Tumor antigen analysis in neuroblastoma by serological interrogation of bioinformatic data

The identification of tumor antigens remains a major objective in tumor immunology, especially in pediatric malignancies where solid tumors often do not express a single dominant antigen. Methods such as the Serological Screening of Recombinant cDNA Expression Libraries (SEREX) have been used in the discovery of tumor‐expressed proteins by virtue of their ability to induce an antibody response. To focus and accelerate this approach, we first identified candidate antigens by gene expression profiling data from clinical neuroblastoma specimens and then used an animal model to generate an antibody response to an engineered cell‐based vaccine. Candidate tumor antigens were expressed as recombinant proteins in a mammalian system and screened for antibody recognition using serum from mice vaccinated with a neuroblastoma cell‐based vaccine engineered to express CD80 and CD86, with or without Treg depletion. Through this procedure, the never in mitosis A (NIMA)‐related kinase NEK2 was identified as a tumor‐associated antigen. Direct testing of serum from patients newly diagnosed with neuroblastoma showed specific serological responses in two of 20 patients. Although NEK2 was not universally recognized, it may serve as a tumor antigen for some patients. (Cancer Sci 2010; 101: 2316–2324)     

Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS‐PC study

We previously conducted a phase I clinical trial combining the HLA‐A*2402‐restricted KIF20A‐derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single‐armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naïve PC patients were enrolled to evaluate primarily the 1‐year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide‐specific immune responses. All enrolled patients received therapy without the HLA‐A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1‐year survival rates between the HLA‐A*2402‐matched and ‐unmatched groups were not significantly different. In the HLA‐A*2402 matched group, patients showing peptide‐specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA‐A*2402‐matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide‐specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.     

Clinical phase I study of elpamotide,a peptide vaccine for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors

Targeting of tumor angiogenesis with vaccines is a potentially valuable approach to cancer treatment. Elpamotide is an immunogenic peptide derived from vascular endothelial growth factor receptor 2, which is expressed at a high level in vascular endothelial cells. We have now carried out a phase I study to evaluate safety, the maximum tolerated dose, and potential pharmacodynamic biomarkers for this vaccine. Ten HLA‐A*24:02‐positive patients with advanced refractory solid tumors received elpamotide s.c. at dose levels of 0.5, 1.0, or 2.0 mg once a week on a 28‐day cycle. Five patients experienced an injection site reaction of grade 1 and 2, which was the most frequent adverse event. In the 1.0 mg cohort, one patient experienced proteinuria of grade 1 and another patient developed both hypertension and proteinuria of grade 1. No adverse events of grade 3 or higher were observed, and the maximum tolerated dose was therefore not achieved. The serum concentration of soluble vascular endothelial growth factor receptor 2 decreased significantly after elpamotide vaccination. Microarray analysis of gene expression in PBMCs indicated that several pathways related to T cell function and angiogenesis were affected by elpamotide vaccination, supporting the notion that this peptide induces an immune response that targets angiogenesis in the clinical setting. In conclusion, elpamotide is well tolerated and our biomarker analysis indicates that this anti‐angiogenic vaccine is biologically active. Clinical trial registration no. UMIN000008336.     

Association of WT1 IgG antibody against WT1 peptide with prolonged survival in glioblastoma multiforme patients vaccinated with WT1 peptide

We previously evaluated Wilms’ tumor gene 1 (WT1) peptide vaccination in a large number of patients with leukemia or solid tumors and have reported that HLA‐A*24:02 restricted, 9‐mer WT1‐235 peptide (CYTWNQMNL) vaccine induces cellular immune responses and elicits WT1‐235‐specific cytotoxic T lymphocytes (CTLs). However, whether this vaccine induces humoral immune responses to produce WT1 antibody remains unknown. Thus, we measured IgG antibody levels against the WT1‐235 peptide (WT1‐235 IgG antibody) in patients with glioblastoma multiforme (GBM) receiving the WT1 peptide vaccine. The WT1‐235 IgG antibody, which was undetectable before vaccination, became detectable in 30 (50.8%) of a total of 59 patients during 3 months of WT1 peptide vaccination. The dominant WT1‐235 IgG antibody subclass was Th1‐type, IgG₁ and IgG₃. WT1‐235 IgG antibody production was significantly and positively correlated with both progression‐free survival (PFS) and overall survival (OS). Importantly, the combination of WT1‐235 IgG antibody production and positive delayed type‐hypersensitivity (DTH) to the WT1‐235 peptide was a better prognostic marker for long‐term OS than either parameter alone. These results suggested that WT1‐235 peptide vaccination induces not only WT1‐235‐specific CTLs as previously described but also WT1‐235‐specific humoral immune responses associated with antitumor cellular immune response. Our results indicate that the WT1 IgG antibody against the WT1 peptide may be a useful predictive marker, with better predictive performance in combination with DTH to WT1 peptide, and provide a new insight into the antitumor immune response induction in WT1 peptide vaccine‐treated patients.     

Active specific immunotherapy targeting the Wilms' tumor protein 1 (WT1) for patients with hematological malignancies and solid tumors: lessons from early clinical trials

There is a growing body of evidence that Wilms' tumor protein 1 (WT1) is a promising tumor antigen for the development of a novel class of universal cancer vaccines. Recently, in a National Cancer Institute prioritization project, WT1 was ranked first in a list of 75 cancer antigens. In this light, we exhaustively reviewed all published cancer vaccine trials reporting on WT1-targeted active specific immunotherapy in patients with hematological malignancies and solid tumors. In all clinical trials, vaccine-induced immunological responses could be detected. Importantly, objective clinical responses (including stable disease) were observed in 46% and 64% of evaluable vaccinated patients with solid tumors and hematological malignancies, respectively. Immunogenicity of WT1-based cancer vaccines was demonstrated by the detection of a specific immunological response in 35% and 68% of evaluable patients with solid tumors and hematological malignancies, respectively. In order to become part of the armamentarium of the modern oncologist, it will be important to design WT1-based immunotherapies applicable to a large patient population, to standardize vaccination protocols enabling systematic review, and to further optimize the immunostimulatory capacity of the vaccine components. Moreover, improved immunomonitoring tools that reveal clinically relevant T-cell responses will further shape the ideal WT1 immunotherapy strategy. In conclusion, the clinical results obtained so far in WT1-targeted cancer vaccine trials reveal an untapped potential for inducing cancer immunity with minimal side effects and hold promise for a new adjuvant treatment against residual disease and against cancer relapse.     

Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients

We investigated peptide cocktail vaccine OCV‐C01 containing epitope peptides derived from KIF20A, vascular endothelial growth factor receptor (VEGFR)1 and VEGFR2 combined with gemcitabine in the adjuvant treatment for resected pancreatic cancer patients. A single‐arm multicenter phase II study was performed on 30 patients with pancreatic ductal carcinoma who underwent pancreatectomy. At each 28‐day treatment cycle, patients received weekly subcutaneous injection of OCV‐C01 for 48 weeks and gemcitabine was administered intravenously at 1,000 mg/m² on days 1, 8 and 15 for 24 weeks. Patients were followed for 18 months. The primary endpoint was disease‐free survival (DFS) and secondary endpoints included safety, overall survival (OS) and immunological assays on peptide‐specific cytotoxic T lymphocyte (CTL) activity and KIF20A expression in resected pancreatic cancer. The median DFS was 15.8 months [95% confidence interval (CI), 11.1–20.6] and the DFS rate at 18 months was 34.6% (95% CI, 18.3–51.6). The median OS was not reached and the OS rate at 18 months was 69.0% (95% CI, 48.8–82.5). The administration of OCV‐C01 was well tolerated. In the per protocol set, there were significant differences in DFS between patients with KIF20A‐specific CTL responses and without (p = 0.027), and between patients with KIF20A expression and without (p = 0.014). In addition, all four patients who underwent R0 resection with KIF20A expression had no recurrence of pancreatic cancer with KIF20A‐specific CTL responses. OCV‐C01 combined with gemcitabine was tolerable with a median DFS of 15.8 months, which was favorable compared with previous data for resected pancreatic cancer.     

The forkhead box M1 transcription factor as a candidate of target for anti‐cancer immunotherapy

The present study attempted to identify a target antigen for immunotherapy for cholangiocarcinoma. Forkhead box M1 (FOXM1) was selected as a candidate antigen based on the data of previous cDNA microarray analysis of clinical samples of cholangiocarcinoma. The level of FOXM1 mRNA was more than 4 times higher in cancer cells in comparison to adjacent normal epithelial cells, in all of 24 samples of cholangiocarcinoma tissues. An immunohistochemical analysis also detected FOXM1 protein in the cancer cells but not in the normal cells. Twenty‐three human FOXM1‐derived peptides predicted to bind to HLA‐A2 were analyzed to determine their ability to induce HLA‐A2‐restricted T cells in HLA‐A2 transgenic mice. FOXM1_362‐370 (YLVPIQFPV), FOXM1_373‐382 (SLVLQPSVKV), and FOXM1_640‐649 (GLMDLSTTPL) peptides primed HLA‐A2‐restricted cytotoxic T lymphocytes (CTLs) in the HLA‐A2 transgenic mice. Human CTL lines reactive to these 3 peptides could also be established from HLA‐A2‐positive healthy donors and cancer patients. Natural processing of the 3 epitopes from FOXM1 protein was confirmed by specific killing of HLA‐A2‐positive FOXM1‐transfectants by peptide‐induced CTLs. FOXM1 is expressed in various types of cancers and it is also functionally involved in oncogenic transformation and the survival of cancer cells. Therefore, FOXM1 may be a suitable target for immunotherapy against various cancers including cholangiocarcinoma.     

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.     

FOXM1在卵巢癌中的研究进展

FOXM1是一种增殖相关的促癌转录因子,多个研究证实,FOXM1在包括卵巢癌的多种实体肿瘤中表达增加,研究表明FOXM1通过多种机制参与卵巢癌的发生、发展等生物学过程,与卵巢癌增殖、侵袭、转移,上皮间质转化及耐药等多方面密切相关.未来通过对FOXM1的深入研究,其作用机制将更加明确,FOXM1可作为卵巢癌临床应用及基因治疗的新靶点.     

CD4+CD25+ regulatory T-cell-inactivation in combination with adenovirus vaccines enhances T-cell responses and protects mice from tumor challenge

Cancer vaccines are a promising approach to treating tumors or preventing tumor relapse through induction of an immune response against tumor-associated antigens (TAA). One major obstacle to successful therapy is the immunological tolerance against self-antigens which limits an effective antitumor immune response. As a transient reduction of immunological tolerance may enable more effective vaccination against self-tumor antigens, we explored this hypothesis in a CEA tolerant animal model with an adenovirus expressing CEA vaccine in conjunction with inactivation of CD4(+)CD25(+) regulatory T cells. This vaccination modality resulted in increased CEA-specific CD8(+), CD4(+) T cells and antibody response. The appearance of a CD4(+) T-cell response correlated with a stronger memory response. The combined CD25(+) inactivation and genetic vaccination resulted in significant tumor protection in a metastatic tumor model. Non-invasive tumor visualization showed that not only primary tumors were reduced, but also hepatic metastases. Our results support the viability of this cancer vaccine strategy as an adjuvant treatment to prevent tumor relapse in cancer patients.     

A phase 1 trial of NY-ESO-1-specific TCR-engineered T-cell therapy combined with a lymph node-targeting nanoparticulate peptide vaccine for the treatment of advanced soft tissue sarcoma

The efficacy of immune checkpoint inhibitors is limited in refractory solid tumors. T-cell receptor gene-modified T (TCR-T)-cell therapy has attracted attention as a new immunotherapy for refractory cold tumors. We first investigated the preclinical efficacy and mode of action of TCR-T cells combined with the pullulan nanogel:long peptide antigen (LPA) vaccine in a mouse sarcoma model that is resistant to immune checkpoint inhibition. Without lymphodepletion, the pullulan nanogel:LPA vaccine markedly increased the number of TCR-T cells in the draining lymph node and tumor tissue. This change was associated with enhanced CXCR3 expression in TCR-T cells in the draining lymph node. In the phase 1 trial, autologous New York esophageal squamous cell carcinoma 1 (NY-ESO-1)-specific TCR-T cells were infused twice into HLA-matched patients with NY-ESO-1⁺ soft tissue sarcoma (STS). The pullulan nanogel:LPA vaccine contains an epitope recognized by TCR-T cells, and it was subcutaneously injected 1 day before and 7 days after the infusion of TCR-T cells. Lymphodepletion was not performed. Three patients with refractory synovial sarcoma (SS) were treated. Two out of the three patients developed cytokine release syndrome (CRS) with low-to-moderate cytokine level elevation. We found obvious tumor shrinkage lasting for more than 2 years by tumor imaging and long-term persistence of TCR-T cells in one patient. In conclusion, NY-ESO-1-specific TCR-T-cell therapy plus vaccination with the pullulan nanogel carrying an LPA containing the NY-ESO-1 epitope without lymphodepletion is feasible and can induce promising long-lasting therapeutic effects in refractory SS (Registration ID: JMA-IIA00346).     

Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors

BACKGROUND:

Preclinical testing suggests the combination of carboplatin and irinotecan has at least additive antitumor activity. The primary objectives of the current study were to determine the maximum tolerated doses (MTDs) and recommended phase 2 doses of carboplatin administered with irinotecan to pediatric patients with refractory solid tumors.

METHODS:

This was a multicenter, open‐label, single‐arm dose escalation study in which subjects with refractory solid tumors received 21‐day treatment cycles of intravenous carboplatin on Day 1 followed by intravenous irinotecan administered daily for 10 days within 2 consecutive weeks. The plasma pharmacokinetics of ultrafiltrable platinum, irinotecan, and 2 irinotecan metabolites were determined during Cycle 1. The interpatient plan for dose escalation at study initiation was to increase irinotecan first followed by increases in carboplatin.

RESULTS:

Twenty‐eight patients with a median age of 8.5 years (range, 1‐21 years) were enrolled with a variety of solid tumors. Two of 6 subjects at the first dose level (carboplatin target area under the curve [AUC], 4.0 mg/mL*min; irinotecan, 18 mg/m²/dose) experienced dose‐limiting gastrointestinal toxicities requiring a dose de‐escalation scheme (carboplatin AUC, 4.0 mg/mL*min; irinotecan, 15 mg/m²/dose). Three of 6 subjects at the second dose level experienced dose‐limiting gastrointestinal complications and bone marrow suppression. A further dose de‐escalation to carboplatin AUC of 4.0 mg/mL*min and irinotecan of 12 mg/m²/dose resulted in dose‐limiting bone marrow suppression in 1 of 13 patients treated at that dose, and therefore was determined to be the MTD. One complete response (in a patient with medulloblastoma) and 3 partial responses (in patients with neuroblastoma, medulloblastoma, and lymphoendothelial carcinoma, respectively) were observed.

CONCLUSIONS:

The recommended phase 2 dose in heavily pretreated pediatric patients is carboplatin (AUC, 4 mg/mL*min on Day 1) and irinotecan (12 mg/m²/ day × 10 days) given every 21 days. Cancer 2009. © 2008 American Cancer Society.     

Cancer patients undergoing chemotherapy show adequate serological response to vaccinations against influenza virus and Streptococcus pneumoniae

Cancer patients receiving chemotherapy are prone to develop infections that might postpone treatment and lead to complications. The aim of our study was to investigate whether a heterogeneous population of patients with solid tumors and malignant lymphoma undergoing chemotherapy would respond serologically to vaccination against influenza and pneumococcal disease. There are no established routines in oncology departments in Norway regarding vaccination of these patients. The study included 35 cancer patients with median age 53 yr (range 20–74) and 38 controls with median age 57 yr (range 43–75). The chemotherapy regimens used were mild or moderately immunosuppressive. After one vaccination, 25 patients (72%) and 34 controls (87%) were serologically protected against two or three influenza strains. A higher proportion of patients with solid tumors (81%) than lymphoma (38%) achieved protection. Age, months on chemotherapy, and curative versus palliative treatment did not influence responses to vaccination. After vaccination with a 23-valent polysaccharide vaccine against pneumococci, most patients and controls achieved protective serum levels of antibodies against the different serotypes, with the exception that fewer patients were protected against serotype 4. The responses in controls were, however, generally stronger to all serotypes. Tumor type did not influence this vaccination response. We conclude that our cancer patients achieved adequate responses to influenza virus and Streptococcus pneumoniae. These are not live vaccines and are therefore safe for immunocompromised patients. Routine vaccinations against influenza virus and Streptococcus pneumoniae should be considered in cancer patients undergoing mild to moderately immunosuppressive chemotherapy.     

Phase I trial of OTS11101, an anti‐angiogenic vaccine targeting vascular endothelial growth factor receptor 1 in solid tumor

OTS11101 is a novel peptide vaccine that acts as an angiogenesis inhibitor by inducing cytotoxic T lymphocyte (CTL) cells that specifically target vascular endothelial cells expressing vascular endothelial growth factor (VEGF) receptor 1. We conducted a phase I study to evaluate the safety, tolerability, maximum tolerated dose, and pharmacodynamic biomarker status of this vaccine. Nine patients with advanced solid tumors received 1.0, 2.0, or 3.0 mg of OTS11101 subcutaneously, once a week in a 28‐day cycle. Three patients experienced grade 1 injection site reactions, which were the most frequent adverse events. Grade 2 proteinuria and hypertension each occurred in one patient. As other toxicities were generally mild, the maximum tolerated dose was not reached. Furthermore, we explored the induction of specific activated CTLs, and biomarkers related to angiogenesis. A pharmacodynamics study revealed that induction of specific CTLs was observed for a dose of 2.0 and 3.0 mg. The serum concentrations of soluble VEGF receptor 1 and 2 after vaccination increased significantly compared with baseline. A microarray was performed to give a comprehensive analysis of gene expression, suggesting that OTS11101 vaccination resulted in T cell activation in a clinical setting. In conclusion, OTS11101 was well tolerated in patients up to 3.0 mg once weekly and our biomarker analysis suggested that this anti‐angiogenesis vaccine is biologically active. (Cancer Sci 2013; 104: 98–104)     

Long‐term follow‐up of patients with resected pancreatic cancer following vaccination against mutant K‐ras

K‐ras mutations are frequently found in adenocarcinomas of the pancreas and can elicit mutation‐specific immune responses. Targeting the immune system against mutant Ras may thus influence the clinical course of the disease. Twenty‐three patients who were vaccinated after surgical resection for pancreatic adenocarcinoma (22 pancreaticoduodenectomies, one distal resection), in two previous Phase I/II clinical trials, were followed for more than 10 years with respect to long‐term immunological T‐cell reactivity and survival. The vaccine was composed of long synthetic mutant ras peptides designed mainly to elicit T‐helper responses. Seventeen of 20 evaluable patients (85%) responded immunologically to the vaccine. Median survival for all patients was 27.5 months and 28 months for immune responders. The 5‐year survival was 22% and 29%, respectively. Strikingly, 10‐year survival was 20% (four patients out of 20 evaluable) versus zero (0/87) in a cohort of nonvaccinated patient treated in the same period. Three patients mounted a memory response up to 9 years after vaccination. The present observation of long‐term immune response together with 10‐year survival following surgical resection indicates that K‐ras vaccination may consolidate the effect of surgery and represent an adjuvant treatment option for the future.     

Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma.

PURPOSE: Poxviral vectors have a proven safety record and can be used to incorporate multiple transgenes. Prior clinical trials with poxviral vaccines have shown that immunologic tolerance to self-antigens can be broken. Carcinoembryonic antigen (CEA) and MUC-1 are overexpressed in a substantial proportion of common solid carcinomas. The primary end point of this study was vaccine safety, with immunologic and clinical responses as secondary end points. EXPERIMENTAL DESIGN: We report here a pilot study of 25 patients treated with a poxviral vaccine regimen consisting of the genes for CEA and MUC-1, along with a triad of costimulatory molecules (TRICOM; composed of B7.1, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 3) engineered into vaccinia (PANVAC-V) as a prime vaccination and into fowlpox (PANVAC-F) as a booster vaccination. RESULTS: The vaccine was well tolerated. Apart from injection-site reaction, no grade > or =2 toxicity was seen in more than 2% of the cycles. Immune responses to MUC-1 and/or CEA were seen following vaccination in 9 of 16 patients tested. A patient with clear cell ovarian cancer and symptomatic ascites had a durable (18-month) clinical response radiographically and biochemically, and one breast cancer patient had a confirmed decrease of >20% in the size of large liver metastasis. CONCLUSIONS: This vaccine strategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted.     

Polyomavirus-driven Merkel cell carcinoma: Prospects for therapeutic vaccine development

Great strides have been made in cancer immunotherapy including the breakthrough successes of anti-PD-(L)1 checkpoint inhibitors. In Merkel cell carcinoma (MCC), a rare and aggressive skin cancer, PD-(L)1 blockade is highly effective. Yet, ~50% of patients either do not respond to therapy or develop PD-(L)1 refractory disease and, thus, do not experience long-term benefit. For these patients, additional or combination therapies are needed to augment immune responses that target and eliminate cancer cells. Therapeutic vaccines targeting tumor-associated antigens, mutated self-antigens, or immunogenic viral oncoproteins are currently being developed to augment T-cell responses. Approximately 80% of MCC cases in the United States are driven by the ongoing expression of viral T-antigen (T-Ag) oncoproteins from genomically integrated Merkel cell polyomavirus (MCPyV). Since T-Ag elicits specific B- and T-cell immune responses in most persons with virus-positive MCC (VP-MCC), and ongoing T-Ag expression is required to drive VP-MCC cell proliferation, therapeutic vaccination with T-Ag is a rational potential component of immunotherapy. Failure of the endogenous T-cell response to clear VP-MCC (allowing clinically evident tumors to arise) implies that therapeutic vaccination will need to be potent anśd synergize with other mechanisms to enhance T-cell activity against tumor cells. Here, we review the relevant underlying biology of VP-MCC, potentially applicable therapeutic vaccine platforms, and antigen delivery formats. We also describe early successes in the field of therapeutic cancer vaccines and address several clinical scenarios in which VP-MCC patients could potentially benefit from a therapeutic vaccine.     

Personalized peptide vaccination for cervical cancer patients who have received prior platinum‐based chemotherapy

A feasibility study was performed to evaluate the immunological efficacy and safety of a personalized peptide vaccine (PPV) for cervical cancer patients who have received platinum‐based chemotherapy. A total of 24 patients with standard chemotherapy‐resistant cervical cancer, including 18 recurrent cases, were enrolled in this study and received a maximum of 4 peptides based on HLA‐A types and IgG levels to the vaccine candidate peptides in pre‐vaccination plasma. The parental protein expression of most of the vaccine peptides was confirmed in the cervical cancer tissues. No vaccine‐related systemic grade 3 or 4 adverse events were observed in any patients. Due to disease progression, 2 patients failed to complete the first cycle of vaccinations (sixth vaccination). Cytotoxic T‐lymphocyte (CTL) or IgG responses specific for the peptides used for vaccination were augmented in half of cases after the first cycle. The median overall survival was 8.3 months. The clinical responses of the evaluable 18 cases consisted of 1 case with a partial response and 17 cases with disease progression; the remaining 6 cases were not evaluable. Performance status, injection site skin reaction and circulating PD‐1⁺CD4⁺ T‐cells were significantly prognostic of overall survival, and multivariate analysis also indicated that the performance status and circulating PD‐1⁺CD4⁺ T‐cells were prognostic. Because of the safety and immunological efficacy of PPV and the possible prolongation of overall survival, further clinical trials of PPV at a larger scale in advanced or recurrent cervical cancer patients who have received prior platinum‐based chemotherapy are recommended.