Phase II Trial of WT1 Analog Peptide Vaccine in Patients with Acute Myeloid Leukemia (AML) in Complete Remission (CR)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3624-3624
Author(s):  
Todd L. Rosenblat ◽  
Mark G. Frattini ◽  
Suzanne M. Chanel ◽  
Tao Dao ◽  
Yvette Bernal ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Phase Ii ◽  
Residual Disease ◽  
Peptide Vaccine ◽  
Disease Free Survival ◽  
Disease Recurrence ◽  
Gm Csf ◽  
Analog Peptide ◽  
Immunologic Activity

Abstract Abstract 3624 WT1 is a transcription factor which has been implicated in leukemogenesis and has been used as a marker of minimal residual disease (MRD). We previously demonstrated the feasibility of vaccinating AML patients in CR with a multivalent WT1 peptide vaccine and inducing immune responses. In an effort to further explore the safety and efficacy of this approach, we are conducting a Phase II study in which the vaccine is administered to AML patients in first CR and who completed all planned postremission chemotherapy. Eligible patients had WT1 transcript detectable by RT-PCR. The vaccine consisted of 4 native and derived WT1 peptides administered with the immune adjuvants Montanide and GM-CSF. Patients received 6 vaccinations over 10 weeks. Early toxicity was assessed at weeks 2 and 4. Immune responses were evaluated at week 12 by CD4+ T cell proliferation, CD3+ T cell interferon-g interferon release (ELISPOT) and WT1 peptide tetramer staining. Patients who were clinically stable and without disease recurrence could continue with up to 6 more vaccinations administered approximately every month. To date, 12 patients have been accrued to the study (6-M, 6-F; median age – 66 years, range 26–73 years). Cytogenetic subtypes varied among the study patients (Favorable-3, Intermediate-5, Unfavorable-4). The median time to vaccination after achieving CR was 7.5 months (range: 3–22 months). One patient was removed early because of relapse prior to receiving the first vaccination. Four patients have received at least 6 vaccines and 2 others have completed 12 vaccinations. Eight patients are alive without evidence of disease. One of these patients has an HLA-A02 subtype and was found to have developed T cells reactive with WT1-A (native peptide) HLA tetramers following 6 vaccinations which persisted (at a lower level) until after the 12th vaccination. Three patients relapsed during vaccination (after 1, 5 and 11 vaccines) and 2 of the 3 have died. Two of the relapsed patients who had sample available for immunologic evaluation, did not develop a CD4+ response to any of the peptides tested. Two other patients discontinued vaccination because of toxicity (hypersensitivity/pain with GM-CSF administration). Both remain in CR. No episodes of anaphylaxis or generalized urticaria were observed. Neither median disease free survival nor overall survival has been reached in this small cohort of patients. These preliminary findings demonstrate that the WT1 peptide vaccine is relatively well tolerated and has immunologic activity. Trial accrual is ongoing and further follow-up is required before any beneficial effect on outcome can be determined. Disclosures: Scheinberg: Formula Pharma: WT1 Vaccine inventor, Patent held by MSKCC and Licensed to Formula Pharma, WT1 Vaccine inventor, Patent held by MSKCC and Licensed to Formula Pharma Patents & Royalties.

scholarly journals Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist

2021 ◽  
Vol 9 (5) ◽  
pp. e002214
Author(s):  
Max O Meneveau ◽  
Gina R Petroni ◽  
Elise P Salerno ◽  
Kevin T Lynch ◽  
Mark Smolkin ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Immune Responses ◽  
Peptide Vaccine ◽  
Disease Free Survival ◽  
T Cell Responses ◽  
Gm Csf ◽  
Cell Responses ◽  
Group 4 ◽  
Tlr7 Agonist

BackgroundExperimental cancer vaccines are traditionally administered by injection in subcutaneous tissue or muscle, commonly with adjuvants that create chronic inflammatory depots. Injection of melanoma-derived peptides induces T cell responses; however, the depots that form following injection may inhibit optimization of the immune response. In skin, epidermal Langerhans cells (LC) are a dominant source of professional antigen presenting cells. We hypothesized that: (1) applying melanoma-derived peptides topically, in proximity to LC, could be immunogenic and safe, with low vaccine-site toxicity and (2) topical toll-like receptor 7 (TLR7) agonist would increase immunogenicity of the peptide vaccine.MethodsTwelve melanoma peptides plus a tetanus helper peptide were combined with granulocyte macrophage colony stimulating factor (GM-CSF) and were administered topically on days 1, 8, and 15, to 28 patients randomized to one of four adjuvant preparations: (1) incomplete Freund’s adjuvant (IFA); (2) IFA plus a TLR7 agonist (imiquimod) administered on days 0, 7, 14; (3) dimethyl sulfoxide (DMSO) or (4) DMSO+ imiquimod administered on day 0, 7, 14. Every 3 weeks thereafter (x 6), the peptides were combined with GM-CSF and were injected into the dermis and subcutis in an emulsion with IFA. Toxicities were recorded and immune responses assayed by ELIspot.ResultsCD8+ T cell responses to transdermal vaccination in DMSO occurred in 83% of participants in group 3 and 86% in group 4, and responses to vaccination in IFA were observed in 29% of participants in group 1 and 14% in group 2. Overall, 61% of participants had CD4+ T cell immune responses to the tetanus peptide, with large, durable responses in groups 3 and 4. Five of seven participants in group 4 had a severe rash, one that was dose limiting. Ten-year overall survival was 67% and disease-free survival was 44%.ConclusionsThese data provide proof of principle for immunogenicity in humans of transdermal immunization using peptides in DMSO. Further study is warranted into the pharmacokinetics and immunobiology of TLR agonists as vaccine adjuvants during transcutaneous application. Overall survival is high, supporting further investigation of this immunization approach.

Phase II clinical trial of mutant Ras peptide vaccine in combination with GM-CSF and IL-2 in advanced cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3067-3067 ◽  
Author(s):  
M. S. Achtar ◽  
A. Toubaji ◽  
V. Herrin ◽  
B. Gause ◽  
M. Hamilton ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Phase Ii ◽  
Peptide Vaccine ◽  
Progression Free Survival ◽  
Advanced Cancer Patients ◽  
Gm Csf ◽  
Therapeutic Modalities ◽  
Novel Proteins

3067 Background: Mutant ras oncogenes produce novel proteins that are processed and displayed through HLA molecules on tumor cells. Therefore, mutant ras is an attractive target for vaccine therapy. We have shown in a previous phase I trial that vaccination with mutant ras peptides produced specific immune responses (IR). Here we tested in a phase II trial the use of specific mutant ras peptides in combination with GM-CSF and IL-2 in advanced cancer patients carrying the ras mutation in their tumors. Methods: We treated 17 patients with advanced cancers (14 CRC, 1 NSCLC and 2 pancreatic) with 5000μg of the corresponding mutant ras peptide given SQ along with GM-CSF and IL-2. GM-CSF was given SQ on days -1,0,1,2 followed by ten days of low dose SQ IL-2. Vaccines were repeated every 5 weeks for a maximum of 15 cycles or until disease progression. Results: 11 patients who received 3 or more vaccinations were tested for immune response by measuring IFN-γ mRNA copies in PBMCs pre and post vaccination. 6/11 patients generated specific IR to the corresponding mutant ras vaccine. The median overall survival and the median progression-free survival for all patients were 25.8 and 13.1 months respectively. However, in the 6 patients with positive IR, it was 39.9 and 17.9 months compared to 18.5 and 15.6 months in the 5 patients who showed no IR. No grade IV toxicity occurred. Most adverse events were Grade I-II toxicities and resolved spontaneously. Grade III toxicities led to IL-2 dose reduction in 3/17 patients (18%). Conclusions: The study showed that vaccination of advanced cancer patients with mutant ras peptides in combination with GM-CSF and IL-2 is safe and can induce specific immune responses. Furthermore, those patients who generated IR showed better clinical outcome, as reflected by PFS and OS. So we believe that this vaccine may form a potentially promising approach in combination with other therapeutic modalities in advanced solid tumors. No significant financial relationships to disclose.

Booster inoculations of the AE37 peptide vaccine enhance immunological responses in a phase II study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3095-3095
Author(s):  
Eleftheria A Anastasopoulou ◽  
Efi Pappou ◽  
Panagiotis Tzonis ◽  
Alexandros Ardavanis ◽  
Sathibalan Ponniah ◽  
...  
Keyword(s):  
High Risk ◽  
Immune Responses ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Peptide Vaccine ◽  
Significant Risk ◽  
Control Group ◽  
Gm Csf ◽  
Ifn Γ ◽  
Disease Free

3095 Background: We are conducting a multicenter randomized phase II trial of AE37, the Ii-Key hybrid peptide of HER2 776-790 (AE36). The purpose of the study is to determine if the AE37 vaccine can prevent recurrence in disease-free conventionally treated node-positive (NP) and high-risk node-negative (NN) breast cancer patients at significant risk for recurrence. Since clinical efficacy is anticipated to occur as the result of long lasting memory immune responses induced by vaccination, repeated booster inoculations were scheduled as part of the trial. Here we present data on immune responses in patients who received boosters up to 24 months after completion of the primary vaccination series (PVS). Methods: The trial is enrolling NP or high-risk NN patients with any degree of HER2 expression (IHC 1-3+ or FISH > 1.2) rendered disease-free following standard of care therapy. The vaccine group (VG) received AE37+GM-CSF and control group (CG) GM-CSF alone in 6 monthly i.d. inoculations followed by boosters administered every 6 months x 4. Immunologic responses were assessed in vivo by dermal reactions at the inoculation site, and in vitro, against the AE36 peptide, with proliferation and IFN-γ ELISPOT assays. Results: 25 patients in the VG and 23 in the CG have completed their boosters. After the last booster (BRC24), 100%, 54% and 54% in the VG (vs. 9%, 18% and 27% in the CG) responded by dermal reaction, proliferation and IFN-γ ELISPOT, respectively. Mean dermal reactions (orthogonal mean in mm) in vaccinated patients was 25.9±3.13 at completion of the PVS (R6) and increased to 35.47±4.35 at BRC24 (p=0.01). VG patients increased their proliferation response (stimulation index, SI) to AE36 from 0.97±0.046 at baseline (R0) before vaccination to 2.27±0.57 at R6 (p=0.0003) which was maintained until BRC24 (SI 2.21±0,33, p<0.0001). The number of IFN-γ specific spots/106 PBMC increased from 26.88±12.36 at R0 to 40.35±17.02 (p=0.07) at R6, up to 62±16.82 (p=0.0076) at BRC24. Conclusions: Our data demonstrate that AE37 vaccine boosters enhance the immune responses against HER elicited during the PVS, thus sustaining long lasting immunity, a prerequisite for possible clinical efficacy which is currently being evaluated. Clinical trial information: NCT00524277.

K562/GM-CSF Vaccination Reduces Tumor Burden, Including Achieving Molecular Remissions, in Chronic Myeloid Leukemia (CML) Patients with Residual Disease on Imatinib Mesylate (IM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2858-2858
Author(s):  
B. Douglas Smith ◽  
Yvette L. Kasamon ◽  
Carole B. Miller ◽  
Christina Chia ◽  
Kathleen Murphy ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Disease Burden ◽  
Residual Disease ◽  
Tumor Vaccine ◽  
Limit Of Detection ◽  
Cell Mediated Immunity ◽  
Rt Pcr ◽  
Gm Csf ◽  
Clinical Responses

Abstract Despite high rates of clinical responses to IM, molecular complete responses are rare. The curative potential of allo transplantation and donor lymphocyte infusions underscores CML’s responsiveness to T cell mediated immunity. K562/GM-CSF is a tumor vaccine derived from a CML cell line that expresses several defined CML associated antigens and has been genetically engineered to produce GM-CSF. A pilot vaccination strategy was developed to determine if K562/GM-CSF immunotherapy in combination with IM could enhance T cell reactivity and clinical responses in pts having persistent, measurable disease by FISH or RT-PCR despite 1 or more years on IM. Eligible pts also had a major cytogenetic response (&lt;35% Ph+ cells) while remaining on a stable dose of IM. Disease burden was measured serially over 12 wks prior to vaccination to assure continued measurability. Four vaccines were administered in 3 wk intervals, each consisting of 1 x 108 irradiated K562/GM-CSF cells distributed over 10 sites, with or without topical 5% Imiquimod cream (a Toll-like receptor 7 agonist) used as a vaccine adjuvant. Disease burden was measured at 6 wk intervals for 9 mos from the first vaccine and specimens were banked for measurement of immune responses. BCR-ABL fusion mRNA was detected by a Taqman one step quantitative RT-PCR assay and expressed as copies of BCR-ABL mRNA per 1000 copies of ABL mRNA. The limit of detection was 1 in 20,000 copies (equivalent to 10−5 CML cells) and the assay reliably resolved differences of 10 fold or greater. A total of 19 (of 20 planned) pts have enrolled with 17 pts having completed all 4 vaccines and at least 1 disease measure since vaccine initiation. The median age is 52 (range 28–76) yrs with a median time from diagnosis to enrollment of 57 (range 16–111) mos. Pts were on IM for a median of 37 (13–53) mos prior. Thirteen previously received interferon. K562/GM-CSF vaccine was well tolerated with grade 1–2 injection site erythema and induration common. Five of 17 evaluable pts had FISH pos disease as their best previous response (BPR) with 3 becoming FISH neg post-vaccine (previous IM therapy durations of +24 mos, +43 mos, +49 mos) and 1 also becoming PCR neg (IM +24 mos). In addition, 3/12 pts whose BPR was FISH neg/PCR pos (IM therapy +15 mos, +39 mos, +51 mos) have become PCR neg post vaccine. Only 1 pt has shown disease progression having entered the study with a relatively heavy disease burden (30% FISH pos). Mean PCR measures pre-vaccine were statistically higher than post-vaccine (p=0.001). K562/GM-CSF vaccine appears to improve responses in pts on IM, including achieving complete molecular remissions, despite long durations of previous IM therapy. Measurement of immune responses to CML associated antigens is ongoing.

scholarly journals A Randomized Placebo-Controlled Efficacy Study of a Prime Boost Therapeutic Vaccination Strategy in HIV-1-Infected Individuals: VRI02 ANRS 149 LIGHT Phase II Trial

2021 ◽  
Vol 95 (9) ◽  
Author(s):  
Y. Lévy ◽  
C. Lacabaratz ◽  
E. Lhomme ◽  
A. Wiedemann ◽  
C. Bauduin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase Ii ◽  
Antiretroviral Treatment ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Vaccine Strategy ◽  
Cell Responses ◽  
Hiv 1

ABSTRACT In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4+ T-cell responses (P < 0.001 for each cytokine compared to W0) measured, predominantly against Gag and Pol/Env, and an increase in HIV-specific CD8+ T cells producing interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α) (P = 0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T-cell subsets by mass cytometry in a subpopulation showed an increase in the W28/W0 ratio for memory CD8+ T cells coexpressing exhaustion and senescence markers such as PD-1/TIGIT (P = 0.004) and CD27/CD57 (P = 0.044) in vaccinees compared to the placebo group. During ATI, all patients experienced viral rebound, with the maximum observed HIV RNA level at W42 (median, 4.63 log10 copies [cp]/ml; interquartile range [IQR], 4.00 to 5.09), without any difference between arms. No patient resumed cART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need for combined immunomodulatory strategies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01492985.) IMPORTANCE In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. Compared to the placebo group, vaccinees elicited strong and polyfunctional HIV-specific CD4+ and CD8+ T-cell responses. However, these immune responses presented some qualitative defects and were not able to control viremia following antiretroviral treatment interruption, as no difference in HIV viral rebound was observed in the vaccine and placebo groups. Several lessons were learned from these results, pointing out the urgent need to combine vaccine strategies with other immune-based interventions.

Immune responses of seven different “promiscuous” T-cell epitopes on chimeric peptide vaccine design

Peptides ◽  
1994 ◽  
pp. 732-733 ◽  
Author(s):  
A. M. DiGeorge ◽  
B. Wang ◽  
S. F. Kobs-Conrad ◽  
P. T. P. Kaumaya
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Peptide Vaccine ◽  
Vaccine Design ◽  
T Cell Epitopes ◽  
Chimeric Peptide

scholarly journals P01.10 IFNy secretion of adaptive and innate immune cells as a parameter to display leukaemia derived dendritic cell (DCleu) mediated immune responses in AML

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A13.1-A13
Author(s):  
LK Klauer ◽  
O Schutti ◽  
S Ugur ◽  
F Doraneh-Gard ◽  
N Rogers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Immune Cells ◽  
Gm Csf ◽  
Adaptive Immune ◽  
Cik Cells ◽  
Adaptive Immune Cells ◽  
Suitable Parameter

BackgroundMyeloid leukaemic blasts can be converted into leukaemia derived dendritic cells (DCleu) with blastmodulatory Kit-I and Kit-M, which have the competence to regularly activate T and immunoreactive cells to gain anti-leukaemic activity or rather cytotoxicity. As innate and adaptive immune responses are notably promoted by the cytokine interferon gamma (IFNy), we hypothesised that the IFNy secretion could be a suitable parameter to display DC/DCleu mediated immunologic activity and even anti-leukaemic cytotoxicity.Materials and MethodsDC/DCleu were generated from leukaemic WB with Kit-I (GM-CSF + OK-432) and Kit-M (GM-CSF + PGE1) and used to stimulate T cell enriched immunoreactive cells. Initiated anti-leukaemic cytotoxicity was investigated with a cytotoxicity fluorolysis assay (CTX). Initiated IFNy secretion of innate and adaptive immune cells (T cells, TCD4+ cells, TCD8+ cells, NKCD56+ cells, NKCD161+ cells, CIKCD56+ cells, CIKCD161+ cells and iNKT) was investigated with a cytokine secretion assay (CSA). In some cases IFNy production was additionally evaluated with an intracellular cytokine assay (ICA). Conclusively, the IFNy secretion of immunoreactive cells was correlated with the anti-leukaemic cytotoxicity.ResultsSignificant amounts of DC and DCleu as well as migratory DC and DCleu could be generated with Kit-I and Kit-M without induction of blast proliferation. T cell enriched immunoreactive cells stimulated with DC/DCleu showed an increased anti-leukaemic cytotoxicity and an increased IFNy secretion of T, NK and CIK cells compared to control. Both the CSA and ICA yielded comparable amounts of IFNy positive innate and adaptive immune cells. The correlation between the IFNy secretion of immunoreactive cells and the anti-leukaemic cytotoxicity showed a positive relationship in T cells, TCD4+ cells, TCD8+ cells and NKCD56+ cells.ConclusionsWe found blastmodulatory Kit-I and Kit-M competent to generate DC/DCleu from leukaemic WB. Stimulation of T cell enriched immunoreactive cells with DC/DCleu regularly resulted in an increased anti-leukaemic cytotoxicity and an increased IFNy dependent immunological activity of T, NK and CIK cells compared to control. Moreover the anti-leukaemic cytotoxicity positively correlated with the IFNy secretion in T cells, TCD4+ cells, TCD8+ cells, NKCD56+ cells. We therefore consider the IFNy secretion of innate and adaptive immune cells to be a suitable parameter to assess the efficacy of in vitro and potentially in vivo AML immunotherapy. The CSA in this regard proved to be a convenient and reproducible technique to detect and phenotypically characterise IFNy secreting cells of the innate and adaptive immune system.Disclosure InformationL.K. Klauer: None. O. Schutti: None. S. Ugur: None. F. Doraneh-Gard: None. N. Rogers: None. M. Weinmann: None. D. Krämer: None. A. Rank: None. C. Schmid: None. B. Eiz-Vesper: None. H.M. Schmetzer: None.

Immunization With Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor as a Vaccine Adjuvant Elicits Both a Cellular and Humoral Response to Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2653-2659
Author(s):  
Douglas G. McNeel ◽  
Kathy Schiffman ◽  
Mary L. Disis
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Antibody Response ◽  
Vaccine Adjuvant ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Cellular Immune ◽  
Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important cytokine for the generation and propagation of antigen-presenting cells and for priming a cellular immune response. We report here that use of recombinant human GM-CSF (rhGM-CSF), administered as an adjuvant in a peptide-based vaccine trial given monthly by intradermal injection, led to the development of a T-cell and antibody response to rhGM-CSF. An antibody response occurred in the majority of patients (72%). This antibody response was not found to be neutralizing. In addition, by 48-hour delayed type hypersensitivity (DTH) skin testing, 17% of patients were shown to have a cellular immune response to the adjuvant rhGM-CSF alone. Thymidine incorporation assays also showed a peripheral blood T-cell response to rhGM-CSF in at least 17% of the patients. The generation of rhGM-CSF–specific T-cell immune responses, elicited in this fashion, is an important observation because rhGM-CSF is being used as a vaccine adjuvant in various vaccine strategies. rhGM-CSF–specific immune responses may be incorrectly interpreted as antigen-specific immunity, particularly when local DTH responses to vaccination are the primary means of immunologic evaluation. We found no evidence of hematologic or infectious complications as a result of the development of rhGM-CSF–specific immune responses.

Sign in / Sign up

Export Citation Format

Share Document