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Clinical Cancer Research 13, 4487, August 1, 2007. doi: 10.1158/1078-0432.CCR-07-0704
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

Vaccination of Colorectal Cancer Patients with Modified Vaccinia Ankara Encoding the Tumor Antigen 5T4 (TroVax) Given Alongside Chemotherapy Induces Potent Immune Responses

Richard Harrop1, Noel Drury1, William Shingler1, Priscilla Chikoti1, Irina Redchenko1, Miles W. Carroll1, Susan M. Kingsman1, Stuart Naylor1, Alan Melcher2, Joanna Nicholls3, Harpreet Wassan3, Nagy Habib3 and Alan Anthoney2

Authors' Affiliations: 1 Oxford BioMedica (UK) Ltd., The Medawar Centre, Oxford, United Kingdom; 2 St. James University Hospital, Leeds, United Kingdom; and 3 The Hammersmith Hospital, London, United Kingdom

Requests for reprints: Richard Harrop, Oxford BioMedica (UK) Ltd., The Medawar Centre, Oxford Science Park, Oxford, OX4 4GA United Kingdom. Phone: 44-1865-783000; Fax: 44-1865-783044; E-mail: r.harrop{at}oxfordbiomedica.co.uk.


   Abstract
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 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: The attenuated strain of vaccinia virus, modified vaccinia Ankara (MVA) encoding the tumor antigen 5T4 (TroVax), has been evaluated in an open-label phase II study in metastatic colorectal cancer patients. The primary objective was to assess the safety and immunogenicity of TroVax injected before, during, and after treatment with cycles of 5-fluorouracil, folinic acid, and oxaliplatin.

Experimental Design: TroVax was administered to 17 patients with metastatic colorectal cancer. In total, 11 patients were considered to be evaluable for assessment of immunologic responses having received a total of six injections of TroVax, administered before, during, and following completion of chemotherapy. Antibody and cellular responses specific for 5T4 and MVA were monitored throughout the study.

Results: Administration of TroVax alongside 5-fluorouracil, folinic acid, and oxaliplatin was safe and well tolerated with no serious adverse events attributed to TroVax. Ten of the 11 evaluable patients mounted 5T4-specific antibody responses with titers ranging from 10 to >1,000. IFN{gamma} enzyme-linked immunospot responses specific for 5T4 were detected in 10 patients with precursor frequencies exceeding 1 in 1,000 peripheral blood mononuclear cells in 4 patients. Of the 11 evaluable patients, 6 had complete or partial responses. 5T4-specific immune responses, but not MVA-specific immune responses, correlated with clinical benefit.

Conclusions: Potent 5T4-specific cellular and/or antibody responses were induced in all evaluable patients and were still detectable during the period in which chemotherapy was administered. These results suggest that TroVax can be added to chemotherapy regimens without any evidence of enhanced toxicity or reduced immunologic efficacy and may provide additional clinical benefit.

Cancer remains one of the biggest causes of mortality in the developed world. For nonmetastatic cancer, surgical resection offers the best chance of a complete cure. However, when the cancer has metastasized, chemotherapy is the most commonly used treatment but is rarely curative and is often associated with significant toxicity. Active specific immunotherapy represents a promising treatment option, which relies on the induction of an efficacious immune response without accompanying deleterious autoimmune reactions. The identification of a tumor-associated antigen, which is expressed on the tumor target (both primary and metastases) but which is absent on all (or at least most) normal tissues, is important for safe and targeted immunotherapy.

The human oncofetal antigen 5T4 is a 72-kDa membrane glycoprotein that is expressed at high levels on the placenta and also on a wide range of human carcinomas, including colorectal, renal, gastric, and ovarian (1–3). Overexpression of 5T4 is associated with metastatic spread and/or poor prognosis in patients with colorectal (4), gastric (5), and ovarian (6) carcinoma. Transfection of tumor cells with 5T4 cDNA results in increased cell motility, suggesting that expression of this molecule may induce metastatic properties (7, 8). The restricted expression of 5T4 on normal tissues and high prevalence on many common human carcinomas make 5T4 an attractive target for cancer immunotherapy. Furthermore, its surface expression means that it could potentially be a target for both cytotoxic T-cell (CTL) and antibody-mediated effector responses.

For a cancer vaccine to be successful, it must stimulate a potent immune response specific for the target antigen. Several tumor-associated antigens have been engineered into vaccinia virus vectors [including modified vaccinia Ankara (MVA)] and the recombinant vaccines shown to induce tumor-associated antigen–specific immune responses in cancer patients (9–11). MVA encoding 5T4 (TroVax) was tested previously in a phase I/II trial in stage IV colorectal cancer patients. This study showed the product to be well tolerated and to induce 5T4-specific immune responses in the majority of patients (12).

Given the encouraging data from the phase I/II study, we wanted to assess the effect of chemotherapy on the ability of TroVax to elicit an immune response. The use of immunotherapy alongside chemotherapy has been viewed as counterintuitive because the latter may suppress the immune system (13). Here, we report on the safety and immunologic efficacy of TroVax administered to colorectal cancer patients alongside 5-fluorouracil (5-FU)/folinic acid and oxaliplatin.


   Patients and Methods
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 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patient characteristics. This phase II trial was an open label study of TroVax administered by i.m. injection to patients with advanced colorectal cancer receiving 5-FU/folinic acid plus oxaliplatin as first-line therapy. All patients had histologically proven colorectal cancer, a WHO performance status of 0, 1, or 2, a life expectancy of ≥3 months, were aged ≥18 years, and had adequate hematologic and liver function. The trial protocol was approved by the United Kingdom Gene Therapy Advisory Committee and the study conducted under a Clinical Trial Exemption granted by the Medicines and Healthcare Products Regulatory Agency (formerly the Medicines Control Agency). The trial was approved by the Local Research Ethics Committees and informed consent was obtained from each patient before enrollment.

Clinical trial design. On entering the trial, each patient underwent chest, abdominal, and pelvic computed tomography (CT) scans to quantify tumor metastases. Further scans were scheduled at weeks 14 and X + 8. Patients received OxMdG (oxaliplatin at 350 mg and the modified de Gramont regimen of calcium folinate at 350 mg simultaneous 2-h i.v. infusion; 5-FU at 400 mg/m2 i.v. bolus; and 5-FU at 2,400 mg/m2 i.v. infusion over 46 h) at 2-week intervals starting at week 4 with up to 12 cycles being administered, depending on clinical response and tolerance. Two TroVax immunizations were given before chemotherapy (weeks 0 and 2), two during (weeks 11 and 17), and two following completion of chemotherapy (weeks X + 2 and X + 6; completion of chemotherapy is indicated as week X). Patients received ~5 x 108 plaque-forming units TroVax via i.m. injection in a volume of 1 mL into the deltoid muscle. Blood was taken after each immunization to assess the induction of immune responses to 5T4 and MVA (see Fig. 1 for sampling schedule). In addition, the plasma concentration of the surrogate marker, carcinoembryonic antigen (CEA), was measured throughout the trial.


Figure 1
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  		Fig. 1. Vaccination, chemotherapy, and blood sampling schedule. The schematic shows each vaccination time point (syringe) and time points at which blood samples were taken for monitoring of immune responses (below the solid arrow) and CT scans were done to monitor disease progression.

 
Antigens. Purified recombinant 5T4 protein (14) was used to monitor antibody responses (by ELISA) and cellular responses [by IFN{gamma} enzyme-linked immunospot (ELISPOT)]. In addition, overlapping 5T4 10mer peptides (Mimotopes), CEF peptides (a pool of CTL epitopes derived from CMV, EBV, and Flu, Mabtech), and MVA were used to measure cellular responses.

Measurement of antibody responses. 5T4- and MVA-specific antibody titers were determined by ELISA as described previously (15). Antibody titers were defined as the greatest dilution of plasma at which the mean absorbance of the test plasma was ≥2-fold the mean absorbance of the negative control (normal human plasma) at the same dilution. A positive antibody response due to vaccination was reported if the postinjection titer was ≥ 2-fold the titer determined before TroVax immunization.

Measurement of IFN{gamma} ELISPOT responses. The IFN{gamma} ELISPOT was used to monitor cellular responses throughout the trial. Briefly, frozen peripheral blood mononuclear cells (PBMC) were thawed and incubated in medium overnight at 37°C, 5% CO2 before use. ELISPOT plates (polyvinylidene difluoride, Millipore) were coated with an anti-IFN{gamma} capture antibody (IFN{gamma} ELISPOT ALD kit, Mabtech). Following blocking, 2 x 105 PBMCs were added to each well and incubated overnight at 37°C, 5% CO2 with the appropriate antigen (depending on PBMC availability, the same panel of antigens was used for all patients and at all time points). Subsequently, spots were enumerated using an automated ELISPOT plate reader (AID). A positive ELISPOT response induced by TroVax was reported if the mean spot-forming units per well in response to antigen was ≥3-fold the mean spot-forming units per well in wells containing medium alone and the mean spot-forming units per well in response to antigen is ≥10 and the antigen-specific frequency after immunization was ≥2-fold the frequency before TroVax vaccination. The frequency of antigen-specific cells is reported as 1:X PBMCs, where X is any value up to 200,000.

Statistical analysis of association between immunologic and clinical responses. Mean 5T4- and MVA-specific ELISA and ELISPOT responses were determined for all evaluable patients from week 2 to 14 or 2 to X + 8. Subsequently, 5T4- or MVA-specific immune responses were correlated with clinical benefit. Two measures of clinical benefit were used: (a) change in tumor burden of all target lesions at weeks 14 and X + 8 expressed as a percentage of the baseline tumor burden or (b) Response Evaluation Criteria in Solid Tumors (RECIST) response score. The latter was calculated by assigning a score for the tumor responses at weeks 14 and X + 8 such that a score of 1 is progressive disease (PD), 2 is unconfirmed stable disease (SD), 3 is confirmed SD, 4 is unconfirmed partial response (PR), 5 is confirmed PR, 6 is unconfirmed complete response (CR), and 7 is confirmed CR. Unconfirmed responses have been defined as situations whereby the best response (at either time point) has not been confirmed at a later time point (e.g., an unconfirmed PR would be a PR at week 14 followed by PD at week X + 8 or a SD at week 14 followed by a PR at week X + 8). The Spearman correlation was used to investigate potential associations between immune response and clinical benefit. A P value <0.05 was deemed significant.


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
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Patients. In total, 17 patients were enrolled in the trial and included in the intention-to-treat (ITT) population. Six patients withdrew from the trial before becoming evaluable for assessment of immunologic and clinical responses as follows: 2 patients (patients 112 and 109) were withdrawn due to PD, 3 patients (patients 106, 111, and 115) withdrew due to serious adverse events unrelated to TroVax, and 1 patient (patient 110) was lost to follow-up. Only one of the nonevaluable patients (patient 112) was on study for sufficient time to have a protocol-mandated CT scan taken at week 14; therefore, no commentary is made on clinical responses in the ITT group, due simply to the lack of CT scan data. The mean age (±SD) of the ITT population was 59.7 ± 7.2 years (range, 47-72 years). The characteristics of the ITT patient group are detailed in Table 1 .


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  		Table 1. ITT patient characteristics

 
Safety. No TroVax-related serious adverse events were reported in the ITT population. The most frequent adverse event related to TroVax administration was soreness at the site of injection that occurred in seven (41%) patients (Table 2 ). The other toxicities experienced by patients were in keeping with those expected form oxaliplatin and 5-FU given at these doses.


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  		Table 2. Adverse events classified as ‘probably’ or ‘definitely’ related to TroVax

 
Antibody responses. 5T4-specific antibody responses were monitored by ELISA at each sampling time point throughout the trial and expressed as a titer (Table 3A ). No patient had a detectable 5T4-specific antibody titer before TroVax immunization and one patient (patient 101) failed to show an increase following vaccination. However, 10 patients showed 5T4-specific antibody titers (range, 10-1,280), which were evident after two or more vaccinations in the majority of patients and remained detectable for all, or part, of the period in which patients received chemotherapy. During the period that patients received chemotherapy (week 4 to approximately week 19), the mean titer was 105, which increased moderately to 121 following completion of chemotherapy (weeks X + 2 to X + 14).


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  		Table 3. 5T4- and MVA-specific antibody responses

 
MVA-specific antibody responses were also monitored by ELISA at each sampling time point (Table 3B). One patient (patient 102) had a detectable MVA-specific antibody titer (2,000) before TroVax immunization. All patients showed either de novo MVA-specific antibody responses or an increase in antibody titer (patient 102) following vaccination with titers ranging from 2,000 to 512,000. Positive responses were detectable after a single vaccination in the majority of patients and remained positive during the period in which patients received chemotherapy. The mean MVA antibody titer for all 11 evaluable patients during the period in which chemotherapy was administered was 22,291, which increased to 46,545 following completion of chemotherapy (weeks X + 2 to X + 14).

TroVax induced IFN{gamma} ELISPOT responses. IFN{gamma} ELISPOT responses to a panel of antigens were monitored using thawed PBMCs directly without any additional in vitro restimulation steps. Responses to the positive control CEF peptide pool, 5T4 peptides, and MVA are detailed in Table 4A . Positive responses to the CEF peptide pool were detected in all 11 evaluable patients with precursor frequencies ranging from 1:19,230 (0.005%) to 1:600 PBMCs (0.16%). The CEF-specific precursor frequencies were highly consistent throughout the trial monitoring period both before and after TroVax vaccination (data not shown). The mean difference in CEF-specific precursor frequencies detected before TroVax vaccination compared with after vaccination was 1.1 (range, 0.46- to 1.8-fold). Positive ELISPOT responses to MVA were detected in 9 patients at baseline and in all 11 evaluable patients after TroVax immunization. Of the nine patients with preexisting MVA responses, only one (patient 117) showed a >2-fold increase in response following vaccination. Mean MVA-specific precursor frequencies increased from 1:38,800 (range, <1:200,000-1:639) before TroVax vaccination to 1:1,025 (range, 1:1,500-1:589) after vaccination, which constituted a mean 35-fold increase (range, 1- to >203-fold). No patient had a detectable 5T4 peptide-specific IFN{gamma} ELISPOT response before TroVax immunization (frequency, <1:200,000). However, following vaccination, PBMCs from nine patients responded to 5T4 peptides with precursor frequencies ranging from 1:18,867 to 1:726 PBMCs. If responses to multiple peptide pools (i.e., 5T4-specific polyclonal responses) are analyzed (Table 4B), precursor frequencies in excess of 1:10,000 PBMCs were detected in seven patients, two of whom had precursor frequencies >1:1,000. If the responses to 5T4 protein are added to those detected to 5T4 peptides, nine patients had 5T4-specific polyclonal responses in excess of 1:10,000 and four had responses >1:1,000. The IFN{gamma} ELISPOT responses detected in patient 105 before (weeks –2 and 0) and following TroVax immunization (weeks 13, 19, and X + 2) are shown in Fig. 2 . No responses were detected to medium alone (RPMI 1640) and relatively consistent CEF-specific responses were seen (<2-fold difference across all sampling time points). Responses to 5T4 peptide pools 13 and 20 were negative before TroVax vaccination but strongly positive after vaccination, including during the period in which the patient received chemotherapy (weeks 13 and 19).


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  		Table 4. Antigen-specific IFN{gamma} ELISPOT responses

 

Figure 2
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  		Fig. 2. IFN{gamma} ELISPOT responses detected in patient 105 following incubation of patients' PBMCs with medium alone (RPMI 1640), CEF peptide pool, and two 5T4 peptide pools (pools 13 and 20). Responses from PBMCs taken before TroVax vaccination (weeks –2 and 0) are shown alongside PBMCs recovered during chemotherapy (weeks 13 and 19) and after chemotherapy (week X + 2).

 
Clinical responses. The levels of circulating CEA were determined throughout the trial. Table 1 summarizes the levels of circulating CEA present at baseline and the lowest levels detected following TroVax immunization. Of the 17 ITT patients, 11 had elevated CEA levels (>5 µg/L) at baseline and 7 of these showed a >50% reduction at ≥1 time point throughout the trial. In the majority of patients, the nadir in CEA levels occurred during the period in which both chemotherapy and TroVax were administered, although in 2 patients (patients 103 and 105), this occurred following the completion of chemotherapy (i.e., after week X).

Radiological responses to the trial therapy were observed in 5 of 11 (45%) evaluable patients at week 14 (six cycles of chemotherapy and three TroVax administrations; Table 5 ). As clinical efficacy was not a primary end point in this study, confirmatory CT scans ≥4 weeks later were not mandated. However, CT scans done at week X + 8 (between weeks 28 and 37) showed continued PRs in three patients and a CR in one patient (patient 102). Table 5 also summarizes that for all but two patients, the response observed at week 14 was maintained. The RECIST response score and the total tumor burden at week X + 8 expressed as a percentage of the total tumor burden at baseline. The median survival was 68 weeks in the 17 ITT patients and 118 weeks in the 11 evaluable patients.


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  		Table 5. Tumor responses detected in all evaluable patients and correlates with immune response

 
Correlation of clinical and immunologic responses. Mean 5T4- and MVA-specific antibody and ELISPOT responses detected between weeks 2 to 14 (i.e., mean responses across 5 sampling time points) and weeks 2 to X + 8 (i.e., mean responses across 11 sampling time points) were calculated and compared with indicators of clinical benefit (RECIST response score or change in tumor burden; Table 5). No association was observed between 5T4- or MVA-specific antibody responses and clinical benefit. However, significant correlations were detected between 5T4-specific ELISPOT responses and RECIST response score (P = 0.006) and change in tumor burden at week X + 8 (P = 0.035). No significant correlations were detected with MVA-specific ELISPOT responses.


   Discussion
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 Abstract
 Patients and Methods
 Results
 Discussion
References
 
Currently, few clinical studies have investigated the use of a cancer vaccine in combination with chemotherapy due to the perceived negative effect of cytotoxic agents on cells of the immune system. In addition to direct effects on the immune system, most chemotherapies are thought to kill tumor cells through the induction of apoptosis, which has traditionally been associated with the induction of tolerance rather than immunity (16). However, numerous pathways have been postulated by which some chemotherapy regimens could augment immunotherapy; these include enhanced cross-presentation of antigens, partial activation of dendritic cells, and promotion of long-term antigen-independent memory (reviewed in ref. 13). For example, the use of low-dose cyclophosphamide has been shown to enhance immune responses against several tumor antigens (17). Such immunostimulatory properties were linked to the ability of low-dose cyclophosphamide to decrease both the number and the activity of regulatory T cells (18, 19). Indeed, decreases in the percentage of regulatory T cells have been associated with a switch from tumor escape to tumor rejection (18, 20).

We have shown that the administration of TroVax in combination with 5-FU/folinic acid and oxaliplatin is both safe and capable of inducing potent 5T4-specific immune responses. Of the 11 patients who completed the TroVax vaccination schedule, all mounted 5T4-specific cellular and/or humoral immune responses. The immune responses detected to 5T4 were, in general, of greater magnitude and longevity than those detected in a phase I/II study in which TroVax was administered as a monotherapy to stage IV colorectal cancer patients (12). Indeed, both the frequency and the magnitude of 5T4-specific immune responses are, to our knowledge, some of the highest reported tumor-associated antigen–specific responses induced in cancer patients following vaccination (21). Antigen-specific precursor frequencies in excess of 1 per 1,000 PBMCs are usually only detected when responses to viral antigens are analyzed. Indeed, the responses to 5T4 reported in this study were frequently as high as those detected to the MVA viral vector. This was true even in circumstances in which a preexisting response to MVA was detected or following the induction of a potent antibody response that frequently occurred following a single TroVax vaccination.

Given that this trial was a small, open-label single-arm study, in which tumor response was not a primary end point, it is not appropriate to comment extensively on the clinical responses detected in this patient cohort. However, the following observations can be made: the frequency of observed CR/PR were of a similar order to those seen in pivotal studies using similar chemotherapy regimens alone (22, 23), indicating no negative effect of TroVax on delivery or activity of the chemotherapy. Although no firm conclusions can be drawn from this study about possible synergism between TroVax and chemotherapy, it was encouraging that a significant correlation between 5T4-specific immune response and clinical benefit was detected. It could be argued that the ability to mount a 5T4-specific immune response is a function of the immunocompetence and general health of the patient, which could explain the trend with clinical benefit. However, immune responses to MVA represent a good internal control for immunocompetence and no significant correlates existed between the magnitude of MVA responses and clinical benefit.

Despite recent progress, a pressing requirement for improved therapies to combat advanced cancer remains. Combining different treatment modalities, such as biological and cytotoxic agents, has scientific and clinical rationale as long as the combined toxicities are not excessive. Here, we have shown that the immunologic efficacy of TroVax has been maintained in the context of a standard of care chemotherapy regimen without additional toxicity.

These data provide further support that combining a cancer vaccine, such as TroVax, with chemotherapy may be beneficial. Further studies aimed at characterizing the timing of vaccination relative to chemotherapy and identifying the optimum chemotherapy regimen may lead to increased clinical benefit. In conclusion, we have shown that TroVax is safe and highly immunogenic when administered to patients alongside 5-fluorouracil/folinic acid and oxaliplatin. Furthermore, a significant correlation between 5T4-specific immune responses and clinical benefit was detected. We believe that these observations provide good justification for the continued development of TroVax alongside other standard of care therapies.


   Acknowledgments
 
We thank Peter Treasure for statistical support, Mike McDonald for his valued comments, and the research nurses involved in this study.


   Footnotes
 
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.

Note: Current address for M.W. Carroll: MNLpharma Ltd., University of Reading Science and Technology Centre, Reading, RG6 6AH United Kingdom.

Received 3/26/07; revised 5/14/07; accepted 5/31/07.


   References
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 Abstract
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 References
 

  1. Hole N, Stern PL. A 72 kD trophoblast glycoprotein defined by a monoclonal antibody. Br J Cancer 1988;57:239–46.[Medline]
  2. Southall PJ, Boxer GM, Bagshawe KD, et al. Immunohistological distribution of 5T4 antigen in normal and malignant tissues. Br J Cancer 1990;61:89–95.[Medline]
  3. Griffiths RW, Gilham DE, Dangoor A, et al. Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy. Br J Cancer 2005;93:670–7.[CrossRef][Medline]
  4. Starzynska T, Marsh PJ, Schofield PF, et al. Prognostic significance of 5T4 oncofetal antigen expression in colorectal carcinoma. Br J Cancer 1994;69:899–902.[Medline]
  5. Starzynska T, Rahi V, Stern PL. The expression of 5T4 antigen in colorectal and gastric carcinoma. Br J Cancer 1992;66:867–9.[Medline]
  6. Wrigley E, McGowan AT, Rennison J, et al. 5T4 oncofetal antigen expression in ovarian carcinoma. Int J Gynecol Cancer 1995;5:269–74.[CrossRef][Medline]
  7. Carsberg CJ, Myers KA, Evans GS, et al. Metastasis-associated 5T4 oncofoetal antigen is concentrated at microvillus projections of the plasma membrane. Cell Sci 1995;108:2905–16.[Abstract]
  8. Carsberg CJ, Myers KA, Stern PL. Metastasis-associated 5T4 antigen disrupts cell-cell contacts and induces cellular motility in epithelial cells. Int J Cancer 1996;68:84–92.[CrossRef][Medline]
  9. Rochlitz C, Figlin R, Squiban P, et al. Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer. J Gene Med 2003;5:690–9.[CrossRef][Medline]
  10. 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]
  11. 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]
  12. Harrop R, Connolly N, Redchenko I, et al. Vaccination of colorectal cancer patients with modified vaccinia ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I/II trial. Clin Cancer Res 2006;12:3416–24.[Abstract/Free Full Text]
  13. Lake RA, Robinson BWS. Immunotherapy and chemotherapy—practical partnership. Nat Rev Cancer 2005;5:397–404.[CrossRef][Medline]
  14. Harrop R, Ryan, MG, Myers KA, et al. Active treatment of murine tumors with a highly attenuated vaccinia virus expressing the tumor associated antigen 5T4 (TroVax) is CD4+ T cell dependent and antibody mediated. Cancer Immunol Immunother 2006;55:1081–90.[CrossRef][Medline]
  15. Braybrooke JP, Slade A, Deplanque G, et al. Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma. Clin Cancer Res 2005;11:1512–20.[Abstract/Free Full Text]
  16. Sauter B, Albert ML, Francisco L, et al. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces maturation of immunostimulatory dendritic cells. J Exp Med 2000;191:423–34.[Abstract/Free Full Text]
  17. Hermans IF, Chong TW, Palmowski MJ, et al. Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res 2003;63:8408–13.[Abstract/Free Full Text]
  18. Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 2004;34:336–44.[CrossRef][Medline]
  19. Lutsiak ME, Semnani RT, De Pascalis R, et al. 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]
  20. Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999;163:5211–8.[Abstract/Free Full Text]
  21. Harrop R, Carroll MW. Viral vectors for cancer immunotherapy. Front Biosci 2006;11:804–17.[CrossRef][Medline]
  22. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–47.[Abstract/Free Full Text]
  23. Braun MS, Adab F, Bradley C, et al. Modified de Gramont with oxaliplatin in first-line treatment of advanced colorectal cancer. Br J Cancer 2003;89:1155–8.[CrossRef][Medline]



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