Vaccines in Ovarian Cancer: Comparison
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Ovarian cancer remains the deadliest of all gynecologic malignancies. Our expanding knowledge of ovarian cancer immunology has allowed the development of therapies that generate systemic anti-tumor immune responses. Current immunotherapeutic strategies include immune checkpoint blockade, cellular therapies, and cancer vaccines. Vaccine-based therapies are designed to induce both adaptive and innate immune responses directed against ovarian cancer associated antigens. Tumor-specific effector cells, in particular cytotoxic T cells, are activated to recognize and eliminate ovarian cancer cells. Vaccines for ovarian cancer have been studied in various clinical trials over the last three decades. Despite evidence of vaccine-induced humoral and cellular immune responses, the majority of vaccines have not shown significant anti-tumor efficacy. Recently, improved vaccine development using dendritic cells or synthetic platforms for antigen presentation have shown promising clinical benefits in patients with ovarian cancer. 

  • ovarian cancer
  • vaccines

1. Dendritic Cell Vaccines

Dendritic cells (DCs) play a critical role in innate and adaptive immune responses. DCs are potent antigen presenting cells that capture and process antigens. Antigen presentation at local lymph node sites by dendritic cells stimulate antigen-specific cytotoxic T cells [63][1]. Vaccine development has sought to capitalize on the role DCs play in antitumor immunity. DCs pulsed with tumor-associated antigens have been shown effective as vaccine therapy in various cancer types [64][2].
Peptide-loaded and tumor lysate-loaded DCs are the two main strategies when using DCs as vaccines. Peptide-loaded DCs are pulsed with recombinant peptides prior to reinfusion. Data from various clinical trials have been published, providing positive efficacy signals (Table 1). Among these trials, Brossart and colleagues administered HER-2/neu or MUC1-derived peptide-pulsed dendritic cells in heavily pretreated metastatic breast and ovarian cancer patients [21][3]. One patient with ovarian cancer progression had a stable disease for over eight months while on therapy. Their study paved the way for additional peptide-pulsed DC vaccination therapies [22,24,27][4][5][6]. Loveland et al. used DCs pulsed with mannan-MUC1 fusion protein in 11 patients with adenocarcinomas. One ovarian cancer patient showed stable disease over three years of treatment [22][4]. Peethambaram et al. administered DCs loaded with recombinant HER-2/neu peptide and a granulocyte-macrophage colony-stimulating factor (GM-CSF) domain [24][5]. Two out of four ovarian cancer patients demonstrated stable disease over 15.7–18.3 months. WT1 peptide vaccines have had modest efficacy as demonstrated in various studies. The addition of low-dose cyclophosphamide prior to vaccination can potentially enhance vaccine potency [25][7]. In one study by Chu et al. using a HER-2/neu, hTERT, and PADRE peptide pulsed vaccine for maintenance therapy after treatment of recurrent ovarian cancer, 6 of 11 patients had no evidence of disease at 36 months, and the three-year progression-free survival was 80% with cyclophosphamide compared with 40% without. More recently, Gray et al. utilized a DC vaccine as maintenance therapy in epithelial ovarian cancer patients previously treated with one or two lines of conventional chemotherapy in complete remission [28][8]. CAN-003 was a phase 2b trial utilizing a MUC-1 protein-targeted DC vaccine. The treatment did not result in an increase in PFS or overall survival (OS), however patients in complete remission after second-line therapy were noted to have an improved OS with vaccination compared with controls (median OS 25.5 months with standard therapy vs. OS not yet reached with vaccination; HR 0.17; 95% CI 0.02–1.44; p = 0.07). DCs pulsed with neoantigen peptides have also been applied in the clinical setting [29,65][9][10]. Morisaki and colleagues administered a neoantigen peptide-pulsed DC in a case study of a woman with advanced stage ovarian cancer [29][9]. Following four rounds of vaccination, the patient had a significant decline in CA-125 levels with evidence of neoantigen-specific CTLs induced by vaccination.
Table 1. Summary of published clinical trials on ovarian cancer vaccines with clinical outcome to date.
VaccineDescriptionTotal Patients (OC Patients)Clinical Outcome *Reference
DCs (peptide-pulsed)
HER-2/neu or MUC1-derived peptidePhase 1/2 study in heavily pretreated metastatic breast and ovarian cancer10 (3)1 SD over 8 months

1 SD over 8 weeks		Brossart et al., 2000 [3]
Mannan-MUC1Phase 1 study in MUC1+ adenocarcinoma11 (1)1 SDLoveland et al., 2006 [4]
mRNA-encoded FR-αPilot study in a patient with recurrent ovarian cancer11 PRHernando et al., 2007 [11]
Lapuleucel-T, pulsed with BA7072, a recombinant fusion protein of HER-2/neu sequences linked to GM-CSFPhase 1 study in HER-2/neu expressing metastatic breast, ovarian, and colorectal cancer18 (4)2 SD over 15.7–18.3 monthsPeethambaram et al., 2009 [5]
HER-2/neu, hTERT, and PADREPhase 1/2 study in advanced ovarian cancer after first recurrence, randomized to receive low-dose cyclophosphamide prior to vaccination116 NED at 36 months

3-yr PFS 80%

3-yr OS 100%		Chu et al., 2012 [7]
WT1 mRNA-loaded DCPhase 1 study in epithelial ovarian carcinoma (OC) and ovarian carcinosarcoma (OCS)2OS 19 (OCS) and 12 (OC) months after drug cessationCoosemans et al., 2013 [12]
Combinations of WT1, MUC1, and CA125Retrospective study including patients with recurrent ovarian cancer561-yr OS 87%

2-yr OS 65%

2 PR, 14 SD

DCR 29%

ORR 3.6%		Kobayashi et al., 2014 [6]
CVac, MUC-1 targeted DCPhase 2b study (CAN-003 trial) in epithelial ovarian cancer as maintenance therapy56PFS 13 months CVac vs. 9 mo standard of care (HR 0.72, p = 0.33)

Median OS 25.5 months with standard therapy vs. not yet reached with CVac (HR 0.17; 95% CI 0.02–1.44; p = 0.07)		Gray et al., 2016 [8]
Neoantigen peptidesPilot study in a patient with advance ovarian cancer1CA-125 decreased from 4470 to 1303 U/mL. Patient expired approx. 1 year from treatment startMorisaki et al., 2020 [9]
DCs (whole tumor lysate-pulsed)
Pulsed with KLH and autologous tumor cell lysatePhase 1 study in advanced gynecologic malignancies8 (6)PFI 25.5 monthsHernando et al., 2002 [13]
Pulsed with autologous tumor cell lysate supernatantPilot study in advanced ovarian cancer where patients were treated with metronomic cyclophosphamide and bevacizumab followed by vaccination62 PR

2 SD		Kandalaft et al., 2013 [14]
DC pulsed with autologous hypochlorous acid-oxidized ov ca lysatePilot study in advanced ovarian cancer52 SD

2 PD

1 mixed response		Chiang et al., 2013 [15]
APCEDEN, whole-tumor lysate pulsed DCsPhase 2 study in refractory solid malignancies51 (7)1 PR

2 SD		Bapsy et al., 2014 [16]
Pulsed with oxidized autologous whole-tumor cell lysatePilot study in recurrent ovarian cancer using autologous vaccine with bevacizumab and cyclophosphamide252 PR

14 SD		Tanyi et al., 2018 [17]
CTA
ESO157–170Phase 1 study in NY-ESO-1-expressing ovarian cancers18PFS 19.0 monthsOdunsi et al., 2007 [18]
NY-ESO-1b peptide and Montanide ISA-51Phase 1 study in “high-risk” ovarian cancer9PFS 13.0 monthsDiefenbach et al., 2008 [19]
Synthetic overlapping long peptide from NY-ESO-1, Montanide ISA-51, and Poly-ICLCPhase 1 study in advanced ovarian cancer in 2nd or 3rd remission286 NED

PFS range of 17–46 months		Sabbatini et al., 2012 [20]
NY-ESO-1, decitabine, and GM-CSFPhase 1 study in relapsed ovarian cancer receiving doxorubicin as salvage therapy121 PR

5 SD		Odunsi et al., 2014 [21]
Protein/Peptide
HER-2/neu and GM-CSFPhase 1 study in stage III or IV breast or ovarian cancer6 (2)Responses short-livedKnutson et al., 2002 [22]
p53-SLPPhase 2 study in recurrent epithelial ovarian cancer202 SDLeffers et al., 2009 [23]
p53-SLPLong term outcomes of 2009 phase 2 study20RR 60.0%

Median DSS 44.0 months		Leffers et al., 2012 [24]
p53-SLP with cyclophosphamidePhase 2 study in recurrent ovarian cancer102 SDVermeij et al., 2011 [25]
Wildtype p53 vaccine with Montanide and GM-CSF; p53-pulsed DCPhase 2 study in high recurrence risk ovarian cancer. Two p53 vaccine approaches tested13Median OS 40.8 and 29.6 months arm A and B, respectively

Median PFS 4.2 and 8.7 months, respectively		Rahma et al., 2012 [26]
Flt3 ligandPilot study in peritoneal carcinomatosis or mesothelioma patients15 (9)No objective responsesFreedman et al., 2003 [27]
Anti-idiotypic antibody vaccine (ACA125)Phase 1/2b study in advanced ovarian cancer119Median OS 19.4 months (range 0.5–56.1 months)

Ab3-positive patients had significantly longer survival time (median 23.4 mo, p < 0.0001) compared with Ab3-negative (median 4.9 mo)		Reinartz et al., 2004 [28]
Regimen 1: predesignated SART2 or ART4-derived peptide

Regimen 2: peptides to which preexisting CTL precursor		Two regimens with different peptide vaccine regimens in recurrent gynecologic cancersRegimen 1: 4 (2)

Regimen 2: 10 (3)		Regimen 1: 0 response

Regimen 2: 1 SD		Tsuda et al., 2004 [29]
Multipeptide vaccine with Montanide ISA-51 and GM-CSFPhase 1 study in HLA-A1+, HLA-A2+, or HLA-A3+ epithelial ovarian, fallopian tube, or primary peritoneal carcinoma9DFS 19 months in 1 patientChianese-Bullock et al., 2008 [30]
WT1 peptide + Montanide ISA51Phase 1 study in gynecological cancer patients with WT1/HLA-A *2402 positive tumors12 (6)1 SDOhno et al., 2009 [31]
WT1 peptide vaccinePhase 2 study in progressive gynecologic cancers40 (24)10 SD

OS HR 1.17 (95% CI 0.44–3.14; p = 0.75)		Miyatake et al., 2013 [32]
Multipeptide vaccine with Montanide ISA-51 and CM-CSFPhase 1 study in HLA-A2+, stage II to IV epithelial ovaria, tubal, or primary peritoneal carcinoma after 1st or 2nd cytoreductive surgery with a complete clinical response15 (8)Median survival not reachedMorse et al., 2011 [33]
Personalized peptide vaccine (based on HLA-A types and IgG responses to peptides in pre-vaccinated plasma) with Montanide ISA-51Phase 2 study in recurrent or persistent ovarian, fallopian tube, or primary peritoneal carcinoma42MST in platinum-sensitive vs. platinum-resistant 39.3 vs. 16.2 months, respectively.

MST with monotherapy vs. in combination with chemotherapy in platinum-sensitive (39.3 vs. 32.2 months, respectively) and platinum-resistant (16.8 vs. 16.1 months, respectively)		Kawano et al., 2014 [34]
Folate receptor alpha with cyclophosphamide primingPhase 1 study in stage II-IV ovarian cancer and stage II-III breast cancer without evidence of disease22 (14)All patients alive at last follow-up of at least 2 years

Median RFS 528 days in patients in first remission

Median OS not reached for those in second remission		Kalli et al., 2018 [35]
Polyvalent vaccine-KLH conjugate (including Globo-H-KLH, GM2-KLH,

Tn-MUC1-32mer-KLH, TF-KLH) with adjuvant OPT-821		GOG 255 – Randomized, double-blinded, phase 2 study in any stage ovarian, fallopian tube, or primary peritoneal carcinoma in 2nd or 3rd complete remission. Patients were randomized to polyvalent vaccine-KLH conjugate + OPT-821 or OPT-821 alone (reference arm)171KLH + OPT-821 was not superior to OPT-821 alone (HR 0.98; 2-sided 95% CI, 0.71–1.36)

Median OS for KLH + OPT-821 and OPT-821 were 47 and 46 months, respectively.		O’Cearbhaill et al., 2019 [36]
Recombinant Viral
Recombinant vaccinia- and fowlpox-NY-ESO-1Pilot study in advanced NY-ESO-1-expressing cancers35 (1)DFI 8 monthsJager et al., 2006 [37]
PANVACPilot study in CEA- or MUC-1-expressing metastatic cancers25 (3)PFS range 2–19 months

OS range 6–21 months		Gulley et al., 2008 [38]
PANVACPilot study in metastatic ovarian and breast cancer with progressive disease26 (14)Median PFS 2 months (range 1–6 months)

Median OS 15.0 months (range 1.5–57+ months)		Mohebtash, et al., 2011 [39]
Recombinant vaccinia- and fowlpox-NY-ESO-1Two parallel phase 2 studies in NY-ESO-1-expressing epithelial ovarian cancer and melanoma47 (22)Median PFS 21 months (95% CI, 16–29 months)

Median OS 48 months (95% CI, not estimable).		Odunsi et al., 2012 [40]
Modified Vaccinian Ankara vaccine delivering wildtype human p53 in combination with gemcitabinePhase 1 study in platinum-resistant recurrent ovarian, fallopian tube, and primary peritoneal carcinoma111 PR

3 SD

Median PFS 3 months (range 0.95–9.2 months)		Hardwick et al., 2018 [41]
Whole tumor cell
FANG, an autologous tumor-based vaccine containing a plasmid encoding GM-CSF and a novel bifunctional short hairpin RNA targeting furin convertasePhase 1 study in advanced cancers27 (5)3 SDSenzer et al., 2012 [42]
Live-attenuated
ANZ-100, a live-attenuated Listeria vaccine and CRS-207, the live-attenuated Listeria strain expressing human mesothelinDual phase 1 study in treatment-refractory mesothelin-expressing cancers (mesothelioma, lung, pancreatic, ovarian) with hepatic metastases9 (2)No clinical responsesLe et al., 2012 [43]
Carbohydrate-based
Theratope ®Phase II/III study in advanced breast and ovarian cancer70 (17)Phase II (40 patients total): 27 patients relapsed (5 ovarian, 22 breast); 23 patients died (5 ovarian, 18 breast)

Phase III (30 patients total): 18 patients relapsed (9 ovarian, 9 breast); 10 patients died (5 ovarian, 5 breast)		Holmberg et al., 2003 [44]
Lewisy-KLH conjugate with QS-21 adjuvantPhase I study in recurrent or persistent ovarian, fallopian tube, or primary peritoneal carcinoma following primary therapy and were in complete clinical remission following additional chemotherapy25Median PFS 6 months

5 patients remained in complete clinical remission at 18 months follow up		Sabbatini et al., 2000 [45]
CR: complete response; CTA: cancer testis antigen; DCs: dendritic cells; DFI: disease-free interval; DFS: disease-free survival; DSS: disease-specific survival; GM-CSF: granulocyte macrophage colony-stimulating factor; HLA: human leukocyte antigen; HR: hazard ratio; hTERT: human telomerase reverse transcriptase; KLH: keyhole limpet hemocyanin; MST: median survival time; NED: no evidence of disease; OC: ovarian cancer; OS: overall survival; PADRE: pan-DR epitope; PFS: progression-free survival; PR: partial response; RFS: relapse-free survival; RR: response rate; SD: stable disease; SLP: synthetic long peptide; WT1: Wilms Tumor 1. * Outcomes correspond with ovarian cancer patients only.
DC vaccines electroporated with mRNA that subsequently is translated into protein have also been studied. Hernando and colleagues transfected DCs with mRNA-encoded folate-receptor-alpha (FR-α) [23][11]. Another study by Coosemans et al. loaded DCs with WT1 mRNA and found a two-month PFS and 64 month OS in their patient with serous epithelial ovarian cancer [26][12].
Whole tumor lysate-loaded DCs utilize whole tumor cells as a source of antigens, generating a variety of antigens associated with a specific tumor. In theory, using neoepitopes from tumor mutations will allow increased efficacy over single antigen vaccines. Bapsy et al. administered a whole tumor lysate-pulsed DC vaccine to 51 patients with advanced solid malignancies [33][16]. Of the seven ovarian cancer patients, one had a partial response and two had stable disease while on therapy. Hernando et al. vaccinated patients with advanced gynecologic malignancies with DCs pulsed with keyhole limpet hemocyanin (KLH) and autologous tumor cell lysate [30][13]. Mean progression-free interval while under vaccination was 25.5 months for patients with progressive or recurrent ovarian cancer.
Other studies have utilized personalized vaccines using autologous tumor lysate-loaded DCs and tumor antigen matched tumor cell lysates [31,32][14][15]. Tanyi et al. tested a personalized vaccine generated by autologous DCs pulsed with oxidized autologous whole-tumor cell lysate. The vaccine was injected into accessible lymph nodes in recurrent ovarian cancer patients and either administered alone, in combination with bevacizumab, or with bevacizumab plus low-dose intravenous cyclophosphamide. The treatment induced T cell responses to autologous tumor antigens and amplified T cell responses against mutated neoepitopes previously unrecognized. Overall survival of patients who showed vaccine treatment responses was 100% at 2 years compared with 25% in non-responders. Rob and colleagues provided encouraging evidence of a personalized dendritic cell vaccine (DCVAC) as maintenance therapy after primary debulking surgery and chemotherapy [66][46]. Interim analysis of his phase 2 trial demonstrated a 5.7-month improvement in PFS in patients receiving DCVAC sequentially after chemotherapy. Ongoing studies are underway to compare autologous oxidized tumor lysate loaded DCs with a ten peptide neoantigen based DC vaccine [65][10].

2. CTA Vaccines

Cancer testis antigen (CTA) are a type of differentiation antigen that is highly expressed in adult male germ cells with low expression in normal tissues and variably expression in tumor cells [67][47]. Among the over 70 cancer testis gene families identified as potential vaccine targets [67][47], NY-ESO-1 has been studied most extensively. NY-ESO-1 is a highly immunogenic tumor antigen that is expressed in up to 40% of ovarian cancer patients [68][48]. NY-ESO-1 expression in ovarian cancer is associated with a more aggressive phenotype, correlating with shorter PFS (22.2 vs. 25.0 months, p = 0.009) and OS (42.9 vs. 50.0 months, p = 0.002) [69][49].
NY-ESO-1 vaccination has been shown to elicit CD4+ and CD8+ T cell responses while demonstrating durable clinical responses [37,70][20][50]. Odunsi and colleagues conducted a phase I study of 18 women with NY-ESO-1-expressing ovarian cancers [35][18]. Patients immunized with the NY-ESO-1 derived peptide ESO157–170 had detectable ESO157–170-reactive CD4+ and CD8+ T cell responses, which correlated with a PFS of 19.0 months. Diefenbach et al. vaccinated “high-risk” ovarian cancer patients (suboptimal tumor debulking, failure of CA-125 to normalize after 3 cycles of chemotherapy, or positive second-look surgery) with NY-ESO-1b peptide and Montanide ISA-51, a vaccine adjuvant [36][19]. Median PFS was found to be 13 months. Sabbatini and colleagues investigated the use of overlapping long peptides from NY-ESO-1 in combination with two different vaccine adjuvants in ovarian cancer patients in second or third remission [37][20]. Of the 28 patients enrolled, 6 had no evidence of disease (NED) with a PFS range of 17–46 months. NY-ESO-1 is regulated by DNA methylation, and preclinical studies have demonstrated enhanced NY-ESO-1 expression and NY-ESO-1-specific CTL-mediated responses in ovarian cancer cell lines when treated with decitabine, a DNA methyltransferase inhibitor [71][51]. This observation provided the rationale for a clinical trial by Odunsi et al. in ovarian cancer patients. NY-ESO-1 vaccine, decitabine, and GM-CSF were administered to determine if epigenetic modulatory drugs improved antitumor response [38][21]. Of the 10 patients evaluable for clinical response, one had a partial response/disease remission and five had stable disease.

3. Protein/Peptide-Based Vaccines

Protein or peptide-based vaccines utilize defined tumor-associated antigens in conjunction with adjuvants. Tumor associated antigens are processed and presented to immune effector cells, in particular T cells, by host dendritic cells. Vaccines targeting HER-2/neu, p53, WT1, CA125, Flt3 ligand, and others have been studied in human clinical trials involving ovarian cancer.
One of the first proteins examined for an ovarian cancer vaccine therapeutic was HER-2/neu. Overexpression of the oncogene HER-2/neu is found in 15–30% of human adenocarcinomas [72][52]. Studies in humans have demonstrated that HER-2/neu MHC class I epitopes can induce interferon-γ-producing CD8+ T cells [39][22]. HER-2/neu protein immunization promotes native HER-2/neu immunity as well as antibody epitope spreading [72,73,74][52][53][54]. To date, there are various ongoing clinical trials involving HER-2/neu vaccine in ovarian cancer.
The tumor-suppressor protein p53 is overexpressed in almost all high grade serous ovarian cancer [75,76][55][56]. Antibodies against mutated p53 have been identified in approximately 25% of ovarian cancer patients [77][57]. Though induction of p53-specific immunity has been achieved with well-tolerated vaccines, the clinical efficacy has been modest thus far [40,41,43][23][24][26]. The overall lack of clinical benefit with a p53-specific vaccine prompted strategies for combination therapy with immunomodulatory agents. Chemotherapy, specifically cyclophosphamide, has been shown to suppress Treg function [78,79][58][59]. Treg cells in ovarian cancer have been shown to be a negative prognostic factor associated with decreased survival [80][60]. Vermeij et al. combined their p53-SLP vaccine with cyclophosphamide and demonstrated a 20% stable disease rate [78][58].
The WT1 protein is expressed in various solid cancers and hematologic malignancies, and has been ranked first in pilot prioritization of 75 cancer antigens [81,82][61][62]. The Wnt/β-catenin pathway has been implicated in the alteration of the ovarian cancer tumor microenvironment through immune cell modulation by improving DC, T cell, and macrophage function [83,84][63][64]. In ovarian cancer, WT1 expression is related to tumor type, grade, and stage, with WT1 expression highly associated with poor overall survival [85][65]. Ohno and colleagues administered a modified WT1 peptide vaccine to gynecological cancer patients with three out of 12 demonstrating stable disease [48][31]. In a phase II trial by Miyatake et al., 40 patients with gynecologic malignancies were given a WT1 peptide vaccine with 40% showing stable disease [49][32].
The CA125 antigen is a mucin-type glycoprotein associated with the cell membrane that has been routinely utilized as a clinical biomarker for screening and response to treatment in ovarian cancer [86][66]. It is a repeating peptide epitope of MUC16, which promotes malignant cell growth and inhibits anti-tumor immune responses [87][67]. In a large study of 119 advanced or recurrent ovarian carcinoma patients, Reinartz et al. utilized an anti-idiotypic antibody vaccine (ACA125) which mimics the CA125 antigen [45][28]. Overall, 68.1% were found to have an immunological response to the vaccine, with median OS of 19.4 months (range, 0.5–56.1 months). The subset of patients with antibodies to ACA125 had significantly longer survival times compared with negative responders (median 23.4 vs. 4.9 months, respectively).
The Flt3 receptor, a member of the receptor tyrosine kinase family, has also been proposed and studied as a potential vaccine antigen. In murine models, the Flt3 ligand enhances antigen-presenting cell function and stimulates natural killer cell precursor growth [44][27]. In a pilot study by Freedman and colleagues, the Flt3 ligand was administered to patients with ovarian cancer and mesothelioma via intraperitoneal and subcutaneous routes. Unfortunately, no objective responses were found.
Kalli and colleagues vaccinated ovarian and breast cancer patients with peptides based on folate receptor alpha, a tumor antigen expressed in a variety of cancers such as ovarian, breast, and lung [52][35]. Following vaccination, IFN-γ-producing T cells were enhanced, however no antibody responses were noted. All patients were alive at last follow-up of at least two years with a median relapse-free survival of 528 days in ovarian cancer patients in first remission and median survival was not reached for those in second remission.
The presentation of multiple peptides in a vaccine might theoretically increase the likelihood of generating T cells responses against a heterogenous tumor cell population and hence induce better anti-tumor responses compared to mono-valent vaccines [47,50][30][33]. A polyvalent vaccine conjugated with KLH and administered with OPT-821, an immunological adjuvant derived from the soapbark tree, was used in patients with ovarian, tubal, or primary peritoneal carcinoma of any stage [53][36]. Positive IgM responses were found in less than 50% of patients with median OS of 47 months.
Efforts have been made to customize cancer vaccines based on pre-existing tumor-specific antigens. Tsuda and colleagues reported on two regimens involving peptide vaccination in recurrent gynecologic cancers [46][29]. In their first study, patients were administered predesignated peptide vaccines, while the second study vaccinated patients with peptides to which preexisting peptide-specific cytotoxic T lymphocyte precursors in peripheral blood were confirmed. No clinical responses were found with the first regimen, however, in the second approach, seven out of 10 patients had enhanced peptide-specific cytotoxic T lymphocytes to additional peptides. Kawano and colleagues used a personalized peptide vaccine where antigens were selected based on pre-existing host immunity [51][34]. IgG responses were found augmented in 96.7% of patients following the 12th vaccination, however 31 of 37 cases showed disease progression, suggesting delayed tumor progression.

4. Recombinant Viral Vaccines

Viral vectors have been engineered to express multiple cancer antigens [88,89][68][69]. Jager et al. utilized recombinant vaccinia-NY-ESO-1 (rV-NY-ESO-1) and recombinant fowlpox-NY-ESO-1 (rF-NY-ESO-1) vaccines in patients with NY-ESO-1-expressing tumors [54][37]. In this study, patients were treated with rV-NY-ESO-1, rF-NY-ESO-1, or rV-NY-ESO-1 followed by rF-NY-ESO-1. One advanced ovarian cancer patient included in the cohort treated with rV-NY-ESO-1 had a clinical response and remained disease-free for 8 months following treatment. Odunsi and colleagues used rV-NY-ESO-1 and rF-NY-ESO-1 in advanced epithelial ovarian cancer and melanoma [57][40]. Of the 22 ovarian cancer patients, 42% had antibody seroconversions with spontaneous CD4+ T cell responses detected in 68% of patients. Fourteen percent had preexisting CD8+ T cell responses, and this increased to 45% post-vaccination.
Gulley and colleagues conducted a pilot study with PANVAC, a recombinant poxviral vaccine containing carcinoembryonic antigen (CEA) and MUC-1 transgenes in combination with 3 costimulatory molecules (B7.1, intracellular adhesion molecule-1, and lymphocyte function-associated antigen 3—collectively known as TRICOM).
The antigens were expressed by a vaccinia virus (PANVAC-V) for primary vaccination and fowlpox (PANVAC-F) for multiple booster vaccinations. Of the ovarian cancer patients treated with PANVAC, median PFS was 18 months (range, 2–19) and median OS was 19 (range, 6–21). A follow-up study using PANVAC in a heavily pre-treated cohort of metastatic breast and ovarian cancer with disease progression was reported by Mohebtash and colleagues [56][39]. In 14 ovarian cancer patients, median PFS was two months (range, 1–6 months) and median OS was 15.0 months (range, 1.5–57+ months).
More recently, Hardwick and colleagues evaluated a Modified Vaccinian Ankara vaccine delivering wild-type p53 (p53MVA) in platinum-resistant ovarian cancer [58][41]. Patients received a combination of p53MVA and gemcitabine. There was one partial response and three with stable disease with a median PFS of three months (range, 0.95–9.2 months). Five of the 11 patients demonstrated increased p53-reactive CD4+ and CD8+ T cells. In a subset analysis, there was a significant difference in median PFS between responders and non-responders (7.0 vs. 2.3 months, respectively).

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