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Efficacy of cancer vaccines in selected gynaecological breast and ovarian cancers: A 20-year systematic review and meta-analysis

Published:November 19, 2020DOI:https://doi.org/10.1016/j.ejca.2020.10.014

      Highlights

      • First meta-analysis in therapeutic vaccines for breast/ovarian cancer.
      • Many alternative approaches have been tested in heterogeneous cohorts.
      • Most patients included in these studies were advanced and heavily pre-treated ones.
      • Response results are only modest, but survival rates are long and toxicity low.
      • More studies are needed to evaluate basic mechanisms and improve vaccines' efficacy.

      Abstract

      Background

      Therapeutic cancer vaccination is an area of interest, even though promising efficacy has not been demonstrated so far.

      Design

      A systematic review and meta-analysis was conducted to evaluate vaccines’ efficacy on breast cancer (BC) and ovarian cancer (OC) patients. Our search was based on the PubMed electronic database, from 1st January 2000 to 4th February 2020.

      Objective

      response rate (ORR) was the primary end-point of interest, while progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Analysis was performed separately for BC and OC patients. Pooled ORRs were estimated by fixed or random effects models, depending on the detected degree of heterogeneity, for all studies with more than five patients. Subgroup analyses by vaccine type and treatment schema as well as sensitivity analyses, were implemented.

      Results

      Among 315 articles initially identified, 67 were eligible for our meta-analysis (BC: 46, 1698 patients; OC: 32, 426 patients; where both BC/OC in 11). Dendritic-cell and peptide vaccines were found in more studies, 6/10 BC and 10/13 OC studies, respectively.
      In our primary BC analysis (21 studies; 428 patients), the pooled ORR estimate was 9% (95%CI[5%,13%]). The primary OC analysis (12 studies; 182 patients), yielded pooled ORR estimate of 4% (95%CI[1%,7%]). Similar were the results derived in sensitivity analyses. No statistically significant differences were detected by vaccine type or treatment schema.
      Median PFS was 2.6 months (95% confidence interval (CI)[1.9,2.9]) and 13.0 months (95%CI[8.5,16.3]) for BC and OC respectively, while corresponding median OS was 24.8 months (95%CI[15.0,46.0]) and 39.0 months (95%CI[31.0,49.0]). In almost all cases, the observed toxicity was only moderate.

      Conclusion

      Despite their modest results in terms of ORR, therapeutic vaccines in the last 20 years display relatively long survival rates and low toxicity. Since a plethora of different approaches have been tested, a better understanding of the underlying mechanisms is needed in order to further improve vaccine efficacy.

      Keywords

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      References

        • D'Amelio E.
        • Salemi S.
        • D'Amelio R.
        Anti-infectious human vaccination in historical perspective.
        Int Rev Immunol. 2015; : 1-32
        • Delany I.
        • Rappuoli R.
        • De Gregorio E.
        Vaccines for the 21st century.
        EMBO Mol Med. 2014; 6: 708-720
        • Rosenberg S.A.
        • Yang J.C.
        • Restifo N.P.
        Cancer immunotherapy: moving beyond current vaccines.
        Nat Med. 2004; 10: 909-915
        • Ophir E.
        • Bobisse S.
        • Coukos G.
        • Harari A.
        • Kandalaft L.E.
        Personalized approaches to active immunotherapy in cancer.
        Biochim Biophys Acta. 2016; 1865: 72-82
        • Lennerz V.
        • Fatho M.
        • Gentilini C.
        • Frye R.A.
        • Lifke A.
        • Ferel D.
        • et al.
        The response of autologous T cells to a human melanoma is dominated by mutated neoantigens.
        P Natl Acad Sci USA. 2005; 102: 16013-16018
        • Lee C.-H.
        • Yelensky R.
        • Jooss K.
        • Chan T.A.
        Update on tumour neoantigens and their utility: why it is good to Be different.
        Trends Immunol. 2018; 39: 536-548
        • Shevach E.M.
        • McHugh R.S.
        • Piccirillo C.A.
        • Thornton A.M.
        Control of T-cell activation by CD4+ CD25+ suppressor T cells.
        Immunol Rev. 2001; 182: 58-67
        • Hori S.
        • Takahashi T.
        • Sakaguchi S.
        Control of autoimmunity by naturally arising regulatory CD4+ T cells.
        Adv Immunol. 2003; 81: 331-371
        • Togashi Y.
        • Shitara K.
        • Nishikawa H.
        Regulatory T cells in cancer immunosuppression - implications for anticancer therapy.
        Nat Rev Clin Oncol. 2019; 16: 356-371
        • Ghiringhelli F.
        • Menard C.
        • Puig P.E.
        • Ladoire S.
        • Roux S.
        • Martin F.
        • et al.
        Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.
        Cancer Immunol Immunother. 2007; 56: 641-648
        • Lutsiak M.E.
        • Semnani R.T.
        • De Pascalis R.
        • Kashmiri S.V.
        • Schlom J.
        • Sabzevari H.
        • et al.
        Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide.
        Blood. 2005; 105: 2862-2868
        • Chu C.
        • Boyer J.
        • Schullery D.
        • Gimotty P.A.
        • Gamerman V.
        • Bender J.
        • et al.
        Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission.
        Cancer Immunol Immunother. 2012; 61: 629-641
        • Garcia A.A.
        • Hirte H.
        • Fleming G.
        • Yang D.
        • Tsao-Wei D.D.
        • Roman L.
        • et al.
        Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia.
        J Clin Oncol. 2008; 26: 76-82
        • Vermeij R.
        • Leffers N.
        • Hoogeboom B.-N.
        • Hamming I.L.E.
        • Wolf R.
        • Reyners A.K.L.
        • et al.
        Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: a single-arm phase II study.
        Int J Canc. 2012; 131: E670-E680
        • Dees E.C.
        • McKinnon K.P.
        • Kuhns J.J.
        • Chwastiak K.A.
        • Sparks S.
        • Myers M.
        • et al.
        Dendritic cells can be rapidly expanded ex vivo and safely administered in patients with metastatic breast cancer.
        Canc Immunol Immunother. 2004; 53: 777-785
        • Azoury S.C.
        • Straughan D.M.
        • Shukla V.
        Immune checkpoint inhibitors for cancer therapy: clinical efficacy and safety.
        Curr Cancer Drug Targets. 2015; 15: 452-462
        • Hodi F.S.
        • Butler M.
        • Oble D.A.
        • Seiden M.V.
        • Haluska F.G.
        • Kruse A.
        • et al.
        Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.
        Proc Natl Acad Sci U S A. 2008; 105: 3005-3010
        • Donnelly R.F.
        Vaccine delivery systems.
        Hum Vaccines Immunother. 2017; 13: 17-18
        • Martin Lluesma S.
        • Wolfer A.
        • Harari A.
        • Kandalaft L.
        Cancer vaccines in ovarian cancer: how can we improve?.
        Biomedicines. 2016; 4: 10
        • Cheang M.C.
        • Chia S.K.
        • Voduc D.
        • Gao D.
        • Leung S.
        • Snider J.
        • et al.
        Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer.
        J Natl Cancer Inst. 2009; 101: 736-750
        • Prat A.
        • Perou C.M.
        Deconstructing the molecular portraits of breast cancer.
        Mol Oncol. 2011; 5: 5-23
        • Loi S.
        • Sirtaine N.
        • Piette F.
        • Salgado R.
        • Viale G.
        • Van Eenoo F.
        • et al.
        Prognostic and predictive value of tumour-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.
        J Clin Oncol. 2013; 31: 860-867
        • Ibrahim E.M.
        • Al-Foheidi M.E.
        • Al-Mansour M.M.
        • Kazkaz G.A.
        The prognostic value of tumour-infiltrating lymphocytes in triple-negative breast cancer: a meta-analysis.
        Breast Canc Res Treat. 2014; 148: 467-476
        • Ali H.R.
        • Provenzano E.
        • Dawson S.J.
        • Blows F.M.
        • Liu B.
        • Shah M.
        • et al.
        Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients.
        Ann Oncol. 2014; 25: 1536-1543
        • Zhang L.
        • Conejo-Garcia J.R.
        • Katsaros D.
        • Gimotty P.A.
        • Massobrio M.
        • Regnani G.
        • et al.
        Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.
        N Engl J Med. 2003; 348: 203-213
        • Hwang W.T.
        • Adams S.F.
        • Tahirovic E.
        • Hagemann I.S.
        • Coukos G.
        Prognostic significance of tumour-infiltrating T cells in ovarian cancer: a meta-analysis.
        Gynecol Oncol. 2012; 124: 192-198
        • Odunsi K.
        Immunotherapy in ovarian cancer.
        Ann Oncol. 2017; 28: viii1-viii7
        • Kandalaft L.E.
        • Odunsi K.
        • Coukos G.
        Immunotherapy in ovarian cancer: are we there yet?.
        J Clin Oncol. 2019; (JCO.19)00508
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6
        • Dafni U.
        • Michielin O.
        • Lluesma S.M.
        • Tsourti Z.
        • Polydoropoulou V.
        • Karlis D.
        • et al.
        Efficacy of adoptive therapy with tumour-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis.
        Ann Oncol. 2019; 30: 1902-1913
        • Sterne J.A.
        • Hernán M.A.
        • Reeves B.C.
        • Savovic J.
        • Berkman N.D.
        • Viswanathan M.
        • et al.
        ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
        BMJ. 2016; 355: i4919
        • Higgins J.P.
        • Altman D.G.
        • Gotzsche P.C.
        • Jüni P.
        • Moher D.
        • Oxman A.D.
        • et al.
        The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Contr Clin Trials. 1986; 7: 177-188
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials revisited.
        Contemp Clin Trials. 2015; 45: 139-145
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Ott P.A.
        • Hu Z.
        • Keskin D.B.
        • Shukla S.A.
        • Sun J.
        • Bozym D.J.
        • et al.
        An immunogenic personal neoantigen vaccine for patients with melanoma.
        Nature. 2017; 547: 217-221
        • Carreno B.M.
        • Magrini V.
        • Becker-Hapak M.
        • Kaabinejadian S.
        • Hundal j.
        • Petti A.A.
        • et al.
        Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells.
        Science. 2015; 348: 803-808
        • Mougel A.
        • Terme M.
        • Tanchot C.
        Therapeutic cancer vaccine and combinations with antiangiogenic therapies and immune checkpoint blockade.
        Front Immunol. 2019; 10 (467-467)
        • Papa A.
        • Caruso D.
        • Strudel M.
        • Tomao S.
        • Tomao F.
        Update on Poly-ADP-ribose polymerase inhibition for ovarian cancer treatment.
        J Transl Med. 2016; 14 (267-267)
        • Pujade-Lauraine E.
        • Ledermann J.A.
        • Selle F.
        • Gebski V.
        • Penson R.T.
        • Oza A.M.
        • et al.
        Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2017; 18: 1274-1284
        • Final A.P.
        Overall survival (OS) results from SOLO2/ENGOT-ov21: a phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation.
        in: ASCO virtual scientific program. 2020
        • Franzese E.
        • Centonze S.
        • Diana A.
        • Carlino F.
        • Guerrera L.P.
        • Di Napoli M.
        • et al.
        PARP inhibitors in ovarian cancer.
        Canc Treat Rev. 2019; 73: 1-9
        • Melief C.J.M.
        • Welters M.J.P.
        • Vergote I.
        • Kroep J.R.
        • Kenter G.G.
        • Ottevanger P.B.
        • et al.
        Strong vaccine responses during chemotherapy are associated with prolonged cancer survival.
        Sci Transl Med. 2020; 12: eaaz8235
        • Massarelli E.
        • William W.
        • Johnson F.
        • Kies M.
        • Ferrarotto R.
        • Guo M.
        • et al.
        Combining immune checkpoint blockade and tumour-specific vaccine for patients with incurable human papillomavirus 16–related cancer: a phase 2 clinical trial.
        JAMA Oncology. 2019; 5: 67-73
        • Harari A.
        • Graciotti M.
        • Bassani-Sternberg M.
        • Kandalaft L.E.
        Antitumour dendritic cell vaccination in a priming and boosting approach.
        Nat Rev Drug Discov. 2020; 19: 635-652
        • Martin-Lluesma S.
        • Graciotti M.
        • Grimm A.J.
        • Boudousquié C.
        • Chiang C.L.
        • Kandalaft L.E.
        Are dendritic cells the most appropriate therapeutic vaccine for patients with ovarian cancer?.
        Curr Opin Biotechnol. 2020; 65: 190-196
        • Nishat S.
        • Andreana P.R.
        Entirely carbohydrate-based vaccines: an emerging field for specific and selective immune responses.
        Vaccines. 2016; 4: 19https://doi.org/10.3390/vaccines4020019
        • Larocca C.
        • Schlom J.
        Viral vector-based therapeutic cancer vaccines.
        Cancer J. 2011; 17: 359-371https://doi.org/10.1097/PPO.0b013e3182325e63
        • Zhao X.
        • Li Z.
        • Gu B.
        • Frankel F.R.
        Pathogenicity and immunogenicity of a vaccine strain of listeria monocytogenes that relies on a suicide plasmid to supply an essential gene product.
        Infect Immun. 2005; 73: 5789https://doi.org/10.1128/IAI.73.9.5789-5798.2005
        • Starks H.
        • Bruhn K.W.
        • Shen H.
        • Barry R.A.
        • Dubensky T.W.
        • Brockstedt D.
        • et al.
        Listeria monocytogenes as a vaccine vector: virulence attenuation or existing antivector immunity does not diminish therapeutic efficacy.
        J Immunol. 2004; 173: 420https://doi.org/10.4049/jimmunol.173.1.420
        • Jiang X.P.
        • Yang D.C.
        • Elliott R.L.
        • Head J.F.
        Vaccination with a mixed vaccine of autogenous and allogeneic breast cancer cells and tumor associated antigens CA15-3, CEA and CA125--results in immune and clinical responses in breast cancer patients.
        Cancer Biother Radiopharm. 2000; 15: 495-505https://doi.org/10.1089/cbr.2000.15.495
        • Scholl S.M.
        • Balloul J.M.
        • Le Goc G.
        • Bizouarne N.
        • Schatz C.
        • Kieny M.P.
        Recombinant vaccinia virus encoding human MUC1 and IL2 as immunotherapy in patients with breast cancer.
        J Immunother. 2000; 23: 570-580https://doi.org/10.1097/00002371-200009000-00007
        • Triozzi P.L.
        • Khurram R.
        • Aldrich W.A.
        • Walker M.J.
        • Kim J.A.
        • Jaynes S.
        Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer.
        Cancer. 2000; 89: 2646-2654https://doi.org/10.1002/1097-0142(20001215)89:12<2646::aid-cncr18>3.0.co;2-a
        • Gilewski T.
        • Ragupathi G.
        • Bhuta S.
        • Williams L.J.
        • Musselli C.
        • Zhang X.-F.
        Immunization of metastatic breast cancer patients with a fully synthetic globo H conjugate: a phase I trial.
        Proc Natl Acad Sci USA. 2001; 98: 3270-3275https://doi.org/10.1073/pnas.051626298
        • Pecher G.
        • Häring A.
        • Kaiser L.
        • Thiel E.
        Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a phase I/II clinical trial.
        Cancer Immunol Immunother. 2002; 51: 669-673https://doi.org/10.1007/s00262-002-0317-z
        • Dols A.
        • Smith 2nd, J.W.
        • Meijer S.L.
        • Fox B.A.
        • Hu H.M.
        • Walker E.
        Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: clinical and immunological results.
        Hum Gene Ther. 2003; 14: 1117-1123https://doi.org/10.1089/104303403322124828
        • Holmberg L.A.
        • Oparin D.V.
        • Gooley T.
        • Sandmaier B.M.
        The role of cancer vaccines following autologous stem cell rescue in breast and ovarian cancer patients: experience with the STn-KLH vaccine (Theratope).
        Clin Breast Cancer. 2003; 3: S144-S151https://doi.org/10.3816/cbc.2003.s.004
        • Avigan D.
        • Vasir B.
        • Gong J.
        • Borges V.
        • Wu Z.
        • Uhl L.
        • et al.
        Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunological and clinical responses.
        Clin Cancer Res. 2004; 10: 4699-4708https://doi.org/10.1158/1078-0432.Ccr-04-0347
        • Svane I.M.
        • Pedersen A.E.
        • Johnsen H.E.
        • Nielsen D.
        • Kamby C.
        • Gaarsdal E.
        • et al.
        Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study.
        Cancer Immunol Immunother. 2004; 53: 633-641https://doi.org/10.1007/s00262-003-0493-5
        • Vonderheide R.H.
        • Domchek S.M.
        • Schultze J.L.
        • George D.J.
        • Hoar K.M.
        • Chen D.Y.
        Vaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes.
        Clin Cancer Res. 2004; 10: 828-839https://doi.org/10.1158/1078-0432.ccr-0620-3
        • Lasalvia-Prisco E.
        • Vázquez J.
        • Golomar W.
        • Larrañaga J.
        • García-Giralt E.
        • Cucchi S.
        • et al.
        Advanced breast cancer: anti-progressive immunotherapy using a thermostable autologous hemoderivative.
        Breast Cancer Res Treat. 2006; 100: 149-160https://doi.org/10.1007/s10549-006-9235-7
        • Loveland B.E.
        • Zhao A.
        • White S.
        • Gan H.
        • Hamilton K.
        • Xing P.X.
        • et al.
        Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma.
        Clin Cancer Res. 2006; 12: 869-877https://doi.org/10.1158/1078-0432.Ccr-05-1574
        • Morita S.
        • Oka Y.
        • Tsuboi A.
        • Kawakami M.
        • Maruno M.
        • Izimoto S.
        A phase I/II trial of a WT1 (Wilms’ tumor gene) peptide vaccine in patients with solid malignancy: safety assessment based on the phase I data.
        Jpn J Clin Oncol. 2006; 36: 231-236https://doi.org/10.1093/jjco/hyl005
        • Ciocca D.R.
        • Frayssinet P.
        • Cuello-Carrión F.D.
        A pilot study with a therapeutic vaccine based on hydroxyapatite ceramic particles and self-antigens in cancer patients.
        Cell Stress Chaperones. 2007; 12: 33-43https://doi.org/10.1379/csc-218r.1
        • Gilewski T.A.
        • Ragupathi G.
        • Dickler M.
        • Powell S.
        • Bhuta S.
        • Panageas K.
        • et al.
        Immunization of high-risk breast cancer patients with clustered sTn-KLH conjugate plus the immunologic adjuvant QS-21.
        Clin Cancer Res. 2007; 13: 2977-2985https://doi.org/10.1158/1078-0432.Ccr-06-2189
        • Mayordomo J.I.
        • Andrés R.
        • Isla M.D.
        • Murillo L.
        • Cajal R.
        • Yubero A.
        • et al.
        Results of a pilot trial of immunotherapy with dendritic cells pulsed with autologous tumor lysates in patients with advanced cancer.
        Tumori. 2007; 93: 26-30
        • Morse M.A.
        • Hobeika A.
        • Osada T.
        • Niedzwiecki D.
        • Marcom P.K.
        • Blackwell K.L.
        • et al.
        Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2.
        J Transl Med. 2007; 5: 42https://doi.org/10.1186/1479-5876-5-42
        • Park J.W.
        • Melisko M.E.
        • Esserman L.J.
        • Jones L.A.
        • Wollan J.B.
        • Sims R.
        Treatment with autologous antigen-presenting cells activated with the HER-2 based antigen Lapuleucel-T: results of a phase I study in immunologic and clinical activity in HER-2 overexpressing breast cancer.
        J Clin Oncol. 2007; 25: 3680-3687https://doi.org/10.1200/jco.2006.10.5718
        • Svane I.M.
        • Pedersen A.E.
        • Johansen J.S.
        • Johansen H.E.
        • Nielsen D.
        • Kamby C.
        • et al.
        Vaccination with p53 peptide-pulsed dendritic cells is associated with disease stabilization in patients with p53 expressing advanced breast cancer; monitoring of serum YKL-40 and IL-6 as response biomarkers.
        Cancer Immunol Immunother. 2007; 56: 1485-1499https://doi.org/10.1007/s00262-007-0293-4
        • Gulley J.L.
        • Arlen P.M.
        • Tsang K.Y.
        • Yokokawa J.
        • Palena C.
        • Poole D.J.
        Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma.
        Clin Cancer Res. 2008; 14: 3060-3069https://doi.org/10.1158/1078-0432.Ccr-08-0126
        • Tsuruma T.
        • Iwayama Y.
        • Ohmura T.
        • Katsuramaki T.
        • Hata F.
        • Furuhata T.
        • et al.
        Clinical and immunological evaluation of anti-apoptosis protein, survivin-derived peptide vaccine in phase I clinical study for patients with advanced or recurrent breast cancer.
        J Transl Med. 2008; 6: 24https://doi.org/10.1186/1479-5876-6-24
        • Disis M.L.
        • Wallace D.R.
        • Gooley T.A.
        • Dang Y.
        • Slota M.
        • Lu H.
        • et al.
        Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer.
        J Clin Oncol. 2009; 27: 4685-4692https://doi.org/10.1200/jco.2008.20.6789
        • Kaumaya P.T.
        • Foy K.C.
        • Garrett J.
        • Rawale S.V.
        • Vicari D.
        • Thurmond J.M.
        • et al.
        Phase I active immunotherapy with combination of two chimeric, human epidermal growth factor receptor 2, B-cell epitopes fused to a promiscuous T-cell epitope in patients with metastatic and/or recurrent solid tumors.
        J Clin Oncol. 2009; 27: 5270-5277https://doi.org/10.1200/jco.2009.22.3883
        • Peethambaram P.P.
        • Melisko M.E.
        • Rinn K.J.
        • Alberts S.R.
        • Provost N.M.
        • Jones L.A.
        • et al.
        A phase I trial of immunotherapy with lapuleucel-T (APC8024) in patients with refractory metastatic tumors that express HER-2/neu.
        Clin Cancer Res. 2009; 15: 5937-5944https://doi.org/10.1158/1078-0432.Ccr-08-3282
        • Norell H.
        • Poschke I.
        • Charo J.
        • Wei W.Z.
        • Erskine C.
        • Piechocki M.P.
        Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial.
        J Transl Med. 2010; 8: 53https://doi.org/10.1186/1479-5876-8-53
        • Baek S.
        • Kim C.S.
        • Kim S.B.
        • Kim Y.M.
        • Kwon S.W.
        • Kim Y.
        • et al.
        Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial.
        J Transl Med. 2011; 9: 178https://doi.org/10.1186/1479-5876-9-178
        • Miles D.
        • Roché H.
        • Martin M.
        • Perren T.J.
        • Cameron D.A.
        • Glaspy J.
        Phase III multicenter clinical trial of the sialyl-TN (STn)-keyhole limpet hemocyanin (KLH) vaccine for metastatic breast cancer.
        Oncologist. 2011; 16: 1092-1100https://doi.org/10.1634/theoncologist.2010-0307
        • Morse M.A.
        • Secord A.A.
        • Blackwell K.
        • Hobeika A.C.
        • Sinnathamby G.
        • Osada T.
        • et al.
        MHC class I-presented tumor antigens identified in ovarian cancer by immunoproteomic analysis are targets for T-cell responses against breast and ovarian cancer.
        Clin Cancer Res. 2011; 17: 3408-3419https://doi.org/10.1158/1078-0432.Ccr-10-2614
        • Hamilton E.
        • Blackwell K.
        • Hobeika A.C.
        • Clay T.M.
        • Broadwater G.
        • Ren X.R.
        • et al.
        Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected].
        J Transl Med. 2012; 10: 28https://doi.org/10.1186/1479-5876-10-28
        • Qi C.J.
        • Ning Y.L.
        • Han Y.S.
        • Min H.Y.
        • Ye H.
        • Zhu Y.L.
        • et al.
        Autologous dendritic cell vaccine for estrogen receptor (ER)/progestin receptor (PR) double-negative breast cancer.
        Cancer Immunol Immunother. 2012; 61: 1415-1424https://doi.org/10.1007/s00262-011-1192-2
        • Rech A.J.
        • Mick R.
        • Martin S.
        • Recio A.
        • Aqui N.A.
        • Powell Jr., D.J.
        • et al.
        CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients.
        Sci Transl Med. 2012; 4: 134ra62https://doi.org/10.1126/scitranslmed.3003330
        • Senzer N.
        • Barve M.
        • Kuhn J.
        • Melnyk A.
        • Beitsch P.
        • Lazar M.
        • et al.
        Phase I trial of “bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell” vaccine (FANG) in advanced cancer.
        Mol Ther. 2012; 20: 679-686https://doi.org/10.1038/mt.2011.269
        • Vassilaros S.
        • Tsibanis A.
        • Tsikkinis A.
        • Pietersz G.A.
        • McKenzie I.F.
        • Apostolopoulos V.
        Up to 15-year clinical follow-up of a pilot Phase III immunotherapy study in stage II breast cancer patients using oxidized mannan-MUC1.
        Immunotherapy. 2013; 5: 1177-1182https://doi.org/10.2217/imt.13.126
        • Bapsy P.P.
        • Sharan B.
        • Kumar C.
        • Das R.P.
        • Rangarajan B.
        • Jain M.
        • et al.
        Open-label, multi-center, non-randomized, single-arm study to evaluate the safety and efficacy of dendritic cell immunotherapy in patients with refractory solid malignancies, on supportive care.
        Cytotherapy. 2014; 16: 234-244https://doi.org/10.1016/j.jcyt.2013.11.013
        • Chen G.
        • Gupta R.
        • Petrik S.
        • Laiko M.
        • Leatherman J.M.
        • Asquith J.M.
        • et al.
        A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer.
        Cancer Inmunol Res. 2014; 2: 949-961https://doi.org/10.1158/2326-6066.Cir-14-0058
        • Takashashi R.
        • Toh U.
        • Iwakuma N.
        • Takenaka M.
        • Otsuka H.
        • Furukawa M.
        • et al.
        Feasibility study of personalized peptide vaccination for metastatic recurrent triple-negative breast cancer patients.
        Breast Cancer Res. 2014; 16: R70https://doi.org/10.1186/bcr3685
        • Tiriveedhi V.
        • Tucker N.
        • Herndon J.
        • Li L.
        • Sturmoski M.
        • Ellis M.
        Safety and preliminary evidence of biologic efficacy of a mammaglobin-a DNA vaccine in patients with stable metastatic breast cancer.
        Clin Cancer Res. 2014; 20: 5964-5975https://doi.org/10.1158/1078-0432.ccr-14-0059
        • Heery C.R.
        • Ibrahim N.K.
        • Arlen P.M.
        • Mohebtash M.
        • Murray J.L.
        • Koenig K.
        • et al.
        Docetaxel alone or in combination with a therapeutic cancer vaccine (PANVAC) in patients with metastatic breast cancer: a randomized clinical trial.
        JAMA Oncol. 2015; 1: 1087-1095https://doi.org/10.1001/jamaoncol.2015.2736
        • Sakamoto S.
        • Matsueda S.
        • Takamori S.
        • Toh U.
        • Noguchi M.
        • Yutani S.
        • et al.
        Immunological evaluation of peptide vaccination for cancer patients with the HLA-A26 allele.
        Cancer Sci. 2015; 106: 1257-1263https://doi.org/10.1111/cas.12757
        • Antonilli M.
        • Rahimi H.
        • Visconti V.
        • Napoletano C.
        • Ruscito I.
        • Zizzari I.G.
        • et al.
        Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: Clinical and immunological data of a phase I/II clinical trial.
        Int J Oncol. 2016; 48: 1369-1378https://doi.org/10.3892/ijo.2016.3386
        • Curigliano G.
        • Romieu G.
        • Campone M.
        • Dorval T.
        • Duck L.
        • Canon J.L.
        • et al.
        A phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer.
        Breast Cancer Res Treat. 2016; 156: 301-310https://doi.org/10.1007/s10549-016-3750-y
        • Higgins M.
        • Curigliano G.
        • Dieras V.
        • Kuemmel S.
        • Kunz G.
        • Fasching P.A.
        • et al.
        Safety and immunogenicity of neoadjuvant treatment using WT1-immunotherapeutic in combination with standard therapy in patients with WT1-positive stage II/III breast cancer: a randomized phase I study.
        Breast Cancer Res Treat. 2017; 162: 479-488https://doi.org/10.1007/s10549-017-4130-y
        • Kalli K.R.
        • Block M.S.
        • Kasi P.M.
        • Erskine C.L.
        • Hobday T.J.
        • Dietz A.
        • et al.
        Folate receptor alpha peptide vaccine generates immunity in breast and ovarian cancer patients.
        Clin Cancer Res. 2018; 24: 3014-3025https://doi.org/10.1158/1078-0432.ccr-17-2499
        • Zhang W.
        • Lu X.
        • Cui P.
        • Piao C.
        • Xiao M.
        • Liu X.
        • et al.
        Phase I/II clinical trial of a Wilms’ tumor 1-targeted dendritic cell vaccination-based immunotherapy in patients with advanced cancer.
        Cancer Immunol Immunother. 2019; 68: 121-130https://doi.org/10.1007/s00262-018-2257-2
        • Chung V.
        • Kos F.J.
        • Hardwick N.
        • Yuan Y.
        • Chao J.
        • Li D.
        • et al.
        Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.
        Clin Transl Oncol. 2019; 21: 363-372https://doi.org/10.1007/s12094-018-1932-2
        • Hernando J.
        • Park T.-W.
        • Kübler K.
        • Offergeld R.
        • Schlebusch H.
        • Bauknecht T.
        Vaccination with autologous tumour antigen-pulsed dendritic cells in advanced gynaecological malignancies: clinical and immunological evaluation of a phase I trial.
        Cancer Immunol Immunother. 2002; 51: 45-52https://doi.org/10.1007/s00262-001-0255-1
        • Fredman R.S.
        • Vadhan-Raj S.
        • Butts C.
        • Savary C.
        • Melichar B.
        • Verschraegen C.
        • et al.
        Pilot study of Flt3 ligand comparing intraperitoneal with subcutaneous routes on hematologic and immunologic responses in patients with peritoneal carcinomatosis and mesotheliomas.
        Clin Cancer Res. 2003; 9: 5228-5237
        • Tsuda N.
        • Mochizuki K.
        • Harada M.
        • Sukehiro A.
        • Kawano K.
        • Yamada A.
        • et al.
        Vaccination with predesignated or evidence-based peptides for patients with recurrent gynecologic cancers.
        J Immunother. 2004; 27: 60-72https://doi.org/10.1097/00002371-200401000-00006
        • Chianese-Bullock K.A.
        • Irvin Jr., W.P.
        • Petroni G.R.
        • Murphy C.
        • Smolkin M.
        • Olson W.C.
        • et al.
        A multipeptide vaccine is safe and elicits T-cell responses in participants with advanced stage ovarian cancer.
        J Immunother. 2008; 31: 420-430https://doi.org/10.1097/CJI.0b013e31816dad10
        • Diefenbach C.S.
        • Gnjatic S.
        • Sabbatini P.
        • Aghajanian C.
        • Hensley M.L.
        • Spriggs D.R.
        • et al.
        Safety and immunogenicity study of NY-ESO-1b peptide and montanide ISA-51 vaccination of patients with epithelial ovarian cancer in high-risk first remission.
        Clin Cancer Res. 2008; 14: 2740-2748https://doi.org/10.1158/1078-0432.ccr-07-4619
        • Galanis E.
        • Hartmann L.C.
        • Cliby W.A.
        • Long H.J.
        • Peethambaram P.P.
        • Barrette B.A.
        • et al.
        Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer.
        Cancer Res. 2010; 70: 875-882https://doi.org/10.1158/0008-5472.can-09-2762
        • Le D.T.
        • Brockstedt D.G.
        • Nir-Paz R.
        • Hampl J.
        • Mathur S.
        • Nemunaitis J.
        • et al.
        A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction.
        Clin Cancer Res. 2012; 18: 858-868https://doi.org/10.1158/1078-0432.ccr-11-2121
        • Leffers N.
        • Vermeij R.
        • Hoogeboom B.N.
        • Schulze U.R.
        • Wolf R.
        • Hamming I.E.
        • et al.
        Long-term clinical and immunological effects of p53-SLP® vaccine in patients with ovarian cancer.
        Int J Cancer. 2012; 130: 105-112https://doi.org/10.1002/ijc.25980
        • Odunsi K.
        • Matsuzaki J.
        • Karbach J.
        • Neumann A.
        • Mhawech-Fauceglia P.
        • Miller A.
        • et al.
        Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients.
        Proc Natl Acad Sci U S A. 2012; 109: 5797-5802https://doi.org/10.1073/pnas.1117208109
        • Rahma O.E.
        • Ashtar E.
        • Czystowska M.
        • Szajnik M.E.
        • Wieckowski E.
        • Bernstein S.
        • et al.
        A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients.
        Cancer Immunol Immunother. 2012; 61: 373-384https://doi.org/10.1007/s00262-011-1100-9
        • Senzer N.
        • Barve M.
        • Kuhn J.
        • Melnyk A.
        • Beitsch P.
        • Lazar M.
        • et al.
        Phase I trial of “bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell” vaccine (FANG) in advanced cancer.
        Mol Ther. 2012; 20: 679-686https://doi.org/10.1038/mt.2011.269
        • Chiang C.L.
        • Kandalaft L.E.
        • Tanyi J.
        • Hagemann A.R.
        • Motz G.T.
        • Svoronos N.
        • et al.
        A dendritic cell vaccine pulsed with autologous hypochlorous acid-oxidized ovarian cancer lysate primes effective broad antitumor immunity: from bench to bedside.
        Clin Cancer Res. 2013; 19: 4801-4815https://doi.org/10.1158/1078-0432.ccr-13-1185
        • Kandalaft L.E.
        • Powell Jr., D.J.
        • Chiang C.L.
        • Tanyi J.
        • Kim S.
        • Bosch M.
        • et al.
        Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer.
        Oncoimmunology. 2013; 2: e2264https://doi.org/10.4161/onci.22664
        • Kawano K.
        • Tsuda N.
        • Matsueda S.
        • Sasada T.
        • Watanabe N.
        • Ushijima K.
        • et al.
        Feasibility study of personalized peptide vaccination for recurrent ovarian cancer patients.
        Immunopharmacol Immunotoxicol. 2014; 36: 224-236https://doi.org/10.3109/08923973.2014.913617
        • Kobayashi M.
        • Chiba A.
        • Izawa H.
        • Yanagida E.
        • Okamoto M.
        • Shimodaira S.
        • et al.
        The feasibility and clinical effects of dendritic cell-based immunotherapy targeting synthesized peptides for recurrent ovarian cancer.
        J Ovarian Res. 2014; 7: 48https://doi.org/10.1186/1757-2215-7-48
        • Odunsi K.
        • Matsuzaki J.
        • James S.R.
        • Mhawech-Fauceglia P.
        • Tsuji T.
        • Miller A.
        • et al.
        Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer.
        Cancer Immunol Res. 2014; 2: 37-49https://doi.org/10.1158/2326-6066.cir-13-0126
        • Baek S.
        • Kim Y.-M.
        • Kim S.-B.
        • Kim C.-S.
        • Kwon Y.
        • Kim H.
        • et al.
        Therapeutic DC vaccination with IL-2 as a consolidation therapy for ovarian cancer patients: a phase I/II trial.
        Cell Mol Immunol. 2015; 12: 87-95https://doi.org/10.1038/cmi.2014.40
        • Dijkgraaf E.M.
        • Santegoets S.J.A.M.
        • Reyners A.K.L.
        • Goedemans R.
        • Nijman H.W.
        • van Poelgeest M.I.E.
        • et al.
        A phase 1/2 study combining gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer.
        Oncotarget. 2015; 6: 32228-32243https://doi.org/10.18632/oncotarget.4772
        • Hardwick N.R.
        • Frankel P.
        • Ruel C.
        • Kilpatrick J.
        • Tsai W.
        • Kos F.
        • et al.
        p53-Reactive T cells are associated with clinical benefit in patients with platinum-resistant epithelial ovarian cancer after treatment with a p53 vaccine and gemcitabine chemotherapy.
        Clin Cancer Res. 2018; 24: 1315-1325https://doi.org/10.1158/1078-0432.ccr-17-2709
        • O’Cearbhaill R.E.
        • Deng W.
        • Chen L.-M.
        • Lucci III, J.A.
        • Behbakht K.
        • Spirtos N.M.
        • et al.
        A phase II randomized, double-blind trial of a polyvalent Vaccine-KLH conjugate (NSC 748933 IND# 14384) + OPT-821 versus OPT-821 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer who are in second or third complete remission: an NRG Oncology/GOG study.
        Gynecol Oncol. 2019; 155: 393-399https://doi.org/10.1016/j.ygyno.2019.09.015