Serological immune responses to influenza vaccine in patients with colorectal cancer

Background

The immune responses to influenza vaccination in patients with colorectal cancer on surveillance or active chemotherapy have not been previously reported. We conducted a prospective influenza vaccination study to determine the serological immune response rate in patients with colorectal cancer.

Methods

During the 2006?C2007 influenza season, patients with colorectal cancer treated at Roswell Park Cancer Institute were offered vaccination with the trivalent influenza vaccine (Fluzone^?, 2006?C2007). Blood samples for hemagglutination inhibition (HI) assay titers were collected before and 3?months after vaccination. Response to vaccination was determined using an endpoint of ??1:40 HI titer ratio or a fourfold HI increase at 3?months from vaccination. A response in HI to at least one of the 3 strains was considered an immune response.

Results

Eighty-five patients with colorectal cancer participated in the study. The immune response in the overall population was 70.6%. No differences in response were noted between the 58 patients on active chemotherapy and the 27 patients on surveillance [Odds Ratio (OR)?=?0.78; P?=?0.8]. The odds of response did not vary by chemotherapy regimen or by chemotherapy-vaccination timing. HI response in all 3 titers concurrently were low in both the chemotherapy (12.1%) and surveillance groups (11.1%) (OR?=?1.10; P?=?1).

Conclusions

Patients with colorectal cancer mount an immune response to influenza vaccination irrespective of their chemotherapy regimen or timing. However, concurrent responses to all three strains in the individual patient with colorectal cancer are uncommon. The investigation of a booster vaccine in this population is warranted.     

Multiple-dose granulocyte-macrophage-colony-stimulating factor plus 23-valent polysaccharide pneumococcal vaccine in patients with chronic lymphocytic leukemia: a prospective, randomized trial of safety and immunogenicity

BACKGROUND: For the current study, the authors sought to determine whether administration of multiple-dose granulocyte-macrophage-colony-stimulating factor (GM-CSF) could improve response to standard 23-valent polysaccharide pneumococcal vaccine (PPV) in patients with chronic lymphocytic leukemia (CLL). METHODS: Patients were allocated randomly to receive PPV either alone or with 3 doses of GM-CSF (250 microg) given before or after vaccination. Serum was obtained before, 4 weeks after, and 12 weeks after vaccination for antibody determination. Thirty-two patients with CLL were given PPV. They were randomized to receive 3 doses of GM-CSF either before or after vaccination or to receive no GM-CSF. RESULTS: A 4-fold rise in immunoglobulin G (IgG) to capsular polysaccharides from Streptococcus pneumoniae types 4, 6B, 9V, 14, 19F, and 23F occurred in <10% of patients in each of the 3 groups. There were no differences in geometric mean IgG levels in any of the 3 groups 4 weeks or 12 weeks after vaccination. CONCLUSIONS: In patients with CLL, the response to pure polysaccharide pneumococcal vaccine was low despite immune enhancement with multiple doses of GM-CSF. In all patients, reactogenicity was minor.     

Clinical Efficacy of a Vaccine-Immunostimulant Combination in the Prevention of Influenza in Patients with Chronic Obstructive Pulmonary Disease and Chronic Asthma

Abstract

Influenza is a leading cause of morbidity and mortality in patients with chronic respiratory diseases. This study compares two influenza prevention schemes in patients with chronic obstructive pulmonary disease and chronic asthma. We enrolled 66 patients, distributed as follows: Group A: 32 subjects treated with influenza vaccine; Group B: 34 patients treated with influenza vaccine and bacterial immunostimulant. The rate of influenza episodes was recorded. Hemoagglutination inhibiting antibody titers for vaccine strains H1N1, H3N2, and B were determined at time 0 (prior to vaccination), and on days 30 and 90 following vaccination. We observed a lower rate of influenza episodes in Group B patients (8.82%) compared to Group A (31.25%) (p<0.05). At day 90 Group B patients presented higher geometric mean antibody titers for strains H1N1 (p=0.07) and H3N2 (p=0.08). Bacterial immunostimulants appear as possible adjuvants in the prevention of influenza episodes, and may prolong antibody response to influenza vaccine strains.     

Influenza vaccination in patients with cancer: an overview

Influenza infection is a potential cause of additional morbidity and mortality in patients who are immunocompromised because of cancer or its treatment. Of particular note, influenza infection may delay or interrupt chemotherapy and necessitate hospitalization. Successful immunization depends on an intact immune system that can produce antibodies in response to antigen exposure. Patients with cancer often have a suppressed immune system, resulting from their disease and/or immunosuppressive therapies, and as a consequence they may have a suboptimal serologic response to influenza vaccination. Since vaccination is the only proven method for preventing influenza infection, the Advisory Committee on Immunization Practices recommends seasonal influenza vaccination for adults without contraindications who have disease- or medication-related immunosuppression. Patients with cancer should be given the trivalent inactivated vaccine. Preliminary data suggest that administering the vaccine between cycles of chemotherapy may yield the best results.     

BTLA expression declines on B cells of the aged and is associated with low responsiveness to the trivalent influenza vaccine

Virus-neutralizing antibody and B cell responses to influenza A viruses were measured in 35 aged and 28 middle-aged individuals following vaccination with the 2012 and 2013 trivalent inactivated influenza vaccines. Antibody responses to the vaccine strains were lower in the aged. An analysis of B cell subsets by flow cytometry with stains for immunoregulators showed that B cells of multiple subsets from the aged as compared to younger human subjects showed differences in the expression of the co-inhibitor B and T lymphocyte attenuator (BTLA). Expression of BTLA inversely correlated with age and appears to be linked to shifting the nature of the response from IgM to IgG. High BTLA expression on mature B cells was linked to higher IgG responses to the H1N1 virus. Finally, high BTLA expression on isotype switched memory B cells was linked to better preservation of virus neutralizing antibody titers and improved recall responses to vaccination given the following year.     

Immunogenicity of influenza vaccine in patients with hemato-oncological disorders

The aim of this study was to measure the production of antihemagglutinin and antineuraminidase antibodies in patients with proliferative diseases of the hematopoietic or lymphatic system, immunized with influenza vaccine in the epidemic season 1995/96. Twenty patients between 22 and 84 years volunteered for vaccination and were vaccinated subcutaneously with a single dose of split trivalent influenza vaccine ("Fluarix", SmithKline Beecham) in autumn 1995 at the outpatients clinic, General Hospital, Toruń, Poland, where they were being treated with anti-cancer chemotherapy. The vaccine consisted of a 0.5 ml dose containing 15 microg hemagglutinin (HA) of each of the following strains: A/Singapore/6/86 (H1N1), A/Johannesburg/33/94 (H3N2) and B/Beijing/184/93. Neuraminidase activity amounted to 17.24x10(-3) U/ml. Antibody production was determined in sera collected before vaccination, 10 days and 28 days after vaccination by the hemagglutinin inhibition test (HI) and neuraminidase inhibition test (NI). Mean fold increase values after vaccination were statistically significant in patients undergoing cytostatic treatment. After 28 days mean fold increase of antihemagglutinin antibodies ranged from 7.9 to 25.2, while in the case of antineuraminidase antibodies these values were between 12.4 and 14.3. It is notable that no adverse reactions were observed after immunization and none of the patients was infected with influenza virus, in spite of the fact that there was a local epidemic in the Toruń region when the study was carried out. The results presented in this paper confirm the beneficial effect of influenza vaccination in high-risk groups of patients with proliferative diseases of the hematopoietic and lymphatic systems.     

The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma.

Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to be an effective vaccine adjuvant because it enhances antigen processing and presentation by dendritic cells. ALVAC-CEA B7.1 is a canarypox virus encoding the gene for the tumor-associated antigen carcinoembryonic antigen (CEA) and for a T-cell costimulatory molecule, B7.1. After an initial dose escalation phase, this study evaluated vaccination with 4.5 x 10(8) plaque-forming units ALVAC-CEA B7.1 alone (n = 30) or with GM-CSF (n = 30) in patients with advanced CEA-expressing tumors to determine whether the addition of the adjuvant GM-CSF enhances induction of CEA-specific T-cells. Patients were vaccinated with vaccine intradermally every other week for 8 weeks. GM-CSF was given s.c. for 5 days beginning 2 days before vaccination. Patients with stable or responding disease after four immunizations received monthly boost injections alone or with GM-CSF. Biopsies of vaccine sites were obtained 48 h after vaccination to evaluate leukocytic infiltration and CEA expression. Induction of peripheral blood CEA-specific T-cell precursors was assessed in HLA-A2 positive patients by an ELISPOT assay looking for the production of IFN-gamma. Therapy was well tolerated. All of the patients had evidence of leukocytic infiltration and CEA expression in vaccine biopsy sites. In the patients receiving GM-CSF, leukocytic infiltrates were greater in cell number but were less likely to have a predominant lymphocytic infiltrate compared with patients receiving vaccine in the absence of the cytokine adjuvant. After four vaccinations, CEA-specific T-cell precursors were statistically increased in HLA-A2 positive patients who received vaccine alone. However, the GM-CSF plus vaccine cohort of HLA-A2 positive did not demonstrate a statistically significant increase in their CEA-specific T-cell precursor frequencies compared with baseline results. The number of prior chemotherapy regimens was negatively correlated with the generation of a T-cell response, whereas there was a positive correlation between the number of months from the last chemotherapy regimen and the T-cell response. ALVAC-CEA B7.1 is safe in patients with advanced, recurrent adenocarcinomas that express CEA, is associated with the induction of a CEA-specific T-cell response in patients treated with vaccine alone but not with vaccine and GM-CSF, and can lead to disease stabilization for up to 13 months.     

Prostate-specific antigen kinetics as a measure of the biologic effect of granulocyte-macrophage colony-stimulating factor in patients with serologic progression of prostate cancer.

PURPOSE: To determine the biologic effect of granulocyte-macrophage colony-stimulating factor (sangramostim, GM-CSF; Immunex Corporation, Seattle, WA) as measured by prostate-specific antigen (PSA) kinetics in patients with serologic progression of prostate cancer after definitive local therapy. PATIENTS AND METHODS: Patients with prostate cancer who had undergone previous definitive surgical or radiation therapy with nonmetastatic, recurrent disease as manifested by a rising PSA between 0.4 ng/mL and 6.0 ng/mL were enrolled on this phase II trial. Patients received 250 micro g/m(2)/day of subcutaneous GM-CSF on days 1 through 14 of a 28-day cycle. PSA was measured at day 1 of each cycle. RESULTS: Thirty patients with serologic progression of prostate cancer were treated. The median pretreatment PSA was 2.9 ng/mL. Of the 29 evaluable patients, three patients (10%; 95% confidence interval, 2% to 27%) achieved a 50% reduction in PSA. For the patients (n = 26) in whom the on-treatment PSA doubling time could be calculated, the median PSA doubling time increased from 8.4 months to 15 months (P =.001), and the median slope of the PSA versus time curve decreased with treatment (P =.004). Therapy was well tolerated by all patients, with an average treatment duration of 16.5 cycles (range, 5 to 33). CONCLUSION: GM-CSF has a biologic effect in patients with serologic progression of prostate cancer after definitive local therapy, as measured by PSA declines and modulation of PSA kinetics.     

Clinical and Serologic Responses After a Two-dose Series of High-dose Influenza Vaccine in Plasma Cell Disorders: A Prospective,Single-arm Trial

BackgroundPatients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population, despite the routine administration of a seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of < 20% after standard influenza vaccination in patients with MM.Patients and MethodsPatients with plasma cell dyscrasia (n = 51) were treated with a 2-dose series of high-dose inactivated trivalent influenza vaccine during the 2014 to 2015 influenza season. Laboratory-confirmed influenza infections were identified through seasonal surveillance, sera were collected for influenza hemagglutination antibody inhibition (HAI) titer assays, and logistic regression models were used to identify the clinical correlates to the HAI serologic responses.ResultsInfluenza vaccine was well tolerated, without any vaccine-related grade ≥ 2 adverse events. Only 3 patients (6%) experienced laboratory-confirmed influenza. The rates of HAI seroprotection against all 3 vaccine strains (A/California/7/2009 [H1N1] pdm09-like virus; A/Texas/50/2012 [H3N2]-like virus; and a B/Massachusetts/2/2012-like virus) increased from 4% at baseline to 49% and 65% after 1 and 2 doses, respectively. The risk factors associated with a lower likelihood of HAI serologic response included plasma cell disorder requiring therapy, less than a partial response found on disease response assessment, and active conventional chemotherapy. Alternatively, active therapy with an immunomodulatory drug alone or with a proteasome inhibitor was associated with a greater likelihood of an HAI serologic response.ConclusionThese data have demonstrated that, in contrast to the historically poor results with standard influenza vaccination, this novel high-dose booster vaccination strategy leads to high rates of seroprotection. Randomized controlled studies are needed to compare this novel strategy to the standard vaccination strategy.     

Humoral immune response to a therapeutic polyvalent cancer vaccine after complete resection of thick primary melanoma and sentinel lymphadenectomy.

PURPOSE: A therapeutic polyvalent cancer vaccine (Canvaxin vaccine; CancerVax Corp, Carlsbad, CA) induces antibodies to a glycoprotein tumor-associated antigen (TA90). However, endogenous immune responses to TA90 have also been reported. This study examined anti-TA90 antibody responses with respect to the survival of patients who received adjuvant vaccine immunotherapy after resection of thick (> or = 4 mm) primary cutaneous melanoma. PATIENTS AND METHODS: Serum specimens were obtained from 54 patients immediately before and then 1, 2, 4, and 6 months after wide local excision of thick primary cutaneous melanoma and sentinel lymphadenectomy. All patients were offered adjuvant therapies with the vaccine, high-dose interferon, or other agents. An enzyme-linked immunosorbent assay was used to determine serial serum titers of immunoglobulin G (IgG) and IgM antibodies against TA90. These titers were correlated with clinical course. RESULTS: Forty-three patients chose vaccine therapy, and 11 patients chose postoperative observation. Preoperative anti-TA90 IgG and IgM titers were similar for vaccine and observation groups (P =.184). At a median follow-up of 26 months, univariate analysis of Cox regression showed that disease-free survival and overall survival of vaccine patients were significantly correlated with maximal IgM response (P =.0006 and.006, respectively) but not with maximal IgG response (P =.73 and.95, respectively). Neither response predicted survival in the observation group. CONCLUSION: Postoperative vaccine therapy may enhance IgG and IgM immune responses to TA90 after surgical resection, but only the IgM response is correlated with improved survival. These findings may become useful to guide selection of patients for postoperative adjuvant therapy of high-risk melanoma.     

Low immunogenicity of seasonal trivalent influenza vaccine among patients receiving docetaxel for a solid tumour: results of a prospective pilot study

Background:

Patients receiving cytotoxic therapy for solid tumours are at risk of severe influenza. However, few data are available regarding the immunogenical efficacy of influenza vaccine in these patients.

Methods:

In this prospective study, 25 patients with breast (n=13) or prostate (n=12) cancer received a trivalent inactivated influenza vaccine along with docetaxel (Taxotere) administration. The influenza virus type A and B antibody titres were measured using haemagglutinin inhibition (Garten et al, 2009) before and 21 days after the vaccination. Seroconversion rate was defined as the percentage of patients with an increase in the serum titres ⩾4 after vaccination.

Results:

Median age was 65 years (range: 33–87 years); 52% were females. Seroconversion rates were low: 28% (95% CI: 23.1–33.3) for H1N1, 8% (95% CI: 7.7–8.3) for H3N2 and 16% (95% CI: 7.7–25) for the B strain. The geometric mean titres ratios were 2.16 (H1N1), 1.3 (H3N2) and 1.58 (B). No serious adverse event (AE) related to the vaccine was reported. All the reported AE were from mild-to-moderate intensity.

Conclusion:

In the patients receiving docetaxel for solid tumours, influenza vaccine triggers an immune response in only one third. Strategies using more immunogenic influenza vaccines must be evaluated in such patients.     

Immunization of colorectal carcinoma patients with a recombinant canarypox virus expressing the tumor antigen Ep-CAM/KSA (ALVAC-KSA) and granulocyte macrophage colony- stimulating factor induced a tumor-specific cellular immune response.

PURPOSE: Colorectal carcinoma cells express the tumor-associated antigen epithelial cellular adhesion molecule (Ep-CAM)/KSA. Passive immunotherapy with monoclonal antibodies using this antigen has shown promising results. Ep-CAM might also be a target for active specific immunotherapy. Expression of the tumor antigen in a viral vector may facilitate appropriate antigen presentation. The feasibility of an Ep-CAM/KSA-specific therapeutic vaccination was investigated in cancer patients. EXPERIMENTAL DESIGN: The full-length Ep-CAM gene was inserted into the avipox virus ALVAC (ALVAC-KSA). Twelve radically operated colorectal carcinoma patients without evidence of remaining macroscopic disease (stages I, II, and III) entered the study. The first 6 patients were immunized with three injections of ALVAC-KSA (10(7.09) CCID(50) per immunization) alone in weeks 0, 3, and 6. The subsequent 6 patients received the same schedule of ALVAC-KSA together with the adjuvant cytokine granulocyte macrophage colony-stimulating factor (GM-CSF; 75 micro g/day for 4 consecutive days). RESULTS: The adverse reactions to the vaccinations were mild except for local skin reactions. In the ALVAC-KSA group a weak T-cell response was induced in 2 of 6 patients. In the ALVAC-KSA/GM-CSF group a marked IFN-gamma response (enzyme-linked immunospot) was induced in 5 of 6 patients. The T-cell response appeared late, 1 month after the last immunization, with a peak at 4-5 months after immunization. No IgG antibodies against Ep-CAM were detected. Before vaccination the majority of patients had a type 1 T-cell response (IFN-gamma) against the vector, which was noted in healthy donors as well. All of the patients developed high titers of IgG antibodies against the vector, and the T-cell response was vigorously boosted. CONCLUSIONS: ALVAC-KSA, in combination with low dose local administration of GM-CSF may induce a strong, IFN-gamma T-cell response (type 1). ALVAC-KSA seems to be an interesting candidate as a cancer vaccine for future clinical development.     

Influenza immunisation in children with solid tumours

We assessed response to immunisation with trivalent split virus influenza vaccine in children with non-leukaemic malignant disease. Children with solid tumours and lymphoma received one or two doses of influenza vaccine, according to current UK guidelines, in autumn 2001 and/or 2002. Children were currently receiving chemotherapy or were within 6 months of completing chemotherapy. Pre and post vaccination sera were assessed for antibodies to the prevalent influenza strains by haemagglutination inhibition (HI). Sixty six children were assessed prior to 69 episodes of vaccination. In 30% episodes, children were susceptible to all three circulating influenza viruses (65% to H1N1, 42% to H3N2 and 90% to B) and only one patient showed protective titres (HI32) against all three strains. Seroresponse rates (4-fold rise in HI) for H1N1, H3N2 and B were 52%, 33% and 51% in 65 episodes. Following immunisation protective titres to all three viruses were seen in 25 episodes (38%) and protective responses to one or two viruses were seen in a further 12 (19%) episodes. There was no significant difference in response rates among children on treatment and off treatment and by intensity of chemotherapy. Children with solid tumours and lymphoma are highly susceptible to influenza infection. Influenza vaccine was well tolerated in this patient group and children showed a significant response to immunisation. These findings support the recommendation for annual influenza vaccination in these children.     

Durable carcinoembryonic antigen (CEA)-specific humoral and cellular immune responses in colorectal carcinoma patients vaccinated with recombinant CEA and granulocyte/macrophage colony-stimulating factor.

PURPOSE: Previous studies have indicated that carcinoembryonic antigen (CEA) might be a suitable immunotherapeutic target in colorectal carcinoma (CRC). The aim of the present study was to analyze the immunological and clinical effects of vaccination with CEA together with the adjuvant granulocyte/macrophage colony-stimulating factor (GM-CSF). EXPERIMENTAL DESIGN: Twenty-four resected CRC patients without macroscopic disease were immunized seven times with recombinant CEA at four different dose levels over a 12-month period. Half of the patients received GM-CSF (80 microg/day for 4 consecutive days) at each immunization. Patients were monitored immunologically for 36 months and clinically for 76 months. T-cell response was evaluated by a [(3)H]thymidine incorporation assay, and IgG response was determined by ELISA. RESULTS: Minor local side effects were common. All 12 patients (100%) in the GM-CSF group developed a CEA-specific T-cell as well as an IgG response. The corresponding figures in the CEA alone group were 9 of 12 (75%) and 8 of 12 (66%), respectively. GM-CSF significantly augmented the amplitude of the T-cell response and the IgG titers. No dose-response relationship was noted. The immune responses at 12 months persisted 24 months after the last vaccination. Anti-CEA IgG titers were associated with increased survival (P < 0.05), whereas standard prognostic factors had no relationship, with the exception of serum CEA value. CONCLUSIONS: Vaccination with recombinant CEA and GM-CSF appears to be a nontoxic regimen inducing potent and durable antigen-specific IgG and T-cell response. The results of this study justify more extensive trials with recombinant CEA protein for immunotherapy of CRC.     

Influenza vaccination in adult patients with solid tumours treated with chemotherapy

Patients with solid tumours receiving chemotherapy are at risk for influenza complications. Yearly influenza vaccination is recommended to patients treated with chemotherapy. However, adherence to vaccination is low, most likely due to lack of data on efficacy, optimal timing and safety of vaccination. There is scarce evidence for the effectiveness of the influenza vaccine in adult patients with solid tumours and chemotherapy on reduction of pneumonia, decreased mortality and fewer interruptions of oncological treatment. A review of 20 non-randomised serological studies in adult patients with different cancer types and chemotherapy provides insight in general trends of response to vaccination. Overall, the magnitude of the antibody response after influenza vaccination (i.e. seroconversion) can be lower than in healthy controls, but the majority of patients with solid tumours is able to mount a timely, protective immunological response (i.e. seroprotection) regardless of chemotherapy schedule, similar to healthy controls. Small sample sizes, patient heterogeneity and lack of comparable study designs limit more specific recommendations related to cancer type and optimal timing of vaccination. The inactivated influenza vaccine is safe to administer to immunosuppressed patients; side-effects are similar to those in healthy individuals. Although vaccination before start of chemotherapy is preferred to ensure optimal protection in adults with solid tumours, also vaccination during chemotherapy can reduce influenza-related complications considering the overall trends in serological response. Given the increased morbidity and mortality of influenza, influenza vaccination should be advocated as an inexpensive and safe preventive measure in patients with solid tumours receiving chemotherapy.     

Induction of high-titer IgG antibodies against multiple leukemia-associated antigens in CML patients with clinical responses to K562/GVAX immunotherapy

The ability to target myeloid leukemia with immunotherapy would represent a significant therapeutic advance. We report here immunological analysis of clinical trials of primary and secondary vaccination with K562/GM-CSF immunotherapy in adult chronic phase chronic myeloid leukemia patients (CML-CP) with suboptimal responses to imatinib mesylate. Using serological analysis of recombinant cDNA expression libraries of K562 with autologous vaccinated patient serum, we have identified 12 novel chronic myeloid leukemia-associated antigens (LAAs). We show that clinical responses following K562/GM-CSF vaccination are associated with induction of high-titer antibody responses to multiple LAAs. We observe markedly discordant patterns of baseline and induced antibody responses in these identically vaccinated patients. No single antigen was recognized in all responses to vaccination. We demonstrate that an additional ‘booster'' vaccination series can be given safely to those with inadequate responses to initial vaccination, and is associated with more frequent induction of IgG responses to antigens overexpressed in K562 vaccine compared with primary CML-CP. Finally, those with induced immune responses to the same LAAs often shared HLA subtypes and patients with clinical responses following vaccination recognized a partially shared but non-identical spectrum of antigens; both findings have potentially significant implications for cancer vaccine immunotherapy.     

Granulocyte-macrophage-colony-stimulating factor added to a multipeptide vaccine for resected Stage II melanoma

BACKGROUND: Forty-eight patients with resected Stages IIA and IIB melanoma were immunized with two tumor antigen epitope peptides derived from gp100(209-217) (210M) (IMDQVPSFV) and tyrosinase(368-376) (370D) (YMDGTMSQV) emulsified with incomplete Freund's adjuvant (IFA). Patients were assigned randomly to receive either peptides/IFA alone or with 250 microm of granulocyte-macrophage-colony-stimulating factor (GM-CSF) subcutaneously daily for 5 days to evaluate the toxicities and immune responses in either arm. Time to recurrence and survival were secondary end points. METHODS: Immunizations were administered every 2 weeks x 4, then every 4 weeks x 3, and once 8 weeks later. A leukapheresis to obtain peripheral blood mononuclear cells for immune analyses and skin testing with peptides and recall reagents was performed before and after eight vaccinations. RESULTS: Local pain and granuloma formation, fever, and lethargy of Grade 1 or 2 were observed. Transient vaccine-related Grade III and no Grade IV toxicity was observed. Seventeen of the 40 patients for whom posttreatment skin tests were performed developed a positive skin test response to the gp100 peptide, but only 1 of the 40 patients developed a positive skin test response to tyrosinase. Immune responses were measured by release of interferon-gamma (IFN-gamma) in an enzyme-linked immunosorbent assay (ELISA) by effector cells in the presence of peptide-pulsed antigen-presenting cells, by cytokine release of IFN-gamma, GM-CSF, and tumor necrosis factor-alpha in a Luminex assay, or by an antigen-specific tetramer flow cytometry assay. Thirty-four of the 39 patients for whom the ELISA data were performed demonstrated an immune response after vaccination, as did 37 of 42 patients by tetramer assay. Enzyme-linked immunosorbent assay, Luminex, and tetramer responses in the GM-CSF/peptide/IFA group were higher than in the peptide/IFA group. Epitope spreading to the MART-1/MelanA 27-35 and 26-35 (27L) epitopes was detected by tetramer assay in 10 patients. Seven of 48 patients experienced disease recurrence with a median of 24 months of follow-up and 2 patients in this intermediate to high risk group have died. CONCLUSION: These data suggest a significant number of patients with resected melanoma mount an antigen-specific immune response against a peptide vaccine. There is a trend for GM-CSF to modestly increase the immune response and support further development of GM-CSF as a vaccine adjuvant.     

Cost-effectiveness of influenza vaccination in working-age cancer patients

BACKGROUND: Despite recommendations to immunize all patients at an increased risk of influenza complications, the vaccine utilization among high-risk nonelderly adults remains low and its cost-effectiveness is unclear. In the current study, the authors analyzed the cost-effectiveness of influenza vaccination in working-age (ages 20-64 years) cancer patients. METHODS: The authors developed a decision-analytic model, from the societal perspective, using epidemiologic, vaccine effectiveness, resource utilization, cost, survival, and utility data from published sources, supplemented with data collected from the authors' own institutional accounting system. Two strategies were compared: influenza vaccination of working-age cancer patients and no vaccination. The base-case patient was assumed to be a 51-year-old cancer patient (the mean age for the National Cancer Institute's Surveillance, Epidemiology, and End Results [SEER] population of working-age patients within 5 years of cancer diagnosis). RESULTS: The effectiveness of the influenza vaccine was 6.02 quality-adjusted life-years (QALYs) at a cost of $30.10. The effectiveness of the no vaccination strategy was 6.01 QALYs at a cost of $27.86. Compared with the no vaccination strategy, the incremental cost-effectiveness ratio of vaccinating working-age cancer patients would be $224.00 per QALY gained. Using the benchmark of $50,000 per QALY, the model was only sensitive to changes in cancer survival (threshold of 2.8 months). CONCLUSIONS: The influenza vaccine is cost-effective for working-age cancer patients with a life expectancy of >or=3 months. All working-age cancer patients who are within 5 years of cancer diagnosis and have a life expectancy of at least 3 months should be vaccinated against influenza.     

Correlations between serum monocyte chemotactic protein-1 levels, clinical prognostic factors, and HER-2/neu vaccine-related immunity in breast cancer patients.

PURPOSE: We studied serum monocyte chemotactic protein-1 (MCP-1) levels in breast cancer patients in relationship to their clinicopathologic variables and immune response to a /neu E75 vaccine. EXPERIMENTAL DESIGN: We measured MCP-1 levels in 32 /neu(+) breast cancer patients before and after vaccination with a /neu E75 peptide + granulocyte macrophage colony-stimulating factor vaccine. Clinical prognostic variables were collected. Vaccine-specific immunologic responses were monitored.RESULTS: Serum MCP-1 levels >250 pg/mL (MCP-high) correlated with favorable prognostic variables. MCP-high patients compared with MCP-low (<250 pg/mL) patients showed statistically significant later onset of disease, earlier stage of disease, fewer nodal metastasis, and less chemotherapy. MCP-high patients had increased levels of preexisting immunity when compared with MCP-low patients (69% versus 21%; P = 0.02). However, MCP-low patients showed higher inducible levels of MCP-1 compared with MCP-high patients (median increase, 41% versus 0%; P = 0.001) after vaccination. Moreover, MCP-low patients with >50% increase in MCP-1 levels (response-high) had worse clinical prognostic variables compared with patients with <50% increase (response-low). Response-high patients had statistically significant more poorly differentiated tumors, later stage of disease, and higher percentage of large tumors. Patients with >30% postvaccination MCP-1 increase also showed significant increases in E75-specific CD8(+) T-cells (0.05% versus 0.38%; P = 0.03) in response to vaccination. CONCLUSIONS: High serum MCP-1 levels in breast cancer patients correlate with favorable prognostic variables and increased preexisting /neu immunity. E75 vaccination induces the largest MCP-1 response in patients with unfavorable clinicopathologic variables. Therefore, low serum MCP-1 levels may identify patients with worse prognosis and those most likely to benefit from this vaccination.