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Cancer vaccines are a type of active immunotherapy with the aim to produce a specific and endogenous immune response to tumor antigens or tumor-associated antigens (TAAs) that are able to target and destroy cancer cells.

From: Vaccines for Cancer Immunotherapy, 2019

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About this pageCancer Vaccines

Teresa Ramirez-Montagut, in Novel Approaches and Strategies for Biologics, Vaccines and Cancer Therapies, 2015

Whole cell cancer vaccines represent one form of active cancer immunotherapy undergoing clinical development. This approach is based on the rationale that tumor cells will contain proteins expressed in the patient’s cancer lesions and will provide multiple tumor antigens for immune recognition. Vaccine platforms based on autologous tumor cells have proven difficult to produce because harvesting patient-specific tumor cells is technically challenging and can be financially costly and time consuming.41 An alternative has been the utilization of cell lines as an allogeneic vaccination strategy where it is expected that the patient’s tumor shares antigens express by the cell lines that will induce immune recognition. Whole cell vaccines are rendered more immunogenic when the tumor cells are genetically modified to express cytokines, chemokines, or costimulatory molecules for immune stimulation. Historically, one cytokine, granulocyte–macrophage colony-stimulation factor (GM-CSF), was found to be superior in the induction of immune responses when compared to other cytokines tested.42 The GM-CSF-secreting whole tumor cell vaccine recruits dendritic cells (DCs) to the site of injection and stimulates antigen uptake, processing, and cross-presentation to CD8 CTLs.43 A recent analysis of studies published in the last 10 to 15 years of clinical experience with gene-modified whole cell vaccines concluded that this strategy lacked sufficient evidence for efficacy in inducing both a strong immune response and a therapeutic response.44

Adrian Bot, ... Neil L. Berinstein, in Plotkin s Vaccines (Seventh Edition), 2018

Whereas various cancer vaccines may be able to prime immune responses specifically to a cancer, the multiple immune inhibitory mechanisms that cancers may use to avoid immune elimination may prevent meaningful clinical responses, particularly in more advanced disease where these inhibitory mechanisms are even more active. As discussed previously in this chapter, checkpoint inhibition either through CTLA-4– or PD-1–mediated T-cell signaling are important immune inhibitory mechanisms. These pathways can now be addressed and reversed with the checkpoint inhibitor monoclonal antibodies that are under clinical development or approved by the FDA. In summary, both the anti–CTLA-4 monoclonal ipilimumab and the anti-PD-1 monoclonal antibodies pembrolizumab and nivolumab have shown objective tumor responses in patients with metastatic melanoma and lung cancer and have been approved for clinical use for these indications.230–232 They represent strong candidates for vaccine combination studies.

These checkpoint antibodies work best in tumors where there is some initial evidence of an immune response such as increased numbers of tumor infiltrating lymphocytes and evidence of granzyme and or interferon production. In such situations there is often evidence of increased levels of PDL1 expression on the tumor cells or local APCs. It is postulated that these preexisting T-cell responses are directed against neoantigens generated through tumorigenesis, hence a correlation between mutational load and response to the checkpoints inhibitors. These findings lead to the hypothesis that a therapeutic cancer vaccine and checkpoint inhibitor combination would be an effective therapeutic combination.

Several early phase clinical trials have been performed to assess such immunotherapeutic combinations. In an early trial, ipilimumab was administered after vaccination with the GM-CSF cellular vaccine GVAX.233 Eleven patients with stage 4 melanoma were treated with ipilimumab infusions every 2 or 3 months starting from 1 to 4 months after GVAX treatment. There were no grade 3 or 4 toxicities. A relationship between therapy induced necrosis and the ratio of intratumoral CD8+/FOXP3+ T cells was discovered, speaking to the detrimental role of Treg cells within the tumor environment. Nine patients with stage 4 ovarian cancer were also similarly evaluated from 1 month to 3 years after treatment. Two cases of grade 3 gastrointestinal toxicities were experienced. Some clinical responses were seen in these patients treated with this combination strategy A similar approach was studied in 30 patients with previously treated pancreatic ductal carcinoma. Patients received ipilimumab every 3 weeks × 4 and then every 3 months alone or with GVAX.234 Two patients receiving ipilimumab alone had stable disease whereas three patients in the combination treatment group had stable disease. Interestingly, 7 of 15 patients had declines in CA19–9 in the combination arm while no declines were seen in the ipilimumab-alone arm. There was a nonstatistically significant trend toward improved survival in the combination treatment arm. Toxicities were comparable in the two arms.

A Phase III trial of ipilimumab alone, gp100 peptide vaccine alone, or gp100 peptide vaccine and ipilimumab combination was completed in 676 patients with metastatic melanoma230 that was described in detail in an earlier section of this chapter.

Thirty patients with castration-resistant prostate cancer were treated with the Vaccinia-based vaccine Prostvac with escalating doses of ipilimumab. Of the 30 patients, 58% had a decline in PSA.235 Associations between OS and certain immune cell subsets either before or after therapy were found. There were trends of association between longer OS and certain immune cell subsets before immunotherapy: lower PD-1+ Tim-3+ Th cells, higher PD-1− Tim-3+ CTL, and a higher number of CTLA-4− Tregs. They also found that an increase in Tim-3+ NK cells postvaccination versus prevaccination was associated with longer OS.

Based on the scientific rationale and evidence to date, the next steps would be to test combinations of vaccines and licensed checkpoint-blocking agents. Notably, a randomized Phase II trial of combining sipuleucel-T with immediate versus delayed CTLA-4 blockade for prostate cancer has been initiated and is currently accruing (NCT01804465). This is an open-label, randomized, multicenter trial in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer. All patients will be treated with standard vaccination with sipuleucel-T (q2wk × 3). Then, patients will be randomized to one of two arms: an immediate treatment arm comprising ipilimumab q3wk × 4 started 1 day following the final dose of vaccine or a delayed treatment arm comprising ipilimumab q3wk × 4 started 3 weeks following the last dose of vaccine. Following this ipilimumab treatment, patients will then be followed monthly for 3 months and then quarterly until disease progression.

A Phase Ib trial with the herpes virus oncolytic vaccine T-VEC and ipilimumab has been reported in 19 patients with stage IIIb or stage IV melanoma.236 Grade 3/4 toxicities occurred in six (32%) of the patients. Two patients experienced grade 3/4 autoimmune toxicities commonly seen in patients with ipilimumab, consisting of colitis, hypophysitis, adrenal insufficiency, and elevated amylase and lipase. The objective response rate was 56%, including 33% complete responses. This objective response rate is higher than the objective response rate seen with T-VEC alone (16%) from a historical control trial. There was an increase in CD8+ T cells seen in tumor sites after combination therapy. The results of the randomized trial leading to regulatory approval of T-VEC have been published in the Journal of Clinical Oncology151: among 436 patients randomly assigned, ORR was significantly higher with T-VEC (16.3%; 95% confidence interval [CI], 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%; odds ratio, 8.9; P .001). ORR was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% vs 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (HR, 0.79; 95% CI, 0.62 to 1.00; P = .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naïve disease. These results build a momentum behind combination approaches to further elevate the clinical response rate and durability of clinical benefit. A randomized trial of T-VEC with pembrolizumab is now underway for patients with advanced melanoma.

Some of these trials have been, or are being performed with, anti-CTLA-4 combinations. Given the improved toxicity and clinical activity of the anti–PD-1s and anti-PDL1s it is likely that combination studies with such agents are of increased interest.

Nivolumab, a human IgG4-blocking antibody against the T-cell PD-1 checkpoint protein, has activity against metastatic melanoma and has been tested in combination with peptide vaccines in melanoma patients. In a Phase I study,237,238 patients with unresectable stage III or IV melanoma who were ipilimumab naïve and had experienced progression after at least one prior therapy or experienced progression after prior ipilimumab received nivolumab at 1, 3, or 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine against well characterized antigens such as MART-1 (melanoma antigen recognized by T cell-1) and NYESO-1. While the combination of nivolumab with vaccine was well tolerated and safe at all doses, the objective response rate for both ipilimumab-refractory and ipilimumab-naïve patients was 25%.

The same group investigated nivolumab plus peptide vaccine as adjuvant therapy in resected stage IIIC and stage IV melanoma patients.239 HLA-A*0201–positive patients with HMB-45–, NYESO-1–, and/or MART-1–positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg IV) with a multipeptide vaccine (gp100, MART-1, and NYESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for eight doses. Thirty-three patients were enrolled. Nivolumab with vaccine was well tolerated as adjuvant therapy and demonstrated immunologic activity with improved survival in patients with high-risk resected melanoma. More specifically, the estimated median relapse-free survival was 47.1 months. Increases of tetramer-specific CD8+ T-cell populations were observed with treatment. These results could support future randomized trials.

Another trial evaluates a Listeria-based vaccine (ADXS31–142) alone and in combination with pembrolizumab (MK-3475) in patients with prostate cancer (NCT02325557). ADS31–142 is aimed to elicit an immune response against PSA. Part A will be dose-determining of ADXS31–142 monotherapy and part B will be dose-determining of ADXS31–142 and pembrolizumab (MK-3475) in combination.

As this field is expanding rapidly, combining checkpoint inhibitors with new-generation vaccines that can generate potent and broad tumor-specific immune responses should be an increasingly effective strategy.

Freda K. Stevenson, ... Natalia Savelyeva, in Cancer Immunotherapy, 2007

Clinical trials of cancer vaccines are widespread, with only limited evidence for efficacy, mainly in hematological tumors (Rosenberg et al., 2004; Timmerman and Levy, 2004). One explanation may be the bias toward patients with advanced melanoma. As pointed out previously and as is the opinion of Mocellin et al. (2004), minimal residual disease is a more realistic setting for vaccine treatment, and it is too early to make judgments, especially with so many novel options for enhancing immunity becoming available. A very wide range of delivery strategies has been used, including peptides, DC-based vaccines, genetically modified whole tumor cell vaccines, viral vaccines, and various combinations. These have either been focused on defined antigens, such as CEA, MUC1, prostate, or melanoma antigens, or have used a less well-defined source of antigen (whole tumor cells or lysates).

According to a publicly available database (Wiley Interscience, http://www.wiley.co.uk/genetherapy/clinical/), 451 gene-based cancer vaccine studies are ongoing as of July 2006. For DNA vaccines, there are 75 clinical trials of DNA vac cination against cancer in progress internationally.

Several small trials are testing protocols of DNA priming and boosting with an MVA or other vectors. A trial of patients with melanoma using a string of peptide sequences induced apparent disease stabilization (Hawkins et al., 2006), but a similar protocol using the L523S antigen from lung cancer yielded disappointing results (Nemunaitis et al., 2006). A naked DNA vaccine trial against PSA, delivered together with cytokines, has also reported encouraging stabilization of PSA levels (Pavlenko et al., 2004) and some evidence of immune responses (Miller et al., 2005). These early investigations are difficult to summarize due to heterogeneity in vaccine design, disease, antigen, patient cohort, and clinical setting. The chapter authors ongoing trial of an epitope-specific DNA fusion gene vaccine derived from prostate-specific membrane antigen and delivered ± electroporation will hopefully answer some questions.

Immune responses are likely to act as important surrogates for efficacy of cancer vaccines. It is vital, therefore, to have robust monitoring methods to make comparisons between different laboratories. Academic collaboratives, such as the Cancer Immunotherapy (CIMT) established in Germany, and academic/commercial collaboratives, such as the Cancer Vaccine Consortium in the United States, are addressing issues of standardization of assays. Antibody assays are relatively straightforward, but CD8+ T cell assays require knowledge of the target peptides and usually have focused on HLA-A2 as a relatively common restriction element.

The range of available technology is rapidly expanding and now includes ex vivo or cultured enzyme-linked immunospot (ELISPOT) assay, flow cytometry-based cytokine secretion detection, single or multicytokine detection systems in enzyme-linked immunosorbent assay (ELISA)-type assays, and quantitative polymerase chain reaction (qPCR)-based detection systems of mRNA for cytokines (Hernandez-Fuentes et al., 2003; Hart and Heije, 2005). In some cases, tetramer binding can be used to measure levels of specific T cells, usually the CD8+ subset. Correlation of immune phenotype with functional capacity of T cells and definition of markers that link cytotoxic function to phenotype will offer potent tools for assessing immune responses in clinical trials (Chattopadhyay et al., 2005; Rubio et al., 2003).

An emerging problem for all vaccine trials arises from the dramatic changes in the regulatory framework. Requirements for formally validated endpoints prior to beginning a trial are in danger of reducing the flexibility needed for developing technologies. The regulatory pressure on pilot clinical trials in academic centers is now reaching a point that virtually prevents the testing of any new approach. A dialogue between regulatory authorities and academic laboratories needs to take place so that promising strategies can be identified before larger trials are initiated, possibly with commercial involvement.

Karrie K. Wong, ... Glenn Dranoff, in Advances in Immunology, 2016

Therapeutic cancer vaccines aim to induce durable antitumor immunity that is capable of systemic protection against tumor recurrence or metastatic disease. Many approaches to therapeutic cancer vaccines have been explored, with varying levels of success. However, with the exception of Sipuleucel T, an ex vivo dendritic cell vaccine for prostate cancer, no therapeutic cancer vaccine has yet shown clinical efficacy in phase 3 randomized trials. Though disappointing, lessons learned from these studies have suggested new strategies to improve cancer vaccines. The clinical success of checkpoint blockade has underscored the role of peripheral tolerance mechanisms in limiting vaccine responses and highlighted the potential for combination therapies. Recent advances in transcriptome sequencing, computational modeling, and material engineering further suggest new opportunities to intensify cancer vaccines. This review will discuss the major approaches to therapeutic cancer vaccination and explore recent advances that inform the design of the next generation of cancer vaccines.

Mahsa Keshavarz-Fathi, Nima Rezaei, in Vaccines for Cancer Immunotherapy, 2019

Therapeutic cancer vaccines have been tested in a variety of tumors. Melanoma is one type of cancers that has received the most attention of researchers and clinicians who do research on immunotherapy. Melanoma has the highest mutation rate among various types of cancer and many tumor antigens associated with this malignancy have been identified. However, the most successful results with cancer vaccines have been achieved in patients with prostate cancer. Sipuleucel-T was the first cancer vaccine approved by the US Food and Drug Administration to treat hormone-refractory prostate cancer, which made it a prototype for cancer vaccine therapy. Here, we will review the characteristics of prostate cancer as well as the promising results of cancer vaccines for different types of cancer, including prostate, melanoma, lung, colorectal, and breast.

Sepideh Razi, Mahsa Keshavarz-Fathi, in Vaccines for Cancer Immunotherapy, 2019

Cancer vaccines, which are a type of immunotherapeutic agents, have been widely studied for prevention and treatment of tumors. Therapeutic cancer vaccines improve patient s immune response against tumor cells. One of the several types of cancer vaccines is whole tumor cell vaccine. Whole tumor cell vaccines, which consist of allogeneic or autologous tumor cells or tumor cell lines, contain a large variety of characterized and uncharacterized tumor-associated antigens that could activate antitumor immune reactions. There are several methods for preparation of these vaccines such as tumor cell lysates, tumor-derived exosomes, and irradiated gene-modified tumor cell lines. This chapter will briefly describe the clinical trials, advantages and disadvantages of these vaccines and will discuss some ways that can help to optimize these vaccines.

A.S. Morris, ... A.K. Salem, in Micro and Nanotechnology in Vaccine Development, 2017

Cancer vaccines need to promote robust cellular tumor-specific immune responses capable of overcoming the immunosuppressive microenvironments within the cancer patient if they are to exhibit therapeutic benefit. Biodegradable polymer-based microparticles (MPs) and nanoparticles (NPs) offer the opportunity to contribute to the stimulation of such responses, and they also possess important advantages over many other vaccine modalities in terms of tunability and safety. This chapter focuses on MP- and NP-based delivery systems for cancer vaccines, beginning with a brief introduction into polymer-based delivery of antigens and adjuvants. Emphasis will be placed on the parameters (eg, size, type of adjuvant) that influence the magnitude and type of immune response generated by MP and NP vaccines as well as elaborating on the motivation for codelivering antigens and adjuvants together rather than separately. Preclinical studies using MP and NP formulations for novel cancer vaccine delivery systems will be discussed.

Neil L. Berinstein, Jeffrey A. Berinstein, in Vaccines (Sixth Edition), 2013

Cancer vaccine development is guided by the paradigm of immunity to viruses (Figure 42-1).1 These concepts are discussed in the chapters on HPV, HBV and EBV. During a successful cell-mediated immune response to a virus that has infected a target organ, viral antigens are presented to antigen-reactive T cells by professional antigen-presenting cells (APCs; particularly dendritic cells [DCs]) in secondary lymphoid organs. Activated T cells then proliferate and differentiate into cytotoxic effector cells (CTLs) that secrete cytokines, including interferon (IFN)-γ and tumor necrosis factor (TNF)-β. Activated CTLs enter the circulation and are guided to the site of infection by chemokines and adhesion molecules, where they kill infected cells by releasing granzymes and perforin or by activating death receptors on the surfaces of the target cells. The magnitude of the CTL response needs to be sufficiently strong (on the order of 1-10/100 CTLs) to clear Epstein-Barr virus infections2 and needs to be maintained for sufficient time (at least weeks to months3) to be effective. The former requirement is usually mediated by high-avidity T cells and the latter requirement is fulfilled by the induction of memory T cells.4 Cancer vaccines should ideally mimic these steps (Figure 42-1), except that the ultimate targets are cancer cells instead of virally infected cells. These steps will be discussed in more detail as they apply to cancer vaccines.

Qianyu Guo, ... Wilson H. MillerJr, in Advances in Cancer Research, 2019

Cancer vaccines are generally divided into two types: preventive (prophylactic) vaccines and therapeutic vaccines. While preventive cancer vaccines target pro-tumorigenic viral infections, therapeutic cancer vaccines aim to boost immune responses for recognition and eradication of tumor cells, and are the focus of this section (Guo et al., 2013). Multiple studies have shown that an effective therapeutic cancer vaccine can elicit robust T cell responses in patients (reviewed by Schumacher Schreiber, 2015). Such T cells can directly destroy the cancer cells, activate diverse immune responses, generate long-term memory, and display remarkable specificity for tumor-derived antigens (Gubin, Artyomov, Mardis, Schreiber, 2015). Given the importance of tumor-specific T cells in anti-tumor immunity, extensive studies seek to design vaccines that can induce efficient T cell responses (Tumeh et al., 2014). Two main classes of tumor-specific antigens have been suggested as promising for the development of anti-tumor vaccines: (1) neoantigens, generated from tumor-specific mutations and (2) non-mutated, but aberrantly expressed self-antigens (Heemskerk, Kvistborg, Schumacher, 2013). Traditional vaccines have targeted aberrantly expressed self-antigens, such as melanoma-associated antigen recognized by T cells (MART-1), as these antigens are widely shared among patients. Unfortunately, clinical benefits of these cancer vaccines remain elusive (Gubin et al., 2015; Tumeh et al., 2014), Moving away from classic tumor-associated self-antigen targeted therapies, recently personalized vaccines against neoantigens have come to the forefront of research, because neoantigens are postulated to induce more potent T cell responses that are not subject to central tolerance, with less or no autoimmune toxicity (Efremova, Finotello, Rieder, Trajanoski, 2017; Heemskerk et al., 2013). Two prerequisite molecular techniques to develop neoantigen-based vaccines have recently became available: deep-sequencing to detect all coding mutations within a tumor to predict potential neoantigens (Efremova et al., 2017), and high-throughput MHC tetramer screening that permits systematic analysis of T cell reactivity against these antigens (Schumacher Schreiber, 2015). Several studies have utilized such techniques to show that it is indeed possible to identify highly immunogenic neoantigens. By using whole-exome sequencing (WES), researchers successfully identified tumor neoantigens that can be recognized by adoptively transferred T cells in melanoma patients (Robbins et al., 2013). The WES technique was soon combined with high-throughput MHC tetramer screening in another study to show that neoantigen-specific T cell reactivity can be further increased by CTLA-4 blockade in melanoma patients (van Rooij et al., 2013). The utilization of epitope prediction algorithms was further added to this experimental setting to better identify potentially immunogenic neoantigens (van Buuren, Calis, Schumacher, 2014). Subsequently, researchers generated personalized neoantigen-based vaccines for patients with late-stage melanoma (Ott et al., 2017). After vaccination, four out of six patients with stage III melanoma showed full responses, and the remaining two patients with stage IV disease showed disease recurrence (Ott et al., 2017). These two patients were subsequently treated with anti-PD-1 blockade, and showed complete radiographic responses (Ott et al., 2017). This proof-of-concept study showed that neoantigen vaccines are both safe and effective to trigger anti-cancer immunity. This may provide potential solutions to the two major challenges in cancer treatment, tumor heterogeneity and targeting tumor cells but not normal cells. However, several challenges in the cancer vaccine space still remain. One of the biggest hurdles is the discovery and validation of neoantigens. Antigens are recognized by CD8+ T cells after a series of processes, including proteasome cleavage, peptide transport into ER and loading onto newly synthesized MHC class I molecules. All these complex processes, however, are predicted by computational methods following the identification of thousands of coding mutations within a tumor biopsy. In the end, only a small fractions of predicted neoantigens are able to elicit effective anti-tumor T cell responses. Currently, identification rates for neoantigen-specific CD8+ T cells from predicted neoantigens is only between 0% and 0.5% (Cohen et al., 2015; Khodadoust et al., 2017; McGranahan et al., 2016; Simoni et al., 2018). Another major concern, especially for patients with late-stage disease, is the long time needed for the generation of vaccines, with average times from biopsy to vaccine administration being roughly 4 months (Ott et al., 2017). Alternative therapies are likely needed during the vaccine preparation period, in order to ensure an optimal patient survival outcome. Moreover, combining checkpoint blockade with neoantigen cancer vaccines also seems to be a promising therapeutic approach (Sahin Tureci, 2018; Vonderheide Nathanson, 2013).

Sepideh Razi, Nima Rezaei, in Vaccines for Cancer Immunotherapy, 2019

Cancer vaccines have been studied for several years. The focus of these vaccines is treatment of patients with cancer. One of the several types of these vaccines is immune cell vaccine. Dendritic cells (DCs), which are a type of antigen presenting cells, have been widely used for development of immune cell vaccines. These cells can be loaded with different tumor-associated antigens (TAAs), including whole tumor cell lysates, RNA, peptides, and tumor cells. Patients receive these DC-based vaccines, then the DCs present TAAs to immune system and activate antigen-specific immune responses against the tumor. This chapter will briefly explain the DC-based tumor vaccines, their clinical trials, advantages and disadvantages, and then will discuss several methods that can help to optimize these vaccines.

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