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1.
Cytotherapy ; 24(8): 861-868, 2022 08.
Article in English | MEDLINE | ID: mdl-35710768

ABSTRACT

Activities involved in the production of certain advanced therapy medicinal products (ATMPs) require standardized approaches to mononuclear cell procurement to ensure the highest product quality, safety and process efficiency. These aims must be achieved while meeting regulatory and accreditation requirements for the procurement of mononuclear cells as starting materials. Mononuclear cells constitute the starting materials for many ATMPs, and this article sets out recommendations for procurement by clinical apheresis, addressing the variation among existing working practices and different manufacturers' requirements that currently poses a challenge when managing multiple different protocols.


Subject(s)
Blood Component Removal
2.
Cancer Immunol Immunother ; 61(12): 2283-94, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22692758

ABSTRACT

Cancer vaccines such as MVA-5T4 (TroVax(®)) must induce an efficacious immune response to deliver therapeutic benefit. The identification of biomarkers that impact on the clinical and/or immunological efficacy of cancer vaccines is required in order to select patients who are most likely to benefit from this treatment modality. Here, we sought to identify a predictor of treatment benefit for renal cancer patients treated with MVA-5T4. Statistical modeling was undertaken using data from a phase III trial in which patients requiring first-line treatment for metastatic renal cell carcinoma were randomized 1:1 to receive MVA-5T4 or placebo alongside sunitinib, IL-2 or IFN-α. Numerous pre-treatment factors associated with inflammatory anemia (e.g., CRP, hemoglobin, hematocrit, IL-6, ferritin, platelets) demonstrated a significant relationship with tumor burden and patient survival. From these prognostic factors, the pre-treatment mean corpuscular hemoglobin concentration (MCHC) was found to be the best predictor of treatment benefit (P < 0.01) for MVA-5T4 treated patients and also correlated positively with tumor shrinkage (P < 0.001). Furthermore, MCHC levels showed a significant positive association with 5T4 antibody response (P = 0.01). The latter result was confirmed using an independent data set comprising phase II trials of MVA-5T4 in patients with colorectal, renal and prostate cancers. Retrospective analyses demonstrated that RCC patients who had very large tumor burdens and low MCHC levels received little or no benefit from treatment with MVA-5T4; however, patients with smaller tumor burdens and normal MCHC levels received substantial benefit from treatment with MVA-5T4.


Subject(s)
Biomarkers, Tumor/immunology , Biomarkers, Tumor/metabolism , Cancer Vaccines/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Anemia/immunology , Anemia/metabolism , Antibodies, Neoplasm/immunology , Cancer Vaccines/immunology , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/metabolism , Hemoglobins/immunology , Hemoglobins/metabolism , Humans , Interferon-alpha/immunology , Interferon-alpha/metabolism , Interleukin-2/immunology , Interleukin-2/metabolism , Kidney Neoplasms/immunology , Kidney Neoplasms/metabolism , Predictive Value of Tests , Prognosis , Retrospective Studies , Vaccines, DNA
3.
Cancer Immunol Immunother ; 60(6): 829-37, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21387109

ABSTRACT

Few immunotherapy compounds have demonstrated a direct link between the predicted mode of action of the product and benefit to the patient. Since cancer vaccines are thought to have a delayed therapeutic effect, identification of the active moiety may enable the development of an early marker of efficacy. Patients with renal cancer and requiring first-line treatment for metastatic disease were randomized 1:1 to receive MVA-5T4 (TroVax(®)) or placebo alongside Sunitinib, IL-2 or IFN-α in a multicentre phase III trial. Antibody responses were quantified following the 3rd and 4th vaccinations. A surrogate for 5T4 antibody response (the immune response surrogate; IRS) was constructed and then used in a survival analysis to evaluate treatment benefit. Seven hundred and thirty-three patients were randomized, and immune responses were assessed in 590 patients. A high 5T4 antibody response was associated with longer survival within the MVA-5T4-treated group. The IRS was constructed as a linear combination of pre-treatment 5T4 antibody levels, hemoglobin and hematocrit and was shown to be a significant predictor of treatment benefit in the phase III study. Importantly, the IRS was also associated with antibody response and survival in an independent dataset comprising renal, colorectal and prostate cancer patients treated with MVA-5T4 in phase I-II studies. The derivation of the IRS formed part of an exploratory, retrospective analysis; however, if confirmed in future studies, the results have important implications for the development and use of the MVA-5T4 vaccine and potentially for other similar vaccines.


Subject(s)
Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/therapy , Kidney Neoplasms/immunology , Kidney Neoplasms/therapy , Aged , Antibodies, Neoplasm/biosynthesis , Antibodies, Neoplasm/immunology , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Female , Humans , Indoles/administration & dosage , Interferon-alpha/administration & dosage , Interleukin-2/administration & dosage , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Pyrroles/administration & dosage , Sunitinib , Vaccines, DNA
5.
Clin Cancer Res ; 16(22): 5539-47, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20881001

ABSTRACT

PURPOSE: The TroVax Renal Immunotherapy Survival Trial was a randomized, placebo-controlled phase III study that investigated whether modified vaccinia Ankara encoding the tumor antigen 5T4 (MVA-5T4) prolonged survival of patients receiving first-line standard-of-care (SOC) treatment for metastatic renal cell cancer. EXPERIMENTAL DESIGN: Patients with metastatic clear cell renal cancer, prior nephrectomy, and good or intermediate prognosis were randomized 1:1 to receive up to 13 immunizations of MVA-5T4/placebo in combination with either sunitinib, interleukin-2 or interferon-α. The primary end point was overall survival. Secondary end points included progression-free survival, overall response rate, and safety. RESULTS: Seven hundred thirty-three patients were recruited (365 MVA-5T4 and 368 placebo). Treatment arms were well balanced for SOC and prognosis. No significant difference in the incidence of adverse events or serious adverse events was observed. No significant difference in overall survival was evident in the two treatment arms (median 20.1 months MVA-5T4 versus 19.2 months placebo; P = 0.55). The magnitude of the 5T4-specific antibody response induced by vaccination with MVA-5T4 was associated with enhanced patient survival. Furthermore, exploratory analyses suggested a number of pretreatment hematologic factors that could identify patients who derive significant benefit from this vaccine. CONCLUSION: MVA-5T4 in combination with SOC was well tolerated, but no difference in survival was observed in the overall study population. Exploratory analyses indicate that there may be subsets of patients who could gain significant benefit from MVA-5T4, but such results would need to be confirmed in future randomized clinical studies.


Subject(s)
Cancer Vaccines/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Double-Blind Method , Female , Humans , Immunotherapy , Male , Middle Aged , Neoplasm Metastasis , Placebos , Prognosis , Survival Analysis , Treatment Outcome , Vaccines, DNA , Young Adult
6.
J Immunother ; 33(9): 999-1005, 2010.
Article in English | MEDLINE | ID: mdl-20948436

ABSTRACT

The attenuated vaccinia virus MVA has been engineered to deliver the tumor antigen 5T4 (MVA-5T4; TroVax), a surface glycoprotein expressed by most solid tumors. MVA-5T4 has been tested in 2 phase I/II and 7 phase II clinical trials in colorectal (4 trials), renal (4 trials), and prostate (1 trial) advanced cancer patients. Data have been collated from all 9 studies and used to investigate the magnitude and kinetics of 5T4-specific antibody responses after vaccination and to identify potential associations between the immune response and patient survival. Antibody responses specific for the 5T4 tumor antigen and the MVA viral vector were quantified in plasma samples taken from cancer patients before and after the treatment with MVA-5T4. Immunologic and survival data were analyzed using proportional hazards regression adjusting for age and gender. Both survival and immunologic response data were available for 189 patients with colorectal (n=73), renal (n=89), and prostate (n=27) cancer. Before the treatment with MVA-5T4, 5T4-specific antibody levels were significantly elevated in cancer patients compared with healthy donors. After MVA-5T4 administration, 5T4-specific antibody responses increased significantly and peaked after 3 to 4 vaccinations. Exploratory analyses showed significant associations between 5T4 antibody responses and overall survival across all 9 trials and in patients with colorectal cancer. The 5T4-specific antibodies were present at higher levels in cancer patients compared with healthy donors and increased significantly after treatment with MVA-5T4. Although the studies were uncontrolled, there were encouraging signs of activity which is associated with the magnitude of 5T4-specific antibody responses.


Subject(s)
Cancer Vaccines/administration & dosage , Colorectal Neoplasms/drug therapy , Immunity, Humoral , Kidney Neoplasms/drug therapy , Prostatic Neoplasms/drug therapy , Adult , Antigens, Neoplasm/immunology , Cancer Vaccines/adverse effects , Colorectal Neoplasms/immunology , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Colorectal Neoplasms/physiopathology , Female , Humans , Immunity, Humoral/drug effects , Kidney Neoplasms/immunology , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Kidney Neoplasms/physiopathology , Male , Membrane Glycoproteins/immunology , Middle Aged , Prostatic Neoplasms/immunology , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Prostatic Neoplasms/physiopathology , Survival Analysis , Vaccination , Vaccines, DNA
7.
J Immunother ; 32(7): 765-72, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19561532

ABSTRACT

Attenuated vaccinia virus, modified vaccinia Ankara (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). MVA-5T4 has been evaluated in an open-label phase 2 trial in metastatic renal cell cancer patients in which the vaccine was administered alone or in combination with interferon-alpha-2b (IFN-alpha). The safety, immunologic, and clinical efficacy of MVA-5T4 with or without IFN-alpha was determined. Twenty-eight patients with metastatic renal cell cancer were treated with MVA-5T4 alone (13) or plus IFN-alpha (15). The 5T4-specific cellular and humoral responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by computed tomography or magnetic resonance imaging scan. MVA-5T4 was well tolerated with no serious adverse event attributed to vaccination. Of 23 intent-to-treat patients tested for immune responses postvaccination, 22 (96%) mounted 5T4-specific antibody and/or cellular responses. One patient treated with MVA-5T4 plus IFN-alpha showed a partial response for >7 months, whereas an additional 14 patients (7 receiving MVA-5T4 plus IFN and 7 receiving MVA-5T4 alone) showed periods of disease stabilization ranging from 1.73 to 9.60 months. Median progression free survival and overall survival for all intent-to-treat patients was 3.8 months (range: 1 to 11.47 mo) and 12.1 months (range: 1 to 27 mo), respectively. MVA-5T4 administered alone or in combination with IFN-alpha was well tolerated in all patients. Despite the high frequency of 5T4-specific immune responses, it is not possible to conclude that patients are receiving clinical benefit. The results are encouraging and warrant further investigation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer Vaccines/immunology , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Adult , Aged , Anemia/chemically induced , Antibodies, Viral/blood , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/immunology , Cancer Vaccines/administration & dosage , Cancer Vaccines/genetics , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Drug Delivery Systems/methods , Enzyme-Linked Immunosorbent Assay , Fatigue/chemically induced , Female , Fever/chemically induced , Humans , Interferon-alpha/administration & dosage , Interferon-gamma/immunology , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Lymphopenia/chemically induced , Male , Middle Aged , Survival Analysis , Treatment Outcome , Vaccination/adverse effects , Vaccination/methods , Vaccines, DNA , Vaccinia virus/genetics , Vaccinia virus/immunology
8.
J Immunother ; 32(4): 424-9, 2009 May.
Article in English | MEDLINE | ID: mdl-19342962

ABSTRACT

Approximately 90% of renal cell tumors overexpress the tumor antigen 5T4. The attenuated strain of vaccinia virus, modified vaccinia Ankara, has been engineered to express 5T4 (TroVax). We conducted an open-label phase 1/2 trial in which TroVax was administered alongside interferon-alpha (IFNalpha) to 11 patients with metastatic renal cell carcinoma. Antigen-specific cellular and humoral responses were monitored throughout the study, and clinical responses were assessed by measuring the changes in tumor burden by computed tomography scan (Response Evaluation Criteria In Solid Tumors). The primary objective was to assess the safety, immunogenicity, and efficacy of TroVax when given alongside IFNalpha. Treatment with TroVax plus IFNalpha was well tolerated with no serious adverse events attributed to TroVax. All 11 patients mounted 5T4-specific antibody responses and 5 (45%) mounted cellular responses. No objective tumor responses were seen, but the overall median time to progression (TTP) of 9 months (range: 2.1 to 26+ mo) was longer than expected for IFNalpha alone. For the 10 clear cell patients the TTP ranged from 3.9 to 26+ months, with a median TTP of 10.4 months. The high frequency of 5T4-specific immune responses and prolonged median TTP for clear cell patients compared with that expected for IFNalpha alone is encouraging and warrants further investigation.


Subject(s)
Cancer Vaccines/therapeutic use , Carcinoma, Renal Cell/drug therapy , Interferon-alpha/therapeutic use , Kidney Neoplasms/drug therapy , Aged , Antibody Formation/immunology , Antigens, Neoplasm/immunology , Cancer Vaccines/administration & dosage , Carcinoma, Renal Cell/immunology , Female , Humans , Immunity, Cellular/immunology , Interferon-alpha/administration & dosage , Kidney Neoplasms/immunology , Male , Middle Aged , Vaccines, DNA
9.
J Transl Med ; 7: 2, 2009 Jan 07.
Article in English | MEDLINE | ID: mdl-19128501

ABSTRACT

BACKGROUND: Interleukin-2 (IL-2) induces durable objective responses in a small cohort of patients with metastatic renal cell carcinoma (RCC) but the antigen(s) responsible for tumor rejection are not known. 5T4 is a non-secreted membrane glycoprotein expressed on clear cell and papillary RCCs. A modified vaccinia virus Ankara (MVA) encoding 5T4 was tested in combination with high-dose IL-2 to determine the safety, objective response rate and effect on humoral and cell-mediated immunity. METHODS: 25 patients with metastatic RCC who qualified for IL-2 were eligible and received three immunizations every three weeks followed by IL-2 (600,000 IU/kg) after the second and third vaccinations. Blood was collected for analysis of humoral, effector and regulatory T cell responses. RESULTS: There were no serious vaccine-related adverse events. While no objective responses were observed, three patients (12%) were rendered disease-free after nephrectomy or resection of residual metastatic disease. Twelve patients (48%) had stable disease which was associated with improved median overall survival compared to patients with progressive disease (not reached vs. 28 months, p = 0.0261). All patients developed 5T4-specific antibody responses and 13 patients had an increase in 5T4-specific T cell responses. Although the baseline frequency of Tregs was elevated in all patients, those with stable disease showed a trend toward increased effector CD8+ T cells and a decrease in Tregs. CONCLUSION: Vaccination with MVA-5T4 did not improve objective response rates of IL-2 therapy but did result in stable disease associated with an increase in the ratio of 5T4-specific effector to regulatory T cells in selected patients. TRIAL REGISTRATION NUMBER: ISRCTN83977250.


Subject(s)
Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Carcinoma, Renal Cell/therapy , Interleukin-2/therapeutic use , Kidney Neoplasms/therapy , Membrane Glycoproteins/immunology , Adult , Aged , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Biomarkers, Tumor/metabolism , CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/adverse effects , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/secondary , Female , Humans , Interleukin-2/immunology , Kaplan-Meier Estimate , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Male , Membrane Glycoproteins/genetics , Middle Aged , Neoplasm Metastasis , T-Lymphocytes, Regulatory/immunology , Vaccines, DNA , Vaccinia virus/genetics
10.
Clin Cancer Res ; 14(22): 7504-10, 2008 Nov 15.
Article in English | MEDLINE | ID: mdl-19010868

ABSTRACT

PURPOSE: The attenuated vaccinia virus modified vaccinia ankara (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). TroVax has been evaluated in an open-label phase II trial in metastatic renal cell cancer patients in which the vaccine was administered in combination with interleukin-2 (IL-2). The safety, immunologic, and clinical efficacy of TroVax in combination with IL-2 was determined. EXPERIMENTAL DESIGN: Twenty-five patients with metastatic renal cell cancer were treated with TroVax plus IL-2. 5T4-specific cellular and humoral responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by computed tomography or magnetic resonance imaging scan. RESULTS: TroVax was well tolerated with no serious adverse event attributed to vaccination. Of 25 intention-to-treat patients, 21 mounted 5T4-specific antibody responses. Two patients showed a complete response for > 24 months and one a partial response for > 12 months. Six patients had disease stabilization from 6 to > 21 months. Median progression-free survival (PFS) and overall survival (OS) were > 3.37 months (range, 1.50- > 24.76) and > 12.87 months (range, 1.90- > 24.76), respectively. A statistically significant relationship was detected between the magnitude of 5T4-specific antibody responses and PFS and OS. CONCLUSION: TroVax in combination with IL-2 was safe and well tolerated in all patients. The high frequency of 5T4-specific immune responses and good clinical response rate are encouraging and warrant further investigation.


Subject(s)
Antineoplastic Agents/administration & dosage , Cancer Vaccines/administration & dosage , Carcinoma, Renal Cell/therapy , Interleukin-2/administration & dosage , Kidney Neoplasms/therapy , Adult , Aged , Antineoplastic Agents/adverse effects , Cancer Vaccines/adverse effects , Cancer Vaccines/immunology , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/mortality , Disease-Free Survival , Female , Humans , Interleukin-2/adverse effects , Kaplan-Meier Estimate , Kidney Neoplasms/immunology , Kidney Neoplasms/mortality , Male , Membrane Glycoproteins/immunology , Middle Aged , Vaccination/adverse effects , Vaccination/methods , Vaccines, DNA , Vaccinia virus/immunology
11.
Int Immunol ; 20(8): 1057-66, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18567615

ABSTRACT

UNLABELLED: The cancer vaccine TroVax, modified vaccinia Ankara encoding the tumor-associated antigen 5T4, has been tested in phase I and II studies in colorectal cancer patients. Monitoring of 5T4-specific immune responses in patients receiving TroVax is critical since it could inform future refinements to the therapeutic or provide a surrogate marker of clinical efficacy. Tumor-specific cytotoxic T lymphocyte (CTL) are considered to be a key component of an effective anti-cancer immune response. Though numerous techniques have been employed to identify CTL epitopes, many are labor intensive, of variable reliability or biased toward common alleles such as human leukocyte antigen (HLA)-A2. A new high-throughput technique, iTopia, enables peptides to be evaluated on the basis of their physical binding properties for HLA alleles. This technique has been utilized to rapidly screen a panel of overlapping peptides, spanning the length of 5T4. Initially, peptides which bound to four class I alleles (A*0101, A*0201, A*0301 and B*0702) were identified and their physical binding characteristics assessed further by analysis of relative affinity and complex stability. 46 putative CTL epitopes have been identified which bind to at least one of the four HLA alleles. Using PBMCs from patients vaccinated with TroVax, we have used the interferon gamma (IFN gamma) ELISpot assay to validate one predicted A1 and two A2 epitopes. CONCLUSION: iTopia represents a rapid and high-throughput technique to identify CTL epitopes.


Subject(s)
Antigens, Neoplasm/immunology , Cancer Vaccines/immunology , Colorectal Neoplasms/immunology , Epitopes, T-Lymphocyte/immunology , Membrane Glycoproteins/immunology , Neoplasms, Glandular and Epithelial/immunology , T-Lymphocytes, Cytotoxic/metabolism , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Epitope Mapping , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/metabolism , HLA-A Antigens/chemistry , HLA-A Antigens/metabolism , HLA-B Antigens/chemistry , HLA-B Antigens/metabolism , Humans , Interferon-gamma/metabolism , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Membrane Glycoproteins/chemistry , Membrane Glycoproteins/metabolism , Neoplasms, Glandular and Epithelial/pathology , Neoplasms, Glandular and Epithelial/therapy , Peptides/chemistry , Peptides/immunology , Peptides/therapeutic use , Protein Binding , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/pathology , Vaccines, DNA
12.
Cancer Immunol Immunother ; 57(7): 977-86, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18060404

ABSTRACT

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 5-fluorouracil, leukovorin and irinotecan. TroVax was administered to 19 patients with metastatic colorectal cancer. Twelve patients had blood samples taken following each of the six injections and were considered to be evaluable for assessment of immunological responses. Both antibody and cellular responses specific for the tumor antigen 5T4 and the viral vector MVA were monitored throughout the study. Administration of TroVax alongside chemotherapy was safe and well tolerated with no SAEs attributed to the vaccine and no enhancement of chemo-related toxicity. Of the 12 patients who were evaluable for assessment of immune responses, ten mounted 5T4-specific antibody responses with titers ranging from 10 to > 5,000. IFNgamma ELISPOT responses specific for 5T4 were detected in 11 patients with frequencies exceeding one in 1,000 PBMCs in five patients. Eight patients presented with elevated circulating CEA concentrations, six of whom showed decreases in excess of 50% during chemotherapy and four had CEA levels which remained stable for > 1 month following completion of chemotherapy. Of the 19 intention to treat (ITT) patients, one had a CR, six had PRs and five had SD. Potent 5T4-specific cellular and/or humoral immune responses were induced in all 12 evaluable patients and were detectable in most patients during the period in which chemotherapy was administered. These data demonstrate that TroVax can be layered on top of chemotherapy regimens without any evidence of enhanced toxicity or reduced immunological or therapeutic efficacy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer Vaccines/therapeutic use , Colorectal Neoplasms/drug therapy , Aged , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cancer Vaccines/adverse effects , Cancer Vaccines/immunology , Colorectal Neoplasms/immunology , Combined Modality Therapy , Female , Fluorouracil/administration & dosage , Humans , Immunotherapy , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Vaccines, DNA
13.
Clin Cancer Res ; 13(15 Pt 1): 4487-94, 2007 Aug 01.
Article in English | MEDLINE | ID: mdl-17671134

ABSTRACT

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. IFNgamma 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.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer Vaccines/therapeutic use , Colorectal Neoplasms/therapy , Vaccinia virus/genetics , Adult , Aged , Cancer Vaccines/immunology , Colorectal Neoplasms/diagnostic imaging , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Enzyme-Linked Immunosorbent Assay , Female , Fluorouracil/administration & dosage , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/immunology , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Lymphatic Metastasis , Male , Membrane Glycoproteins/immunology , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Tomography, X-Ray Computed , Vaccination , Vaccines, DNA
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