetaxel alone arm (P = 0.041; ref. 7).

Newer strategies for the treatment of metastatic androgen-independent prostate cancer are currently being evaluated. The development of vaccine strategies designed to break tolerance and generate a sustained immune response against prostate cancer represents a novel therapeutic approach. Preclinical and clinical studies with a range of vaccines have shown that the induction of T-cell responses directed against a self-antigen can lead to antitumor activity in the absence of toxicity. Both carbohydrate and glycoprotein vaccines using "self" antigens have been administered to patients with prostate cancer. Clinical studies have not yet determined which of these antigens would contribute to the most potent vaccine. Globo H hexasaccharide is a carbohydrate vaccine that has elicited antibody responses as well as declines in PSA velocities when administered to prostate cancer patients (8). MUC-1 and prostate-specific membrane antigen have also been used as targets in various prostate cancer clinical studies (9–11). PSA is a potential target for a prostate cancer vaccine owing to its restricted expression on prostate cancer and normal prostatic epithelium. Miller et al. (12) conducted a phase I trial using a PSA DNA vaccine (pVAX/PSA DNA) in patients with hormone refractory prostate cancer, showing induction of T cells to PSA peptides in patients following vaccine. Because the majority of prostate cancer vaccines tested thus far have used "self" antigens, vaccines and vaccine strategies must be developed to enhance the immunogenicity of these targets.

An advantage of using recombinant poxvirus when developing cancer vaccines is that recombinant proteins derived from genes inserted and transcribed in viral genomes are more immunogenic than protein in adjuvant (13–15). The use of poxviral vectors to stimulate an immune response to PSA has been evaluated in several clinical trials (16, 17). The Eastern Cooperative Oncology Group reported (18) a randomized phase II study in which 64 patients with increasing PSA following definitive local therapy with no evidence of disease on scans were randomized to receive four vaccinations with recombinant fowlpox vector (rF-) expressing the PSA gene (rF-PSA, designated "F" for fowlpox) alone or in sequence with recombinant vaccinia vector (rV-) expressing PSA (rV-PSA, designated "V"; ref. 18). Patients in arm A received monthly vaccination of FFF, arm B with FFFV, and arm C with VFFF. There was a substantial difference in PSA progression-free survival favoring the VFFF arm (arm C), lending further support to the use of vaccinia priming and avipox vector boosting (19–22). This study has recently been updated with a median follow-up time of 50 months. The median time to PSA progression is 9.2, 9.1, and 18.2 months for arms A, B, and C, respectively. The median time to clinical progression has still not been reached for any treatment group with 80% of men in arms A and B free of disease progression compared with 90% of men in arm C free of clinical progression (P = 0.73, log-rank test). These results suggest that men with hormone-dependent prostate cancer and an increasing PSA may derive long-term clinical benefit from vaccinations with poxviruses expressing PSA (23).

Costimulatory molecules are critical in the generation of potent T-cell responses, especially to weak antigens such as tumor-associated antigens (TAA). The initiation of a potent immune response requires at least two signals for the activation of naive T cells by antigen-presenting cells. The first signal is antigen specific, delivered through the T-cell receptor via the peptide/MHC, and causes the T cell to enter the cell cycle. The second "costimulatory" signal involves the interaction of a costimulatory molecule [such as B7.1 (CD80)] expressed on antigen-presenting cells, with its ligand on the T cell (the ligand for B7.1 is CD28 and CTLA4; refs. 24–26).

We have recently reported the results of two phase II prostate cancer clinical trials where we administered rV-PSA mixed with a recombinant vaccinia containing the T-cell costimulatory molecule B7.1 along with booster vaccinations of avipox-PSA. In the first study, 30 patients with localized prostate cancer were randomized in a 2:1 fashion to receive radiation therapy with vaccination or radiation therapy alone (27). There were eight monthly vaccine injections administered to the patients randomized to the combination therapy in this study. Seventeen of 19 patients assigned to the vaccine arm received all eight doses. Thirteen of these 17 patients had enhanced increases in PSA-specific T cells compared with none in the radiation alone group. This study showed that the vaccine could be given safely and that specific T-cell responses were achieved in the majority of patients (27). In the second study, 42 patients with nonmetastatic hormone-refractory prostate cancer were randomized to receive either vaccination or antiandrogen therapy with nilutamide. If, after 6 months of treatment, the patients had no metastasis and their PSA continued to increase, they could then receive a combination of both treatments. Three patients who had received nilutamide had been removed from the study due to side effects. No significant side effects were observed among the patients treated with vaccine. The patients on the vaccine arm had a 9.9-month time to treatment failure versus 7.6 months in the nilutamide treated group (not statistically significant). After 6 months, eight of the patients in the nilutamide group had vaccine added to treatment, which resulted in an additional time to treatment failure of 5.2 month resulting in a median time to treatment failure of 15.9 months from onset of nilutamide. Twelve patients in the vaccine group received nilutamide with a median time to treatment failure of 13.9 months and a median of 25.9 months from initiation of vaccine (28). Thus, there is precedent for combining this vaccine strategy with other standard therapies for prostate cancer. In the study reported here, we have employed this vaccine regimen in the metastatic setting to determine the effect of docetaxel on immunologic activity as well as the safety and clinical efficacy of this vaccine.

The administration of cytotoxic chemotherapy can result in bone marrow suppression and has been traditionally perceived to have a negative effect on immune function. Recent data suggest, however, that taxane-based chemotherapy may actually exert beneficial immunomodulatory effects through a variety of mechanisms, including cytokine production and T-cell infiltration of tumor cells (29, 30). In the study reported here, we examine the effect of combining docetaxel and vaccine therapy and their combined effect on immunologic activity as well as the safety and clinical efficacy of treatment strategy in patients with metastatic androgen-independent prostate cancer.


   Patients and Methods
Top
 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patient eligibility. Patients must have had metastatic androgen-independent prostate cancer with evidence of disease progression based on the following criteria: (a) an increasing serum PSA level using the PSA consensus criteria (31); (b) a new metastatic finding on bone scan; and/or (c) progression of disease on CT scan. Patients on antiandrogen therapy must have undergone antiandrogen withdrawal and still show evidence of an increasing PSA. All patients signed the consent form that was approved by the National Cancer Institute Institutional Review Board.

Additional eligibility criteria were required as follows: age of at least 18 years; anticipated survival of 6 months; Eastern Cooperative Oncology Group performance status of 0 to 2; adequate organ function as defined by normal hematopoietic, renal, and hepatic function; HIV seronegativity; no concurrent use of steroids (except for dexamethasone comedication with docetaxel administration); and finally, all patients had to be HLA-A2 positive. Contraindications to enrollment included prior therapy with docetaxel for prostate cancer, history of radiation to >50% of nodal groups, recent major surgery, serious intercurrent illness, and clinically active brain metastasis. As a precaution for the administration of vaccinia, patients had no evidence of being immunocompromised as defined by a diagnosis of altered immune function, including active or history of eczema, atopic dermatitis, or autoimmune disease (autoimmune neutropenia, thrombocytopenia, or hemolytic anemia; HIV; systemic lupus erythematosus, Sjogren syndrome, or scleroderma; myasthenia gravis; Goodpasture syndrome; Addison's disease, Hashimoto's thyroiditis, or active Graves' disease).

Study design and treatment. This trial was primarily designed to evaluate the immunologic effect as well as the safety and efficacy of a vaccination regimen composed of priming with rV-PSA admixed with rV-B7.1 followed by boosting with rF-PSA, relative to the effects of the same vaccine strategy given 1 day following the first weekly dose of docetaxel and dexamethasone (administered for 3 of 4 consecutive weeks) in patients with metastatic androgen-independent prostate cancer. The vaccine was administered 2 weeks apart during the first month. In patients receiving the combination of vaccine and docetaxel, chemotherapy commenced at the beginning of the second month of treatment. Twenty-eight patients were enrolled onto this randomized phase II trial approved by the National Cancer Institute Institutional Review Board and conducted at the National Cancer Institute. As part of the vaccine regimen, patients also received 100 µg of granulocyte macrophage colony-stimulating factor s.c. at the site of the vaccine beginning on the day of vaccine for 4 consecutive days. Fourteen patients were randomized to receive vaccine with docetaxel and dexamethasone comedication; 14 patients received vaccine alone. The study was designed to show that the vaccine + docetaxel arm is not worse than that of the vaccine alone arm with respect to change in precursor frequency. With 14 patients in each arm, with a one-sided 0.05 {alpha} level test, there was 95% power to detect a change in precursor frequency in the vaccine + docetaxel arm that is 50% less than the vaccine arm, provided that the associated change is equal to 0.78 of each difference. Patients continued therapy monthly until there was progression of metastatic disease by PSA criteria (31) or scans, toxicity, or refusal of further treatment. Restaging scans were done every 3 months. Patients randomized to the vaccine arm only were allowed at time of progression on or after day 85 (determined by scans or PSA criteria) to remain on study with the discontinuation of vaccine but with the addition of docetaxel and dexamethasone (see Fig. 1). Serum immunologic markers and PSA levels were followed as secondary end points while patients continued to receive treatment on the protocol. All patients consented to have peripheral blood mononuclear cells collected before each vaccination for immunologic testing using the ELISPOT assay as a read-out.


Figure 1
View larger version (25K):
[in this window]
[in a new window]
  		Fig. 1. Twenty-eight patients were randomized, 14 per arm. Six of fourteen on the combination arm continued on study beyond the initial 3 months. Eleven of 14 patients on vaccine alone had vaccine discontinued at time of progression and received docetaxel alone.

 
Vaccine formulation. Each of the three viral vaccine products was constructed and manufactured by Therion Biologics Corporation (Cambridge, MA) and was provided by the Cancer Therapy Evaluation Program, National Cancer Institute. rV-PSA (NSC #697729) and rV-B7.1 (NSC #699018) were prepared from virus derived from the Wyeth (New York City Board of Health) strain of vaccinia. The rV-PSA was constructed by the insertion of the entire human PSA gene into the viral genome whereas the rV-B7.1 was constructed by the insertion of the entire human B7.1 costimulatory molecule gene into the viral genome. The priming vaccine compromised 3.51 x 108 plaque-forming units of rV-PSA admixed with 1.17 x 108 plaque-forming units of rV-B7.1 (3:1 ratio) administered s.c. A sterile, nonadherent dressing (i.e., "Telfa") was used to cover the site. The rF-PSA (NSC #694450) also contained the entire gene for human PSA inserted into the fowlpox virus. This vector, used for each of the vaccine boosts, was injected s.c. in alternating sites at 1.5 x 109 plaque-forming units.

Immunoassays. The primary immunologic variable for comparing immune responses in HLA-A2-positive patients was determined by an ELISPOT assay using C1R-A2 cells as antigen-presenting cells as previously described (32). This assay measures the frequency of IFN-{gamma} releasing T cells in response to PSA-3 peptide (VISNDVCAQV) and Flu peptide (GILGFVFTL) in pre- and post-vaccination peripheral blood mononuclear cells. Briefly, 96-well plates (Millipore Corp., Bedford, MA) were coated with 100 µL/well capture monoclonal antibody against human IFN-{gamma} at a concentration of 10 µg/mL for 12 hours at room temperature. Plates were blocked for 30 minutes with RPMI 1640 plus 10% human AB serum. Peripheral blood mononuclear cells (2 x 105) were added to each well. PSA-3-pulsed C1R-A2 cells were added to each well as antigen-presenting cells at an effector/antigen-presenting cell ratio of 1:3. Unpulsed C1R-A2 cells were used as a negative control. Flu peptide was used as a positive control. Cells were incubated for 24 hours and lysed with PBS/0.05% Tween. Biotinylated anti-IFN-{gamma} antibody, diluted to 2 µg/mL in PBS/Tween containing 1% bovine serum albumin, was added and incubated overnight in 5% CO2 at 37°C. Plates were then washed thrice and developed with avidin/alkaline phosphatase for 2 hours; after which, each well was examined for positive spots. Spots in each well were counted using an ImmunoSpot Analyzer (Cellular Technology Ltd., Cleveland, OH). Additional peptides were used for the determination of immune responses to antigens distinct from the antigen used in the vaccination (antigen cascade). Additional peptides used were MUC-1 agonist (ALWGQDVTSV), prostate-specific membrane antigen (LLHETDSAV), and prostatic acid phosphatase (ALDVYNGLL). Assays for anti-PSA, granulocyte macrophage colony-stimulating factor, and B7-1 antibodies were also done as previously described (27, 33, 34).

Statistical considerations. The primary objective of the study was to show that the vaccine with docetaxel and dexamethasone change in precursor frequency was not significantly worse than that in the vaccine only arm. A Wilcoxon rank-sum test was used to compare the change in precursor frequency between the combination arm versus the vaccine alone arm. Secondary analyses to evaluate progression-free survival were done using the Kaplan-Meier method. Comparison between the rate of change of the PSA pre- and post-initiation of treatment was done by first using linear regression on all available values up through the on-study date and obtaining the least squares estimate of a slope in that fashion. This was repeated using the values beginning 1 month after the on-study date and continuing through 3 months after the on-study date. It was determined that the relative difference in the posttreatment versus pretreatment slope, obtained by the relationship (postslope – preslope) / preslope, would be the preferred measure for evaluating the change in PSA velocity because this measure was less dependent on the baseline values than were the absolute differences between the two slopes. The statistical significance of this relative change between the two slopes was determined by the Wilcoxon signed-rank test. Relative changes between two arms were compared with a Wilcoxon rank-sum test. All P values are two tailed.


   Results
Top
 Abstract
 Patients and Methods
 Results
Discussion
 References
 
The baseline characteristics of the 28 enrolled patients are shown in Table 1. For 11 patients on the vaccine arm, the vaccine was discontinued at the time of disease progression (increasing PSA and/or progression on scans) and docetaxel therapy was initiated. The age of patients and Gleason score were similar in the two arms. Although the combination arm had a higher median PSA level (129.1 ng/dL), the mean on-study PSA was higher for those patients on the vaccine alone arm (247 ng/dL) and for those patients who received docetaxel alone at the time of crossover (338.8 ng/dL). Finally, the number of patients with bone only disease (85%) was higher in the vaccine alone arm, with more patients in the combination arm (50%) having both bone and soft tissue disease.


View this table:
[in this window]
[in a new window]
  		Table 1. Demographics

 
Toxicity. The vaccine therapy was tolerated well with only grade ≤2 toxicity related to the vaccine itself. Two patients randomized to the combination of vaccine and docetaxel experienced grade 3 lymphopenia, with one of these patients also experiencing arthralgias, hyperglycemia, and infection without neutropenia. It was felt that the dexamethasone comedication was responsible for the lymphopenia and hyperglycemia and possibly contributed to the infection.

Immune responses. Eleven HLA-A2-positive patients on the vaccine arm alone and 11 HLA-A2-positive patients on the combination of vaccine and docetaxel were able to be evaluated for induction of PSA-specific T-cell responses before and following 3 monthly cycles of therapy as shown in Fig. 2. Endogenous T-cell responses to flu peptide are also shown for each time of peripheral blood mononuclear cells draw. The median fold increase in PSA-specific T cells in both arms was 3.33 (P = 0.92). Thus, this vaccine regimen with weekly docetaxel and dexamethasone could be given without inhibiting measured immune responses to the vaccine.


Figure 2
View larger version (11K):
[in this window]
[in a new window]
  		Fig. 2. Eleven HLA-A2-positive patients on the vaccine arm alone and 11 HLA-A2-positive patients on the combination of vaccine and docetaxel were evaluated for induction of PSA-specific T-cell responses employing the ELISPOT assay as described in Patients and Methods before and following three monthly cycles of therapy. A t test was used to compare the change in precursor frequency between the combination arm versus the vaccine alone arm to detect a relevant difference in precursor frequency. The median fold increase in both arms was 3.33 (P = 0.92).

 
Recent studies have shown distinct immune responses not only to TAAs found in the vaccine but also to multiple other TAAs not found in the vaccine, but found in the tumor cells; this phenomenon is known as epitope spreading and/or antigen cascade. Peripheral blood mononuclear cells from three patients who received the vaccine alone were evaluated for the presence of T cells directed against known HLA-A2 epitopes of three additional prostate cancer–associated antigens as well as PSA (see Table 2). The peripheral blood mononuclear cells were obtained before vaccination and postvaccination each month during the first 3 months of vaccinations for a total of four time points. The presence of T cells directed against a known Flu HLA-A2 epitope was used as a positive control. All three patients had detectable levels of T cells to Flu at all four time points. Although all were negative for T cells directed against these antigens prevaccination, all three patients developed T-cell responses to at least one of the prostate-associated TAAs (other than PSA) at the various postvaccination time points. These included the generation of T cells directed against prostate-specific membrane antigen, prostatic acid phosphatase, and/or MUC-1 (Table 2). In addition, in some patients there were corresponding trends in the immune responses observed and the corresponding serum PSA responses, as seen in Table 3. In case studies #2, 6, and 7 (Table 3), although the PSA-specific T cells initially increased, there was also an initial increase in PSA levels. Three patients on the combination of docetaxel and vaccine had increased PSA-specific T-cell responses with declining serum PSA levels. One patient (case study #6) maintained immune response for up to 267 days of initiating therapy with continued PSA decline. Three patients who crossed over to docetaxel postvaccine continued to maintain PSA-specific T-cell responses that correlated with declining serum PSA levels. In case study #8, the patient's serum PSA level stabilized for ~1 year following crossover before progressing at day 427. However, he continued to have additional increases in T-cell response with docetaxel therapy alone during this period. The patient in case study #2 (Table 3) experienced a 65% decline in his PSA level following crossover to docetaxel therapy alone over a period of >7 months; additionally, he experienced a >3-fold increase in his T-cell response during this time period.


View this table:
[in this window]
[in a new window]
  		Table 2. Precursor frequencies of T cells specific for PSA, prostate-specific membrane antigen, prostatic acid phosphatase, and MUC-1 peptides from peripheral blood mononuclear cells of patients before and at different time points after vaccination

 

View this table:
[in this window]
[in a new window]
  		Table 3. Immune and PSA responses (case studies)

 
Serum PSA declines and changes in velocity. Serum PSA level declines were observed in 3 of the 14 patients in the vaccine alone arm although none of these declines were >50% (Table 4). In the combination arm, 6 of 14 patients had a decline in serum PSA from baseline, with 3 patients showing declines of >75% (Table 4). Finally, 11 patients on the vaccine alone arm at time of progression went on to receive docetaxel alone. Using their progression PSA level on the vaccine as a new baseline, 9 of 11 patients had a decline in serum PSA. Five patients had declines of >50%, with two of these patients having declines of >75% (Table 4). To validate the significance of these responses, serum prostatic acid phosphatase levels were also obtained along with the PSA levels. The serum prostatic acid phosphatase levels either declined or were stable when serum PSA declines were noted (data not shown). No anti-PSA antibody was detected in any of these patients at a minimal serum dilution of 1/50.


View this table:
[in this window]
[in a new window]
  		Table 4. PSA declines

 
Using linear regression, PSA velocity was calculated for patients enrolled on vaccine with docetaxel as well as for those patients receiving docetaxel following vaccine progression (Table 5). These results were also compared with those from a historical set of patients treated at our institution with the same disease stage who received the same dose and schedule of docetaxel as a single agent (6). For those patients with multiple PSA values at both pretreatment and posttreatment time points, we found that the PSA velocities stabilized or decreased in 9 of 9 patients on the combination arm, 8 of 11 patients who received docetaxel following vaccine progression, and 13 of 17 patients in the historical control group receiving docetaxel alone (6). Thus, it seems that vaccine either in combination with or before docetaxel therapy may have a positive effect on patients' PSA levels when compared with a historical control using the same dosing in the same patient population. Furthermore, we calculated the median change in relative PSA velocity for each of these three groups (Fig. 3 displays the actual change in PSA velocity). The median relative changes in median PSA velocity in the docetaxel postvaccine and docetaxel alone arms were similar (–83% and –95%, respectively; P = 0.42) and the median relative changes in velocity were also similar to that for the combination arm of vaccine and docetaxel (–83%; P > 0.70 for both comparisons with the combination arm). Each relative change was significantly different from zero (P < 0.005).


View this table:
[in this window]
[in a new window]
  		Table 5. Slopes of serum PSA velocity pre- and post-therapy

 

Figure 3
View larger version (17K):
[in this window]
[in a new window]
  		Fig. 3. Pre- and post-therapy serum PSA velocities for patients receiving docetaxel alone (historical control), docetaxel with vaccine, or docetaxel following vaccine. Velocities are determined as ng/mL/d. The median relative change in median PSA velocity in the docetaxel postvaccine and docetaxel alone arms was similar (–83% and –95%, respectively; P = 0.42). The median relative change in velocity for the combination arm of vaccine and docetaxel was –83% (P > 0.70 for both comparisons with the combination arm). Each relative change was significantly different from zero (P < 0.005). See Patients and Methods for calculations of PSA velocity.

 
Progression-free survival. Table 6 shows the median progression-free survival, which takes into account both radiographic progression as well as disease progression attributable to an increasing serum PSA level. These results are imprecise because of the limited number of patients enrolled on this trial, which was not specifically designed to address the duration of progression-free survival. Patients on the vaccine alone arm had a median time of progression of 1.8 months, with the majority of patients progressing as a result of increasing serum PSA levels (64.3%). Patients who were randomized to receive docetaxel with vaccine had a median progression-free survival of 3.2 months; the majority of these patients progressed radiographically (57.1%). Eleven of the vaccine only patients at the time of progression remained on study after the vaccine was discontinued and weekly docetaxel was added. The median progression-free survival of these patients was 6.1 months. As an informal comparison, in a similar group of 25 patients with the same disease characteristics treated at the same institution using the same single agent docetaxel regimen, the median progression-free survival was 3.7 months (6).


View this table:
[in this window]
[in a new window]
  		Table 6. Progression-free survival

 

   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
To our knowledge, this is the first randomized trial showing that a vaccine can be administered with weekly docetaxel and dexamethasone comedication without compromising the ability of the patient to mount a T-cell–specific response against the TAA as compared with the administration of the vaccine alone. The use of chemotherapeutic agents for the treatment of human malignancies has been based on the well-characterized cytotoxic effects on malignant cells. It has been thought by some that because of these effects, chemotherapy would have a negative effect on the immune system. However, recent experimental studies in vitro support the concept that certain anticancer agents may actually (a) exhibit immune modulatory activities, (b) up-regulate cell surface expression of MHC molecules and/or TAAs on tumors, and/or (c) up-regulate Fas expression on malignant cells rendering them more sensitive to immune destruction. Detailed in vitro preclinical studies involving 5-fluorouracil, cisplatin, and cyclophosphamide have shown these agents to have the ability to up-regulate components of the immune system (35–39).

Machiels et al. (40) published in vivo preclinical data addressing the issue of chemotherapy and cancer vaccines. This study indicated that taxane therapy (employing taxol) may in fact increase T-cell precursors rather than deplete them. The data presented in this study support the following two conclusions of that study (40): (a) Taxol chemotherapy, when given in a defined sequence with a murine granulocyte macrophage colony-stimulating factor–secreting neu-expressing whole-cell vaccine, enhances the potential of the vaccine to delay tumor growth in tolerized neu transgenic mice. The optimal immunomodulating dose for each chemotherapeutic agent seems to be just above doses that begin to induce cytopenias. (b) The enhanced antitumor response seems to be mediated, at least in part, by an increase in number and function of antigen-specific T cells, in particular the Th1 response. Preclinical data from that study (40) indicated that administering taxane therapy 1 day before a single vaccine can enhance both the immunologic and tumor response.

Earlier clinical studies have evaluated the role of combining vaccines with standard chemotherapy agents. In a colorectal cancer trial with an anti-idiotype murine monoclonal antibody vaccine, which mimics a highly tumor-restricted carcinoembryonic antigen epitope postresection, 32 patients were randomized to treatment with 2 mg of aluminum hydroxide–precipitated vaccine intracutaneously or 2 mg of vaccine mixed with 100 µg of the QS-21 adjuvant s.c. every other week, then monthly until disease recurrence. Patients consenting to this trial had differing stages of disease. Four patients with Dukes stage B2, 11 with Dukes stage C, and 8 with Dukes stage D had their tumors completely resected. Nine patients with Dukes stage D carcinoma were incompletely resected, which was attributable to positive margins postoperatively. Fourteen patients underwent chemotherapy with 5-fluorouracil concomitantly with CeaVac. Ten patients relapsed or had progressive disease ranging from 6 to 30 months. Two patients died at 14 and 20 months, respectively. All 32 patients showed idiotype-specific T-cell responses, of which 75% were carcinoembryonic antigen specific. These T-cell responses were measured by proliferation of patients' peripheral blood mononuclear cells in response to carcinoembryonic antigen. The concomitant use of chemotherapy did not impair this immune response (41, 42). Although this trial was not designed to examine survival, the authors noted that several of the high risk patients seemed to do better than expected as measured by historical controls.

Other clinical trials have combined chemotherapeutic agents with cancer vaccines. In a recent single arm study by Noguchi et al. (43), 13 metastatic hormone refractory prostate cancer patients who previously failed to respond to prior peptide vaccination were treated with a peptide-based vaccine along with low-dose estramustine. Estramustine combines a nitrogen mustard moiety with estradiol and is approved by the Food and Drug Administration for use in patients with metastatic prostate cancer. In this study, 11 of these patients who received more than one cycle of treatment were eligible for immunologic and clinical evaluation. There was no significant immunosuppression in most cases when the peptide plus a half dose (280 mg/d) of estramustine was administered whereas severe immunosuppression was observed in the first two patients who received both the peptide plus a full dose (560 mg/d) of estramustine. Augmentation of peptide-specific CTL precursors or peptide-specific immunoglobulin G was observed in 6 of 11 and 10 of 11 cases, respectively (43). However, without a vaccine alone control arm, it is unclear what effect the estramustine has on the ability of the vaccine to mount an immune response in this study.

The question of whether steroids would inhibit immune responses was also a concern in designing this study. Clinical data suggest that "short bursts" of steroids may not adversely affect the immune system. A study by Fairchok et al. (44) evaluated the immunogenicity of the influenza virus vaccine in children receiving short-course prednisone for acute asthmatic exacerbations. Children were randomized to receive influenza virus vaccine with or without steroids. Those randomized to steroids received prednisone (2 mg/kg/d for 5 days). The results showed no diminished immune responses in the steroid group (44). In a different study, the effect on the immune system of ICU patients treated with "stress dose steroids" was investigated. Patients who received a short course of high dose steroids (1 g of methylprednisolone) had an immune response to a tetanus toxoid equivalent to that in patients who did not receive the steroids (45). It is important to note that the immune responses measured in both those studies were antibody responses. These are thus the first studies, to our knowledge, to show that "short bursts" of steroids do not inhibit T-cell responses.

The primary end point of this study was to determine the effects of docetaxel on the ability to mount a specific T-cell response to the vaccine. We also evaluated the ability in select patients who received the vaccine alone to mount T-cell responses to epitopes on other prostate cancer antigens not found in the vaccine. Although none of the three patients were vaccinated against prostatic acid phosphatase, MUC-1, or prostate-specific membrane antigen, all three patients tested mounted T-cell responses to one or more of these prostate-associated antigens at various time points following initiation of the vaccine. Because none of these three patients received docetaxel during these time points, it is possible that the immune responses postvaccination were related to the direct effects of immune targeting of the prostate gland induced by the vaccine. Destruction of some of the prostate cancer cells through PSA-specific T cells elicited from the vaccine may have resulted in release of other antigens from the tumor, allowing for the generation of T cells specific for these other prostate-associated antigens. This phenomenon of "antigen cascade" has been reported by others (46, 47). In a recent study conducted by Gulley et al. (27), six of eight patients with localized prostate cancer mounted immune responses following vaccination with a PSA vaccine to four prostate antigens not contained in the vaccine. This phenomenon has also occurred when using a different PSA-based vaccine strategy. Harada et al. recently reported the results of a patient vaccinated every 2 weeks with four different HLA-A24+ peptides, including PSA 248-257 peptide. After 3 months, the patient's disease progressed and estramustine was added along with the vaccinations and he achieved a response to this treatment for an additional 12 months. Increased levels of immunoglobulin G were found to be reactive to PSA-derived epitopes other than those peptides administered in this study, suggesting that the peptide vaccination induced epitope spreading of immunoglobulin G in this particular patient (48).

We also evaluated clinical responses to the combination therapy, vaccine alone, and chemotherapy after progression on vaccine. We also informally compared these results with a historical control group in the same patient population using the identical dosing of docetaxel that was given in this study. Whereas progression-free survival in the combination arm was similar to that of the historical group (median, 3.2 versus 3.7 months), there was somewhat more of an increase in progression-free survival in the patients who received docetaxel following disease progression on vaccine alone (6.1 versus 3.7 months). We also noted a few instances in which patients who crossed over to docetaxel postvaccine continued to maintain PSA-specific T-cell responses that corresponded to declining serum PSA levels. Two of these patients actually had additional increases in the T-cell responses when crossing over to docetaxel therapy alone over a period of 308 and 427 days, respectively.

The vaccine employed in this study was rV-PSA admixed with rV-B7.1 as a prime, followed by rF-PSA booster vaccines. Since the initiation of this trial, preclinical studies have shown that the insertion of multiple costimulatory molecule genes (B7.1, ICAM-1, and LFA-3; designated TRICOM) into poxvirus vectors, along with a transgene for a tumor antigen, results in a more vigorous immune response to the tumor antigen, as well as a more vigorous antitumor response, as compared with the use of a vector containing only the B7.1 transgenes (19, 49, 50). New vaccines containing the transgenes for PSA and this triad of costimulatory molecules (designated rV-PSA-TRICOM and rF-PSA-TRICOM) have recently entered both phase I and phase II trials (51, 52). In a recent study by Gulley et al., 25 patients with metastatic androgen-independent prostate cancer who had not undergone prior chemotherapy have been enrolled to a study using these newer vaccine agents. Sixteen patients have undergone restaging evaluation at 3 months. Three of these patients have shown PSA declines during this period, two patients with PSA declines of >30%, and one patient with a decline of >50%. One patient at 8 months has experienced a partial response by RECIST criteria with >50% decrease in unidimensional measurement of his hilar adenopathy. Another patient had a 29% decrease in his soft tissue disease (52). Thus, these new vaccines seem to be more potent than the vaccine used in the study reported here, and it is possible that we may achieve a better clinical response when combining these new generation vaccines with weekly docetaxel in this patient population. We are also examining other combination strategies with these newer vaccines and have recently initiated a clinical study combining the rV-PSA-TRICOM and rF-PSA-TRICOM vaccines with an anti CTLA-4 antibody.

In summary, to our knowledge, this is the first randomized study evaluating the role of a cancer vaccine with chemotherapy and steroids versus vaccine alone to determine the effect on T-cell–specific immune responses to the vaccine in the combination arm compared with the vaccine alone. There was no deleterious effect on the ability to mount immune responses when using monthly vaccines in combination with weekly docetaxel and dexamethasone. Furthermore, T-cell–specific immune responses to prostate cancer epitopes not contained in the vaccine were elicited in three patients following the administration of vaccine alone. Based on recent preclinical data from our laboratory, it may be advantageous to administer these pox vector vaccines before chemotherapy to enhance immune responses. Future approaches using more potent vaccines, containing multiple costimulatory molecules along with docetaxel, may lead to more effective therapeutic approaches for patients with metastatic androgen-independent prostate cancer.


   Acknowledgments
 
We thank Debra Weingarten for her editorial assistance in the preparation of this manuscript.


   Footnotes
 
Grant support: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/22/05; revised 11/23/05; accepted 12/ 9/05.


   References
Top
 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

  1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30.[Abstract/Free Full Text]
  2. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus predisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–12.[Abstract/Free Full Text]
  3. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20.[Abstract/Free Full Text]
  4. Beer TM, Eilers KM, Garzotto M, Egorin MJ, Lowe BA, Henner WD. Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 2003;21:123–8.[Abstract/Free Full Text]
  5. ASCENT Clinical Trial. 2004. Available from: http://www.novacea.com/431.asp.
  6. Dahut WL, Gulley J, Arlen P, et al. Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol 2004;22:2532–9.[Abstract/Free Full Text]
  7. Ozkan M, Eser B, Er O, Dogu GG, Altinbas M. Inhibition of angiogenesis: thalidomide or low-molecular-weight heparin. J Clin Oncol 2005;23:2113; author reply 2113–4.[Free Full Text]
  8. Slovin SF, Ragupathi G, Adluri S, et al. Carbohydrate vaccines in cancer: immunogenicity of a fully synthetic globo H hexasaccharide conjugate in man. Proc Natl Acad Sci U S A 1999;96:5710–5.[Abstract/Free Full Text]
  9. Pantuck AJ, van Ophoven A, Gitlitz BJ, et al. Phase I trial of antigen-specific gene therapy using a recombinant vaccinia virus encoding MUC-1 and interleukin 2 in MUC-1-positive patients with advanced prostate cancer. J Immunother 2004;27:240–53.[CrossRef][Medline]
  10. Tjoa B, Boynton A, Kenny G, Ragde H, Misrock SL, Murphy G. Presentation of prostate tumor antigens by dendritic cells stimulates T-cell proliferation and cytotoxicity. Prostate 1996;28:65–9.[CrossRef][Medline]
  11. Tjoa BA, Simmons SJ, Elgamal A, et al. Follow-up evaluation of a phase II prostate cancer vaccine trial. Prostate 1999;40:125–9.[CrossRef][Medline]
  12. Miller AM, Ozenci V, Kiessling R, Pisa P. Immune monitoring in a phase 1 trial of a PSA DNA vaccine in patients with hormone-refractory prostate cancer. J Immunother 2005;28:389–95.[CrossRef][Medline]
  13. Correale P, Walmsley K, Zaremba S, Zhu M, Schlom J, Tsang KY. Generation of human cytolytic T lymphocyte lines directed against prostate-specific antigen (PSA) employing a PSA oligoepitope peptide. J Immunol 1998;161:3186–94.[Abstract/Free Full Text]
  14. Correale P, Walmsley K, Nieroda C, et al. In vitro generation of human cytotoxic T lymphocytes specific for peptides derived from prostate-specific antigen. J Natl Cancer Inst 1997;89:293–300.[Abstract/Free Full Text]
  15. Kass E, Schlom J, Thompson J, Guadagni F, Graziano P, Greiner JW. Induction of protective host immunity to carcinoembryonic antigen (CEA), a self-antigen in CEA transgenic mice, by immunizing with a recombinant vaccinia-CEA virus. Cancer Res 1999;59:676–83.[Abstract/Free Full Text]
  16. Eder JP, Kantoff PW, Roper K, et al. A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin Cancer Res 2000;6:1632–8.[Abstract/Free Full Text]
  17. Gulley J, Chen AP, Dahut W, et al. Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV-PSA) in patients with metastatic androgen-independent prostate cancer. Prostate 2002;53:109–17.[CrossRef][Medline]
  18. Kaufman HL, Wang W, Manola J, et al. Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): a Trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2004;22:2122–32.[Abstract/Free Full Text]
  19. Hodge JW, McLaughlin JP, Kantor JA, Schlom J. Diversified prime and boost protocols using recombinant vaccinia virus and recombinant nonreplicating avian pox virus to enhance T-cell immunity and antitumor responses. Vaccine 1997;15:759–68.[CrossRef][Medline]
  20. Aarts WM, Schlom J, Hodge JW. Vector-based vaccine/cytokine combination therapy to enhance induction of immune responses to a self-antigen and anti-tumor activity. Cancer Res 2002;62:5770–7.[Abstract/Free Full Text]
  21. Marshall JL, Hoyer RJ, Toomey MA, et al. Phase I study in advanced cancer patients of a diversified prime and boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J Clin Oncol 2000;18:3964–73.[Abstract/Free Full Text]
  22. Marshall J, Gulley JL, Arlen PM, et al. A phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM (B7–1/ICAM-1/LFA-3) alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without GM-CSF, in patients with CEA-expressing carcinomas. J Clin Oncol 2004;23:720–31.[Medline]
  23. Kaufman HL, Wang W, Manola J, et al. Phase II prime/boost vaccination using poxviruses expressing PSA in hormone dependent prostate cancer: follow-up clinical results from ECOG 7897. Proc Am Soc Clin Oncol 2005;24:4501a.
  24. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell 1992;71:1065–8.[CrossRef][Medline]
  25. Chen L, Ashe S, Brady WA, et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 1992;71:1093–102.[CrossRef][Medline]
  26. Freeman GJ, Freedman AS, Segil JM, Lee G, Whitman JF, Nadler LM. B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J Immunol 1989;143:2714–22.[Abstract]
  27. Gulley JL, Arlen PM, Bastian A, et al. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res 2005;11:3353–62.[Abstract/Free Full Text]
  28. Arlen PM, Gulley JL, Todd N, et al. Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer. J Urol 2005;4:539–46.
  29. Chan OT, Yang LX. The immunological effects of taxanes. Cancer Immunol Immunother 2000;49:181–5.[CrossRef][Medline]
  30. Mason K, Staab A, Hunter N, et al. Enhancement of tumor radioresponse by docetaxel: involvement of immune system. Int J Oncol 2001;18:599–606.[Medline]
  31. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999;17:3461–7.[Abstract/Free Full Text]
  32. Arlen P, Tsang KY, Marshall JL, et al. The use of a rapid ELISPOT assay to analyze peptide-specific immune responses in carcinoma patients to peptide vs. recombinant poxvirus vaccines. Cancer Immunol Immunother 2000;49:517–29.[CrossRef][Medline]
  33. Hodge JW, Grosenbach DW, Aarts WM, Poole DJ, Schlom J. Vaccine therapy of established tumors in the absence of autoimmunity. Clin Cancer Res 2003;9:1837–49.[Abstract/Free Full Text]
  34. Kass E, Panicali DL, Mazzara G, Schlom J, Greiner JW. Granulocyte/macrophage-colony stimulating factor produced by recombinant avian poxviruses enriches the regional lymph nodes with antigen-presenting cells and acts as an immunoadjuvant. Cancer Res 2001;61:206–14.[Abstract/Free Full Text]
  35. Maas IW, Boven E, Pinedo HM, et al. The effects of {gamma}-interferon combined with 5-fluorouracil or 5-fluoro-2-deoxyuridine on proliferation and antigen expression in a panel of human colorectal cancer cell lines. Int J Cancer 1991;48:749–56.[Medline]
  36. Abdalla EE, Blair GE, Jones RA, Sue-Ling HM, Johnston D. Mechanism of synergy of levamisole and fluorouracil: induction of human leukocyte antigen class I in a colorectal cancer cell line. J Natl Cancer Inst 1995;87:489–96.[Abstract/Free Full Text]
  37. Aquino A, Prete SP, Greiner JW, et al. Effect of the combined treatment of 5-fluorouracil, {gamma}-interferon or folinic acid on carcinoembryonic antigen expression in colon cancer cells. Clin Cancer Res 1998;4:2473–81.[Abstract/Free Full Text]
  38. Lutsiak MEC, Semnani RT, De Pascalis R, Kashmiri SVS, Schlom J, Sabzevari H. Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low dose cyclophosphamide. Blood 2005;105:2862–8.[Abstract/Free Full Text]
  39. Terando A, Mule JJ. On combining antineoplastic drags with tumor vaccines. Cancer Immunol Immunother 2003;52:680–5.[CrossRef][Medline]
  40. Machiels JP, Reilly RT, Emens LA, et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 2001;61:3689–97.[Abstract/Free Full Text]
  41. Foon KA, John WJ, Chakraborty M, et al. Clinical and immune responses in advanced colorectal cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen. Clin Cancer Res 1997;3:1267–76.[Abstract]
  42. Foon KA, John WJ, Chakraborty M, et al. Clinical and immune responses in resected colon cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen. J Clin Oncol 1999;17:2889–95.[Abstract/Free Full Text]
  43. Noguchi M, Itoh K, Yao A, et al. Immunological evaluation of individualized peptide vaccination with a low dose of estramustine for HLA-A24+ HRPC patients. Prostate 2005;63:1–12.[Medline]
  44. Fairchok MP, Trementozzi DP, Carter PS, Regnery HL, Carter ER. Effect of prednisone on response to influenza virus vaccine in asthmatic children. Arch Pediatr Adolesc Med 1998;152:1191–5.[Abstract/Free Full Text]
  45. Johnson JR, Denis R, Lucas CE, et al. The effect of steroids for shock on the immune response to tetanus toxoid. Am Surg 1987;53:389–91.[Medline]
  46. Weber J, Sondak VK, Scotland R, et al. Granulocyte-macrophage-colony-stimulating factor added to a multipeptide vaccine for resected stage II melanoma. Cancer 2003;97:186–200.[CrossRef][Medline]
  47. Disis ML, Gooley TA, Rinn K, et al. Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol 2002;20:2624–32.[Abstract/Free Full Text]
  48. Harada M, Matsueda S, Yao A, Noguchi M, Itoh K. Vaccination of cytotoxic T lymphocyte-directed peptides elicited and spread humoral and Th1-type immune responses to prostate-specific antigen protein in a prostate cancer patients. J Immunother 2005;28:368–75.[Medline]
  49. Grosenbach DW, Barrientos JC, Schlom J, Hodge JW. Synergy of vaccine strategies to amplify antigen-specific immune responses and anti-tumor effects. Cancer Res 2001;61:4497–505.[Abstract/Free Full Text]
  50. Hodge JW, Sabzevari H, Yafal AG, Gritz L, Lorenz MGO, Schlom J. A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res 1999;59:5800–7.[Abstract/Free Full Text]
  51. Arlen PM, Gulley J, Dahut W, et al. A phase I study of sequential vaccinations with recombinant fowlpox-PSA (L155)-TRICOM (rF) alone, or in combination with recombinant vaccinia-PSA (L155)-TRICOM (rV), and the role of GM-CSF, in patients (pts) with prostate cancer. Program/Proc Am Soc Clin Oncol 2004;23:2522a.
  52. Gulley JL, Todd N, Dahut W, Schlom J, Arlen P. A phase II study of PROSTVAC-VF vaccine, and the role of GM-CSF, in patients (pts) with metastatic androgen insensitive prostate cancer (AIPC). Proc Am Soc Clin Oncol 2005;24:2504a.



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
R. A. Madan, J. L. Gulley, J. Schlom, S. M. Steinberg, D. J. Liewehr, W. L. Dahut, and P. M. Arlen
Analysis of Overall Survival in Patients with Nonmetastatic Castration-Resistant Prostate Cancer Treated with Vaccine, Nilutamide, and Combination Therapy
Clin. Cancer Res., July 15, 2008; 14(14): 4526 - 4531.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
C. T. Garnett, J. Schlom, and J. W. Hodge
Combination of Docetaxel and Recombinant Vaccine Enhances T-Cell Responses and Antitumor Activity: Effects of Docetaxel on Immune Enhancement
Clin. Cancer Res., June 1, 2008; 14(11): 3536 - 3544.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. L. Gulley, P. M. Arlen, K.-Y. Tsang, J. Yokokawa, C. Palena, D. J. Poole, C. Remondo, V. Cereda, J. L. Jones, M. P. Pazdur, et al.
Pilot Study of Vaccination with Recombinant CEA-MUC-1-TRICOM Poxviral-Based Vaccines in Patients with Metastatic Carcinoma
Clin. Cancer Res., May 15, 2008; 14(10): 3060 - 3069.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
J. Schlom, J. L. Gulley, and P. M. Arlen
Paradigm Shifts in Cancer Vaccine Therapy
Experimental Biology and Medicine, May 1, 2008; 233(5): 522 - 534.
[Abstract] [Full Text] [PDF]

Home page
 Am Soc Clin Oncol Ed BookHome page
J. Schlom, P. M. Arlen, and J. L. Gulley
Immunotherapies with Other Therapeutic Modalities: New Paradigms for Clinical Trial Design
ASCO Educational Book, January 1, 2008; 2008(1): 101 - 106.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. Kiniwa, Y. Miyahara, H. Y. Wang, W. Peng, G. Peng, T. M. Wheeler, T. C. Thompson, L. J. Old, and R.-F. Wang
CD8+ Foxp3+ Regulatory T Cells Mediate Immunosuppression in Prostate Cancer
Clin. Cancer Res., December 1, 2007; 13(23): 6947 - 6958.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
C. Taylor, D. Hershman, N. Shah, N. Suciu-Foca, D. P. Petrylak, R. Taub, L. Vahdat, B. Cheng, M. Pegram, K. L. Knutson, et al.
Augmented HER-2 Specific Immunity during Treatment with Trastuzumab and Chemotherapy
Clin. Cancer Res., September 1, 2007; 13(17): 5133 - 5143.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. Schlom, P. M. Arlen, and J. L. Gulley
Cancer Vaccines: Moving Beyond Current Paradigms
Clin. Cancer Res., July 1, 2007; 13(13): 3776 - 3782.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
E. J. Small, N. Sacks, J. Nemunaitis, W. J. Urba, E. Dula, A. S. Centeno, W. G. Nelson, D. Ando, C. Howard, F. Borellini, et al.
Granulocyte Macrophage Colony-Stimulating Factor-Secreting Allogeneic Cellular Immunotherapy for Hormone-Refractory Prostate Cancer
Clin. Cancer Res., July 1, 2007; 13(13): 3883 - 3891.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
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]

This Article
Right arrow Abstract Freely available
Right arrow