Cancer vaccines: Precepts, problems and promises

Cancer is one of the leading causes of death, with over 60 per cent of the deaths occurring in the developing countries alone. WHO reports the second highest rate of cancer incidence in India, next only to USA. Cancer has a multifaceted character, quite inherent in its origin. It is an abominable impairment of health, affecting almost all the body organs of people at all the ages, with its risk augmenting with age (Figure 1). Normal cells become cancerous because of DNA damage rewiring of crucial signalling pathways deep down at the molecular level. Tumours exist at the expense of the body’s health. While a benign tumour remains localized to a specific place in the body, the malignant i.e., cancerous tumours rapidly grow by infiltrative growth via metastasis (i.e., spread) to other locations in the body via lymph or blood.

Of the myriad approaches conventionally employed to treat or prevent cancer, the vital ones include chemotherapy, surgery and radiation. In recent years, increasing efforts have been made to explore diverse alternative options, including vaccination strategies for the treatment as well as prevention of carcinogenesis. Cancer vaccines are biological response modifiers designed to effectively induce tumor-specific cytotoxic T cells, the key effector cells in immune responses against tumours to enable them to mount an attack against cancer cells in the body.

The pivotal goal of cancer immunotherapy is to control tumours by boosting patient's immune system. Cancer vaccines currently under development are designed to stimulate body’s immune sentries primarily B or T cells, to mount an attack against foreign entities. Thus these offer significant potential for effective, non-toxic and outpatient-based approach to cancer therapy. A cancer treatment vaccine employs cancer cells, parts of cells, or pure antigens to boost the immune response against cancer cells already present in the body. As the immune system has special cells for memory, it is hoped that it will help keep cancer from coming back. The objective of cancer immunotherapy is to create a therapeutic possibility due to the recognition of tumour antigens by the host’s immune system. The pre-clinical and clinical studies have demonstrated that the immune system is able to recognize and mount antibody and T-cell responses against cancer, and in rare instances, even reject a tumour.

Figure 2 endeavours to classify various immunotherapeutic approaches to combat or prevent cancer as a hierarchical chart.

1. Tumour cell vaccines: Vaccines are cultivated using actual cancer cells removed during surgery from the same patient or a different patient. The cells are first attenuated and then injected into the patient. While the cells are dead, the antigens are still recognized by the immune system, which then respond by attacking the attenuated cells and the live cancer cells carrying the antigen. The cells are treated in the laboratory, usually with radiation, chemicals and/or new genes, so they cannot form more tumours. The immune system recognizes antigens on these cells, seeks out and attacks other cells with these antigens that are still present in the body. Most tumour cell vaccines are autologous, i.e., made of killed tumour cells taken from the same person for whom these will later be used. Other tumour vaccines are allogeneic, i.e. the cells for the vaccine come from someone other than the patient being treated.

2. Antigen/adjuvant vaccines: Specific protein fragments or peptides stimulate the immune system to fight tumour cells. One or more cancer cell antigens can be combined with a substance that causes an immune response, usually termed as an adjuvant. Adjuvants are usually compounds, capable to increase and/or modulate intrinsic immunogenicity of an antigen and thus assist new vaccines to induce potent and persistent immune response(s). The main type of adjuvants developed before the advent of specific ligands include mineral salts emulsions and immune-stimulating complexes, carrying both immune-stimulant and carrier activities. More specific and promising adjuvants, and formulations targeting antigen-presenting cells or favouring antigen capture, such as Toll-like receptor agonists, have recently been developed recently. These vaccines boost the immune system using only one antigen(s), rather than whole tumour cells that contain several thousands of antigens, usually proteins or peptides. Antigen vaccines may be specific for a certain type of cancer, but not for a specific patient like with autologous tumour cell vaccine(s). Often, several antigens in a vaccine are combined to get a stronger immune response.
 
3. DNA vaccine and viral vector vaccine: Plasmid DNA and viral vector-based cancer vaccines have myriad inherent features that make them promising cancer vaccine candidates. The designed DNA vaccine containing DNA plasmid, codes for antigenic protein. When this vaccine is injected into the host, antigenic protein gets translated, alerting the body’s immune system to generate immunization memory cells. This approach can be facilitated by genetic engineering using recombinant viral vectors expressing tumour antigens, cytokines, or both, from an immunogenic virus particle. Figure 3 illustrates pictographically the mechanistic of systemic immunization using tumour specific immune modulators.
 
4. Anti-idiotypic vaccines: Since antibodies are molecules containing protein and carbohydrate and these can themselves act as antigens and induce an antibody response. These are, therefore, the vaccines made up of antibodies that see other antibodies as the antigen(s) and bind to it. Thus, the anti-idiotype vaccines can stimulate the body’s immune system against tumour cells.
 
5. Dendritic cell vaccine: "Dendritic cells (DCs) are the guys who are training the fighters," says Pawel Kalinski, a distinguished immunologist at the University of Pittsburgh in Pennsylvania, about their role in activating T cells, DCs are special cells in the body that help the immune system to recognize cancer cells. They break down cancer cells into smaller pieces (including antigens), and then hold out these antigens so that the T cells can spot them. This makes it easier for the immune system cells to recognize and attack cancer cells. DCs are believed to be the most important antigen-presenting cells of the body, initiators and modulators of immune response(s) both.

6.  Ongoing developments in industry:  Provenge (known generically as Sipuleucel-T), an immunotherapy for prostate cancer is a lead product of Dendreon, a biotechnology company based in Seattle USA. The US FDA approved the therapeutic cancer vaccine for the first time in April 2010, for use in patients with metastatic hormone-refractory prostate cancer. A number of other vaccines such as Onyvax-P® (VaxOnco Inc., Seoul, South Korea) and Junovan® (Takeda Pharmaceutical Company Limited, Osaka, Japan) are in the late-stage clinical trials for various tumour types. MAGE-A3, a human gene encoding for a tumor-specific antigen is documented to induce an immune response against MAGE-A3-expressing cancer cells. However, Cell Genesys (GVAX), CancerVax (Canvaxin), Genitope Corp (MyVax personalized immunotherapy), and Favrille Inc (FavId) are instances of cancer vaccine projects that have been terminated owing to poor phase III results, despite promising phase II data and strong immune responses. The authors have undertaken an extensive endeavour to furnish a global overview of the current status of development of cancer vaccines. Table 1 provides a terse account on the various cancer vaccines which are undergoing various phases of clinical research.

Epilogue: The past scepticism towards this type of therapeutic innovation is now getting replaced with great expectations. The domain is now moving towards the development of alternative vaccination technologies, capable of generating stronger, more durable and efficient immune responses against specific tumour-associated antigens, in combination with cheaper and more standardized manufacturing. Genetic vaccines, in this context, are emerging among the most promising methodologies. Several evidences point to combinations of different genetic immunization modalities (heterologous prime/boost) as a powerful approach to induce superior immune responses and achieve greater clinical efficacy. Vaccines against cancers have not been as effective as vaccines against infectious diseases.  

Better understanding of how cancer cells manipulate the immune system could lead to the development of new drugs that block those processes and thereby improve the effectiveness of cancer treatment vaccines. Combination of a cancer treatment vaccine with a drug that would block the negative effects of one or more of these suppressive cytokines on killer T cells might improve the vaccine’s effectiveness in generating potent killer T cell antitumor responses. The failure of past cancer vaccine trials may plausibly be due to several factors including inappropriate choice of tumour antigen, use of non-optimal antigen delivery system or vaccination schedule, selection of the wrong patient group etc. Despite the challenges and potential pitfalls, there are several positive factors that seemingly indicate that conducting clinical trials of cancer vaccines in the preventive setting is a viable approach for future research.

In a nutshell, immunotherapy has immense promise to act as surrogate to multiple inpatient chemotherapeutic, radiological, and surgical interventions employed conventionally. Extensive and intensive research efforts, accordingly, need to be undertaken to unfold the prospects of such off-the-shelf cancer vaccines for effectual and cost-effectual therapy of cancer.