Adjuvant Active Specific Immunotherapy Research Articles

Extent and Location of Tumor-Infiltrating Lymphocytes in Microsatellite-Stable Colon Cancer Predict Outcome to Adjuvant Active Specific Immunotherapy.

To determine the prognostic and predictive value of tumor-infiltrating lymphocytes (TIL) in colon cancer in a cohort of patients who previously took part in a trial on adjuvant active specific immunotherapy (ASI). We determined the number and location of CD3 and CD8 positive T cells in archival tumor samples of 106 colon cancers. We correlated stromal and epithelial TIL numbers with tumor stage and treatment and determined the effects on disease-specific survival (DSS) and recurrence-free interval (RFI). On the basis of the data presented, we concluded that (i) high numbers of stromal CD3 T cells have positive prognostic value measured as DSS for patients with stage II microsatellite-stable tumors and (ii) high numbers of epithelial CD8-positive T cells have positive prognostic value measured as RFI for the group of patients with stage II microsatellite-stable tumors as well as for the whole group (so stage II plus stage III together). Furthermore, we concluded that high numbers of pre-existing stromal CD3-positive T cells are of positive predictive value in adjuvant ASI treatment measured as DSS as well as RFI. ASI therapy may contribute to an improved DSS and RFI in patients with microsatellite-stable colon tumors harboring high numbers of pre-existing stromal CD3(+) TIL. Validation in future clinical trials is awaited.

Extent and location of tumor infiltrating lymphocytes in microsatellite stable colon cancer predict outcome to adjuvant active specific immunotherapy

Meeting abstracts To determine the prognostic and predictive value of tumor infiltrating lymphocytes (TIL) in colon cancer in a cohort of patients who previously took part in a trial on adjuvant Active Specific Immunotherapy (ASI). Vermorken et al.[[1][1]] conducted a multicenter clinical trial on

Abstract 1649: Extent and location of tumor infiltrating lymphocytes in colon cancer predicts outcome to adjuvant active specific immunotherapy

Abstract Purpose: We investigated the prognostic and predictive value of tumor infiltrating lymphocytes (TIL) in colorectal cancer in a cohort of patients who previously took part in a trial on adjuvant Active Specific Immunotherapy (ASI). Experimental Design: We determined the numbers of CD3+ and CD8+ cells in archival tumor samples of 110 colorectal cancer patients as total infiltrating TIL, intraepithelial TIL and stromal TIL. Survival curves were used to determine the prognostic and predictive value of TIL. Results: Patients with microsatellite instable (MSI) tumors had higher numbers of intraepithelial CD3+ and CD8+ TIL compared to patients with microsatellite stable (MSS) tumors. Patients with MSI tumors had a good prognosis. Patients with MSS cancers with high intraepithelial or stromal TIL numbers had a better prognosis compared to those with low TIL numbers. Significant survival benefits were found for the disease specific survival (DSS) and recurrence free interval (RFI) for patients with high infiltrates of stromal CD3+ or intraepithelial CD8+ cells. Additionally high numbers of total CD8+ and high stromal CD8+ cells gave a significant difference in RFI compared to low TIL numbers. The numbers of TIL found in MSS tumors also have predictive value with respect to response to adjuvant ASI treatment. Compared to controls significance was reached in ASI treated patients with high total CD3, high stromal CD3 or high stromal CD8 numbers in DSS as well as RFI. Conclusion: ASI therapy is effective in patients with MSS colorectal tumors harboring high numbers of preexisting stromal CD3 or CD8 positive TIL. Citation Format: Erik Hooijberg, Annelies W. Turksma, Marc Shamier, Kevin Lam, Veerle MH Coupe, Vincent A. de Weger, Jeroen AM Belien, Alfons J. van den Eertwegh, Gerrit A. Meijer, Chris JLM Meijer. Extent and location of tumor infiltrating lymphocytes in colon cancer predicts outcome to adjuvant active specific immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1649. doi:10.1158/1538-7445.AM2014-1649

Clinical Effects of Adjuvant Active Specific Immunotherapy Differ between Patients with Microsatellite-Stable and Microsatellite-Instable Colon Cancer

Active specific immunotherapy (ASI) consisting of an autologous tumor cell vaccine given as adjuvant treatment has been shown to improve recurrence-free survival of patients with colon cancer. The aim of the current retrospective study was to investigate whether the beneficial effects of ASI given as adjuvant treatment correlated with microsatellite instability (MSI), which is considered an important biologic determinant of colon cancer. Microsatellite status was assessed on archival tumor material from patients with stage II and III colon cancer. Microsatellite status was next associated with clinical outcome in control and ASI treatment groups using Kaplan-Meier analysis. We identified 162 (83%) microsatellite-stable tumors (MSS) and 34 (17%) MSI tumors. Patients with MSI tumors did well in recurrence-free interval (RFI) as well as disease-specific survival (DSS) irrespective of treatment arm and tumor stage. Patients with MSI tumors had significantly fewer recurrences and prolonged DSS than those with MSS tumors. Patients with MSS Dukes B tumors who received ASI treatment showed a significantly improved recurrence-free survival compared with controls. ASI treatment did not improve recurrence-free interval or DSS for patients with MSS Dukes C tumors. This retrospective study indicated that patients with MSI tumors did well, irrespective of treatment arm and tumor stage. The data also indicate that the clinical benefit, measured as recurrence-free survival, from adjuvant ASI treatment of patients with colon cancer was restricted to patients with MSS Dukes B tumors.

Active Specific Immunotherapy, given as adjuvant treatment, improves survival of patients with microsatellite stable colorectal tumors, but not of patients with microsatellite instable colorectal tumors

It has been documented that Active Specific Immunotherapy (ASI), given as adjuvant treatment, improves survival of patients with stage II and III colorectal cancer. Here we report on the effects of adjuvant ASI in patients with Micro Satellite Stable (MSS) versus Micro Satellite Instable (MSI) tumors. From 196 patients with stage II or stage III colorectal cancer who previously participated in the ASI trial published by Vermorken et al. in the Lancet (1999;353:345–50), we collected frozen tumor samples and/or paraffin-embedded tumor material. From this material DNA was extracted and microsatellite status was assessed. Kaplan–Meier curves were plotted to determine survival associations with microsatellite status and treatment group (placebo versus adjuvant ASI treatment). From 196 of the original 256 patients participating in the trial we retrieved good quality archival tumor DNA for further analysis of microsatellite status. We subsequently identified 162 (83%) Micro Satellite Stable tumors and 34 (17%) Micro Satellite Instable tumors. Irrespective of microsatellite status, the current study showed a significant survival benefit for those patients receiving ASI treatment (P = 0.012), as expected based on the results of Vermorken et al. New to this is that irrespective of treatment, patients with MSI tumors showed significantly fewer recurrences than patients with MSS tumors (P = 0.03). Taking both MS status and treatment into account, we found no significant difference in survival between ASI versus placebo treated patients bearing MSI tumors. In contrast to this, we found that patients with MSS tumors benefited from ASI treatment in that ASI treated patients showed significantly improved survival (P < 0.05). It can be concluded that ASI will benefit only patients with MSS tumors, since only they showed significant improved survival upon ASI therapy. For the MSI group there is most likely no benefit of ASI therapy.

Abstract 3741: Adjuvant active specific immunotherapy improves survival of patients with micro-satellite stable colorectal tumors, but not with micro-satellite instable tumors

Abstract Purpose: It has been documented that Active Specific Immunotherapy (ASI), given as adjuvant treatment, improves survival of patients with stage II and III colorectal cancer (CRC). Here we report on the effects of ASI on Micro-Satellite Stable (MSS) versus Micro-Satellite Instable (MSI) tumors. Materials and Methods: From 196 patients with stage II or stage III CRC who previously participated in the ASI trial published previously (Vermorken et al. Lancet), we collected frozen tumor samples and/or paraffin embedded tumor material. From this material DNA was extracted and microsatellite stability status was assessed. Microsatellite status was associated with clinical outcome in both the placebo and ASI treatment groups using Kaplan Meier analysis. Results: From 196 patients participating in the trial we retrieved good quality archival tumor DNA for further analysis of microsatellite stability (MS). We subsequently identified 162 (83%) MSS tumors and 34 MSI (17%) tumors. Irrespective of MS status a significant survival benefit for patients receiving ASI treatment (P=0.012) was observed, confirming previous results. New to this is that irrespective of treatment, patients with MSI tumors showed significantly less recurrences than patients with MSS tumors (P = 0.03). Taking both MS status and treatment into account we found no significant difference in survival between ASI treated versus placebo receiving patients with MSI tumors. In contrast, patients with MSS tumors benefited from ASI treatment showing a significantly improved recurrence free survival (P=&amp;lt;0,05). Conclusion: It can be concluded that only patients with MSS tumors will benefit from adjuvant ASI since only they showed significant improved recurrence free survival on ASI therapy. For the MSI group there is most likely no benefit of ASI therapy. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3741.

A Phase II Prospective Multi-Institutional Trial of Adjuvant Active Specific Immunotherapy Following Curative Resection of Colorectal Cancer Hepatic Metastases: Cancer and Leukemia Group B Study 89903

A Phase II Prospective Multi-Institutional Trial of Adjuvant Active Specific Immunotherapy Following Curative Resection of Colorectal Cancer Hepatic Metastases: Cancer and Leukemia Group B Study 89903

A Phase II Prospective Multi-institutional Trial of Adjuvant Active Specific Immunotherapy Following Curative Resection of Colorectal Cancer Hepatic Metastases: Cancer and Leukemia Group B Study 89903

Patients with curatively resected colorectal cancer hepatic metastases often harbor occult metastatic disease and are at high risk of experiencing recurrence. This patient cohort is ideally suited to test novel therapies such as immunotherapy. We treated patients-post-hepatic resection-with anti-idiotype monoclonal antibody vaccines to the tumor-associated antigens carcinoembryonic antigen (CeaVac) and human milk fat globule (TriAb), both of which are co-expressed in more than 90% of colorectal cancer patients. Vaccinations commenced 6-12 weeks post-hepatic resection and consisted of four biweekly treatments of 2 mg CeaVac and TriAb, then monthly treatments for 2 years, then on every other month for 3 years. The primary endpoint was to investigate the proportion of patients recurrence-free at 2 years, and the objective of the study was to demonstrate that at least 58% would be recurrence-free at this time to consider the regimen worthy of further study. Between July 2001 and October 2004, 56 patients were accrued; 52 patients with margin-negative resection were eligible for analysis. Hepatic lobectomy was performed in 56% of patients with a median of one metastasis (range 1-3). Of the 52 eligible patients, 49 were evaluable for the primary end point. Median follow-up was 3.1 years. The proportion of patients recurrence-free at 2 years was 39%, with a lower confidence bound (LCB) of 0.29. Median recurrence-free survival was 16 months. The 2-year overall survival was 94% (95% CI, 0.81, 0.98). Only 10% of patients had documented grade-3 adverse events. Anti-idiotype monoclonal antibody vaccine therapy with CeaVac and TriAb as an adjuvant to curative resection of colorectal cancer hepatic metastases is well tolerated but did not improve 2-year recurrence-free survival when compared with the expected value of 40% reported for hepatic resection alone.

Somatic gene mutations predict outcome of patients receiving adjuvant active specific immunotherapy after resection of stage IV melanoma

7522 Background: Cyoreductive surgery plus adjuvant active specific immunotherapy can improve prognosis in stage IV melanoma, if patients are carefully selected. Chemokine receptor 5 (CCR5) is involved in T-cell immunity and dendritic cell activation. Interleukin-10 (IL-10) is immunosuppressive in melanoma. We hypothesized that a somatic CCR5 gene mutation (delta) 32 bp deletion, in conjunction with increasing CD14-derived IL-10 might reflect an unfavorable immune response and ultimately a poorer survival after complete resection and postoperative immunotherapy for stage IV melanoma. Methods: Stage IV melanoma patients enrolled for at least 6 months in phase II trials of Canvaxin specific active immunotherapy (CancerVax Corp, Carlsbad, CA) after complete resection were randomly identified. Genomic DNA extracted from peripheral blood monocytes (PBM) was screened for CCR5 mutation; PCR product size and sequencing verified mutations. Double-staining flow cytometry of serial PBM specimens determined IL-10 levels from CD14+ monocytes. Statistical tests were log-rank, chi-square and student’s T-test. Results: Of the 91 patients, 53 (58%) were men. Median age was 47 years (range, 19–82). Twenty-eight (31%) patients had M1a, 22 (24%) M1b, and 41 (45%) had M1c metastases. Seventy-four (81%) patients had wild-type (Wt) CCR5 gene, 13 (14%) had heterozygous (HtM) CCR5 mutation, and 4(5%) had homozygous (HoM) mutation. At a median follow-up of 38 months, 5-year survival was significantly (p=0.031) higher with Wt CCR5 than HtM/HoM CCR5 (55.6±6.1% vs. 21.4±10.8%). Increasing IL-10 levels (n=10) combined with CCR5 mutation decreased median survival to 9 months and eliminated 5-year survival; by contrast, Wt CCR5 plus decreasing IL-10 was associated with 5-year survival of 76±5% (p<0.0001). Multivariate analyses confirmed the prognostic superiority of CCR5 mutation and IL-10 level vs. age, gender or M stage. Conclusions: Somatic mutations of CCR5 and increasing expression of CD14-derived IL-10 were correlated with poor outcome in stage IV melanoma. These somatic-derived gene products might be used to identify patients for active specific immunotherapy or other treatments. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CancerVax CancerVax

Immunomodulation of responses to active immunization with a polyvalent immunotherapeutic: cyclophosphamide, H2 blockade, IL-2/IFNα and GM-CSF

2564 Background: Strong humoral and cellular immune responses in patients with melanoma receiving a specific active immunotherapeutic (Canvaxin; CancerVax Corp, Carlsbad, CA) have been correlated with improved survival. We examined the impact of several immunomodulators on the strength of immune response. Methods: Analysis of sequential phase II clinical trials using Canvaxin alone (n=446) or in combination with cyclophosphamide (n=92), cimetidine (n= 357), indomethacin (n=54) or IL-2/INFα (n=71) was performed with regard to maximal immune response within 16 weeks of treatment. A randomized clinical trial (n= 97) of Canvaxin with or without the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was also analyzed. Delayed-type hypersensitivity (DTH) to vaccine was measured in all trials. IgM and IgG responses to the TA90 tumor-associated antigen were measured prospectively in the GM-CSF trial. Results: DTH responses were greater in patients with stage IV melanoma with concurrent cyclophosphamide (mean induration 20.6 mm with cyclophosphamide vs. 14.2 without, p=0.011). This was not seen in patients with stage III disease or in any stage with cimetidine, indomethacin or IL-2/IFNα treatment. The randomized GM-CSF trial did not show a significant difference (by logistic regression) in maximal DTH response (15.9± 9.7 mm with GM-CSF vs. 16.7 ± 9.9 mm without). There was a significant increase in maximal anti-TA90 IgM titers in the GM-CSF arm (797 ± 622 vs. 541 ± 533; p=0.0123), but no difference in anti-TA90 IgG (680 ± 557 with GM-CSF vs. 612 ± 510 without GM-CSF.) Maximal absolute lymphocyte counts during treatment were also elevated in the GM-CSF arm. Adverse event profiles were not markedly different, but GM-CSF patients reported more grade 1–2 fatigue. Conclusions: These data suggest that the addition of cyclophosphamide to adjuvant active specific immunotherapy in stage IV melanoma impacts DTH responses, and GM-CSF increases IgM response. Since this represents an impact on both the cellular (DTH) and humoral (IgM) arms of immunity, further study of modulator combinations is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CancerVax CancerVax

Adjuvant active specific immunotherapy of stage II and stage III colon cancer with an autologous tumor cell vaccine: first randomized phase III trials show promise

We performed three multi-institutional, prospectively randomized, controlled clinical trials, assessing the therapeutic effect of post-resection adjuvant active specific immunotherapy in patients with stage II and stage III colon cancer. In each study four outcomes were considered: time-to-disease recurrence, overall survival intervals, disease-free survival intervals, and recurrence-free survival intervals using the Kaplan–Meir method for generating curves and the log-rank test used to compare efficacy distributions. In addition, a meta-analysis of the three phase III trials was performed since the trials had proven homogeneity. Two main analyses were performed: (1) the intent-to-treat colon cancer patients from all three studies; and (2) analyzable colon cancer patients in all three studies. The conclusion of these analyses is that adjuvant active specific immunotherapy provided significant clinical benefits in patients with stage II colon cancer and appears to be an important new adjuvant treatment for these patients.

Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial

Colon cancer is curable by surgery, but cure rate depends on the extent of disease. We investigated whether adjuvant active specific immunotherapy (ASI) with an autologous tumour cell-BCG vaccine with surgical resection was more beneficial than resection alone in stage II and III colon cancer. In a prospective randomised trial, 254 patients with colon cancer were randomly assigned postoperative ASI or no adjuvant treatment. ASI was three weekly vaccinations starting 4 weeks after surgery, with a booster vaccination at 6 months with 10(7) irradiated autologous tumour cells. The first vaccinations contained 10(7) BCG organisms. We followed up patients for time to recurrence, and recurrence-free and overall survival. Analysis was by intention to treat. The 5.3 year median follow-up (range 8 months to 8 years 11 months) showed 44% (95% CI 7-66) risk reduction for recurrence in the recurrence-free period in all patients receiving ASI (p=0.023). Overall, there were 40 recurrences in the control group and 25 in the ASI group. Analysis by stage showed no significant benefit of ASI in stage III disease. The major impact of ASI was seen in patients with stage II disease, with a significantly longer recurrence-free period (p=0.011) and 61% (18-81) risk reduction for recurrences. Recurrence-free survival was significantly longer with ASI (42% risk reduction for recurrence or death [0-68], p=0.032) and there was a trend towards improved overall survival. ASI gave significant clinical benefit in surgically resected patients with stage II colon cancer. ASI has minimal adverse reactions and should be considered in the management of stage II colon cancer.

Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial

Background: A phase III, randomized, double-blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia melanoma oncolysate (VMO) was performed in patients with stage III (American Joint Commission on Cancer) melanoma to determine the efficacy of VMO to increase the disease-free interval (DFI) or overall survival (OS) in these patients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using VMO, two subsets—men aged 44–57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease—showed an overall survival advantage with VMO therapy. A final analysis of data from this trial was performed in May 199 6 and is reported here. The design of future melanoma vaccine trials is discussed based on information learned from this first randomized, multicenter trial of ASI therapy. Study Design: A polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus (V). Patients were accrued from 11 United States institutions and were randomized by the Statistical Center at the University of Alabama, Birmingham. Two hundred fifty patients were randomized to treatment with either VMO (1 U containing 2 mg of total protein derived from 5 × 10 6 melanoma cells and 10 5.6 50% tissue culture infectious dose of vaccinia virus) or control V (1 U containing 10 5.4 50% tissue culture infectious dose of vaccinia virus) once a week for 13 weeks and then once every 2 weeks for a total of 12 months, or until recurrence. Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis. Results: Two hundred seventeen patients were found to be eligible according to the inclusion criteria. Data from these patients were analyzed for DFI and OS after a median followup of 46.3 months (50.2 months for VMO and 41.3 months for V). This final analysis showed no statistically significant increase in either DFI (p = 0.61) or OS (p = 0.79) of patients treated with VMO (n = 104) compared with V (n = 113). At 2-, 3-, and 5-year intervals, 47.8%, 43.8%, and 41.7% of patients treated with VMO were disease-free, respectively, compared with 51.2%, 44.8%, and 40.4% of patients treated with V. At the same intervals, 70.0%, 60.0%, and 48.6% of patients treated with VMO survived, compared with 65.4%, 55.6%, and 48.2% of patients treated with V. In a retrospective subset analysis, male patients aged 44–57 years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3% improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treatment with VMO when compared with V (n = 18) (p = 0.046). Conclusions: This study was a randomized, multicenter, placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO when compared with V showed no difference in either DFI or OS. In a retrospective subset analysis, however, a subset of men with one to five positive nodes, between the ages of 44 and 57 years, showed a survival advantage with VMO. This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma. An appropriate control arm also must be included in ASI trials.

Therapeutic benefit of adjuvant active specific immunotherapy (A.S.I.) with autologous tumor-vaccines in patients with colon cancer. Results of a randomised fase III study

Therapeutic benefit of adjuvant active specific immunotherapy (A.S.I.) with autologous tumor-vaccines in patients with colon cancer. Results of a randomised fase III study

Therapeutic benefit of adjuvant active specific immunotherapy (A.S.I.) with autologous tumor-vaccines in patients with colon cancer. Results of a randomised fase III study

Therapeutic benefit of adjuvant active specific immunotherapy (A.S.I.) with autologous tumor-vaccines in patients with colon cancer. Results of a randomised fase III study

999 Newcastle disease virus infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma

An active specific immunization (ASI) procedure with two types of autologous tumor cell vaccines (ATV) is tested for adjuvant immunotherapy of resected colorectal carcinoma to provide preliminary information on local immunological skin responses, side effects and two year survival rates. For vaccine preparation, the tumor derived freshly isolated and cryopreserved cells were thawed, purified by PercolI density centrifugation and depleted of tumor infiltrating lymphocytes by immunomagnetic-beads. Atter inactivation by 200 Gy, the cells of this ATV were either infected by Newcastle Disease Virus (NDV) or they were admixed with Bacillus Calmette Guerin (BCG) organisms. Vaccination was performed in the arm beginning 6–8 weeks after operation, 3 times at two week intervals. Of 57 patients that received ASI, 48 were treated by virus infected autologous tumor cell vaccine (ATV-NDV) and 9 with the BCG admixed vaccine (ATV/BCG). The mean value of delayed hypersensitivity skin reactions (DTH) from ATV-NDV treated patients was 18 mm for the first vaccination and 26 and 29 mm for the following ones. While application of ATV-NDV was associated with only mild side effects, the ATV/BCG vaccine lead to long lasting ulcers and to more serious side-effects. The 2 year survival rates obtained with ATV-NDV was 97.9% while the survival rate with ATV/BCG was 66.7% (P Thus, the type and quality of the tumor vaccine for ASI-treatment appears to be important. The findings with ATV-NDV necessitate corroboration in a prospective randomised controlled study

A phase III randomized, doúble-blind, multiinstitutional trial of vaccinia melanoma oncolysate-active specific immunotherapy for patients with stage II melanoma

In a Phase II trial, surgical adjuvant active specific immunotherapy using a live vaccinia virus-augmented allogeneic polyvalent melanoma cell lysate, vaccinia melanoma oncolysate (VMO), produced a significant disease free interval (DFI) in patients with International Union Against Cancer Stage II melanoma with positive lymph nodes. Therefore, a Phase III randomized prospective, double-blind, multiinstitutional, surgical adjuvant VMO trial was performed to determine the efficacy of VMO to increase the DFI and the overall survival in this group of patients with Stage II disease. Two hundred and fifty patients with Stage II melanoma were divided into two postsurgical groups. One group received VMO (total protein equals 2 mg/ml) and the other received the placebo of live vaccinia vaccine virus (V) (10(5.4) TCID50/ml), an adjuvant component of the VMO. Patients initially received these biologics once a week for 13 weeks and then once every 2 weeks for an additional 39 weeks or until recurrence. All surviving patients have been followed for at least 30 months. Statistical analysis of survival data (n = 217) for this first interim analysis shows that there is no statistically significant (P = 0.99) increase in DFI of patients treated with VMO (n = 104) when compared with V (n = 113). The median DFI is 38.0 months for patients treated with VMO and 37.0 months for patients treated with V. At 2- and 4-year intervals, 70 and 38%, respectively, of patients treated with VMO vs. 66 and 36%, respectively, of patients treated with V were free of melanoma. The median overall survival is not available because the patients treated with VMO have not yet reached the 50% mark and the median overall survival is 45.0 months for patients treated with V. At 2- and 4-year intervals, 70 and 38%, respectively, of VMO-treated patients survived when compared with 66 and 36%, respectively, of patients treated with V. Although the overall survival of patients treated with VMO is not statistically significant (P = 0.88) at this point, there is an increasing trend in the overall survival of patients treated with VMO; a 10% increase at the 4-year time point. Moreover, in the subset analysis, VMO-treated male patients (n = 63) showed a 17% improvement in survival at 4-year time point when compared with male patients treated with V (n = 67) (P = 0.19) at the same time point and male patients (n = 20) between the ages of 44 and 57 having 1-5 positive lymph nodes showed a 37% difference in overall survival at the 4-year time point when compared with those patients treated with V (n = 18) (P = 0.13) at the same time point. In this first interim analysis, active specific immunotherapy with VMO vs. V showed no difference in the disease free interval or overall survival. Subset analyses likewise showed no significant differences in outcome but the data suggest a potential difference in immunoreactivity between male and female patients with melanoma that awaits further follow up and may merit further investigation.

Prospectively randomized trial of adjuvant active-specific immunotherapy for human colorectal cancer

Prospectively randomized trial of adjuvant active-specific immunotherapy for human colorectal cancer