Cancer Vaccines and Immunotherapy

Cancer immunotherapies, including cancer vaccines, are novel investigational cancer therapies. In contrast to chemotherapy and radiotherapy regimens that are often associated with severe side effects, cancer immunotherapy stimulates the body’s immune system and natural resistance to cancer, thus offering a gentler means of cancer treatment that is less damaging to the rest of the body. Surgery is generally (but not always) performed, prior to immunotherapy, to remove most of the tumor (Hanna MG, Jr. et al 2001; Jocham D et al 2004). Vaccination or immunotherapy prompts the immune system to kill residual cancer cells that persist after surgery and could result in the cancer recurring.

The status of the patient’s immune system is the key physiological factor affecting the outcome of cancer immunotherapy. However, each individual’s immune status is in turn affected by several factors (including age, tumor-induced and surgery-associated immunosuppression, and nutritional status) that need to be assessed, and some require continuous monitoring for the successful application of immunotherapeutic regimens. Immune cells play a central role in mediating the effects of immunotherapy, and specific nutritional supplements that enhance immune cell function can be effective in preparing patients for immunotherapy or vaccination (Malmberg KJ et al 2002).

Therapeutic cancer vaccines developed for melanoma, renal cell carcinoma, and colorectal cancer have shown benefits in phase III trials by extending the disease-free survival period (before relapse) and overall survival. In addition, several immunotherapy clinical trials have been performed for metastatic breast cancer and non-Hodgkin’s lymphoma.

The Immune System and Cancer

Evidence showing the role of the immune system in detecting and killing cancer cells has been available for some time (Richardson MA et al 1999; Wiemann B et al 1994; Hellstrom IE et al 1968; Oliver RT et al 1989; Penn I 1986, 1988; Vose BM et al 1985). This knowledge has been used in developing immunotherapies to bolster the immune system’s natural capacity to counteract cancer cells.

How Does the Immune System Detect Cancer Cells?

Cancer cells display abnormal proteins (antigens) on their surface, and the immune system can detect and destroy cancer cells because of these proteins (Knuth A et al 1991; Naftzger C et al 1991). (An antigen is a substance that causes the immune system to make a specific immune response.)

The immune system has an innate ability to resist cancer development; however, in most cases, the immune system fails due to a series of sophisticated strategies that tumor cells use to evade immune detection. These strategies range from methods designed to hide tumor cells, to active incapacitation of immune cells by tumor-produced agents that lower the immune system’s responses, which are known as immunosuppressive agents (Cordon-Cardo C et al 1991; Junker U et al 1996; Pantel K et al 1991; Ranges GE et al 1987; Sarris AH et al 1999; Staveley-O'Carroll K et al 1998). Therefore, a prerequisite to successful cancer immunotherapy is the implementation of strategies to boost the immune system’s natural resistance to cancer.

T cells and B cells (lymphocytes) are immune system cells responsible for what is known as specific immunity (Brodsky FM et al 1991; Janeway CA, Jr et al. 1994; Levine TP et al 1991). By contrast, other immune cells (for example, eosinophils, natural killer (NK) cells, and macrophages) generate non-specific responses to infections by bacteria and parasites (Klein E et al 1993; Mantovani A et al 1992). T cells and B cells respond only when they detect specific markers that identify infected cells (Brodsky FM et al 1991; Janeway CA, Jr et al. 1994; Levine TP et al 1991).

Why Do Tumors Escape Immune Detection?

Under normal circumstances, all cells display segments of their proteins on their surface. Upon infection with a viral or bacterial agent, cells display on their surface sample segments from these foreign proteins (Brodsky FM et al 1991; Janeway CA, Jr et al. 1994; Levine TP et al 1991). T cells and B cells patrolling the body for foreign invaders seek and destroy any cells that display these foreign proteins on their surface. These proteins are called antigens, substances that can stimulate a specific immune response or activity.

In cancer, the tumor cell also displays a sample of its abnormal proteins on its surface, which can signal the immune system that it is no longer a normal, healthy cell. These protein segments—either from proteins over-produced in the cancer cell or from viral or bacterial proteins that infected the cell and caused the cancer—act as red flags and attract the attention of T cells and B cells (Wang RF 1999). Tumor cells evade immune detection by failing to display protein segments (antigens) on their surface, thus, in effect, hiding from immune cells (Cordon-Cardo C et al 1991; Pantel K et al 1991).

In aggressive cases, tumor cells can also evade immune detection by producing agents that reduce immune cell activity (Junker U et al 1996; Ranges GE et al 1987; Sarris AH et al 1999; Staveley-O'Carroll K et al 1998). Alternatively, the immune system may not be able to cope with a tumor’s rapid growth if the initial immune response to the tumor is not sufficient to reject or control it completely. Despite the immune system’s natural ability to detect and kill cancer cells, in most circumstances the immune system fails to control tumor growth. The goal of immunotherapy is to specifically target tumor antigens as a means of killing cancer cells (Knuth A et al 1991; Naftzger C et al 1991). Table 1 shows some tumor antigens (substances that stimulate an immune response) that form the basis of cancer vaccines in clinical studies.

Table 1: Tumor antigens form the basis of vaccines in clinical development

Types of Immunotherapy

Monoclonal Antibody (mAb). Monoclonal antibodies target specific tumor antigens, such as tumor growth factors, and can enhance the immune response against cancer. Many monoclonal antibodies (for example, Herceptin®) have other anti-cancer activities such as biological response modification and signal transduction inhibition, which slow or prevent cancer growth signals. Monoclonal antibody therapies for various cancers are outlined in Table 1.

Herceptin®. Approximately 25 percent to 30 percent of breast cancer patients exhibit an excess of the protein HER-2/neu (a member of the human epidermal growth factor receptor family), which can be measured in the blood via its extracellular domain (Hayes DF et al 2001). HER2/neu-positive breast cancer cells are associated with aggressive disease and decreased overall survival.

Herceptin® (trastuzumab) is the first monoclonal antibody that "targets" the HER2/neu protein on human cancer cells. This drug is approved for the treatment of metastatic breast cancers that are HER2-positive (Luftner D et al 2005) and provides a median overall response rate of 23 percent (Vogel CL et al 2001). Herceptin® attaches to HER2 present on cancer cells, thus preventing cancer proliferation and inducing cancer cell death (apoptosis). Herceptin® is also a biological response modifier and a mediator of antibody-dependent cell-mediated cytotoxicity via natural killer cells and monocytes (Baselga J et al 2001). Because Herceptin® damages the heart, an echocardiogram and complete blood count are usually monitored.

Cytokine Therapy

Cytokines such as interleukin-2 and the interferons (alpha, beta, and gamma) have been used clinically in cancer patients.

Interleukin-2 (IL-2). Interleukin-2 (IL-2) is naturally produced in the body by T cells after activation by antigen, but it can also be given as a drug (immunotherapy). Clinical use of IL-2 counteracts the immunodeficiency state caused by the tumor and conventional treatments. IL-2 does not directly affect cancer cells; rather, its effects result from its ability to stimulate immune reactions in the body. Used as immunotherapy for metastatic melanoma (7 percent complete response) and kidney cancer (9 percent complete response), IL-2 can mediate durable regression (that is, prevent cancer recurrence) (Rosenberg SA 2001). However, a significant side effect of IL-2 therapy is vascular leak syndrome (Baluna R et al 1997).

Various interleukin-2 dosing schedules and combinations with interferon alpha (IFN-alpha) have been tested in patients with advanced melanoma. Response rates reported with IL-2 alone or in combination with IFN-alpha vary from 10 percent to 41 percent, with a small but significant proportion of durable responses (Keilholz U et al 2002a). High-dose interleukin-2 immunotherapy is useful in patients with metastatic renal cell carcinoma, and even in highly selected dialysis patients (Brusky JP et al 2006; McDermott DF et al 2005). IL-2 combined with thalidomide can produce durable, active responses in patients with metastatic renal cell carcinoma (Amato RJ et al 2006).

Treatment of skin and soft-tissue melanoma metastases by injection of IL-2 directly into the tumors resulted in complete response in 62.5 percent of patients (the longest remission lasting 38 months) and partial response in 21 percent of patients (Radny P et al 2003).

Preoperative immunotherapy with interleukin-2 in pancreatic cancer patients achieved a positive effect on postoperative complications and increased two-year survival (33 percent in the treated group compared to 10 percent in the control group) (Angelini C et al 2006).

Interferon. Interferons (IFNs) are produced naturally in the body in response to viral infections, but they can also be given as a drug (immunotherapy). Interferon alfa has immunomodulatory, anti-angiogenic, anti-proliferative, and anti-tumor properties (Iqbal Ahmed CM et al 2003) against leukemia (CLL, CML, and HCL) (Bonifazi F et al 2001; Guilhot F et al 2004) and lymphoma (Jonasch E et al 2001), and, in combination with other anti-cancer agents, against breast cancer (Nicolini A et al 2005). Adjuvant high-dose interferon alfa-2b is approved for all melanoma patients with intermediate- and high-risk disease, but it benefits only 20 percent to 30 percent of patients and its use is limited due to its toxicity (Tsao H et al 2004). A favorable outcome in patients with high-risk melanoma treated with adjuvant interferon alfa-2b appears to depend on the development of autoimmunity during or after treatment (Gogas H et al 2006). Adverse reactions to interferon therapy include flu-like symptoms of fever, chills, fatigue, and muscle aches.

Gene Therapy. Cancer gene therapy has provided preliminary results through phase I clinical trials. In advanced breast cancer or melanoma patients, gene therapy with MetXia-P450 (a novel recombinant retroviral vector that encodes the human cytochrome P450 type 2B6 gene) was safe, well tolerated, and produced an anti-tumor response, suggesting it merits further clinical assessment (Braybrooke JP et al 2005).

In mesothelioma patients, gene therapy with intrapleural adenoviral (Ad) vector encoding the herpes simplex virus thymidine kinase "suicide gene" (Ad.HSVtk/ganciclovir) was safe, well tolerated, and resulted in long-term durable responses in two patients, which may have been due to induction of anti-tumor immune responses. The researchers hypothesize that approaches aiming to enhance the immune effects of adenoviral gene transfer (that is, with the use of cytokines) may lead to increased numbers of therapeutic responses in otherwise untreatable pleural (lung) cancers (Sterman DH et al 2005).

Cancer Vaccines

In contrast to chemotherapy and radiotherapy, cancer vaccines are not associated with any serious side effects. Cancer vaccines and the immune system have the ability to mount and amplify antigen-specific anti-tumor responses (Sprent J et al 2001, 2002). These activities cannot be produced by chemotherapy or radiotherapy. Once the immune system generates T cells specific for a particular antigen, a group of “memory cells” that remember this antigen will remain in the body, and in the event of a second threat from that antigen, an immune response will be mounted much faster than the first one (Sprent J et al 2001, 2002).

Phase I clinical studies assessing the safety of cancer vaccines have shown them to be associated with no toxicities outside reports of mild flu-like symptoms, irritation at the vaccination site, and fatigue (Carr A et al 2003; Soiffer R et al 2003; Woodson EM et al 2004).

Preventive cancer vaccines are being developed as a means of preventing cancers caused by chronic viral, bacterial, and parasitic infections that are associated with up to 20 percent of all cancer cases, including cervical and liver cancers (Bhopale GM et al 2004; Herrera LA et al 2005).

Therapeutic cancer vaccines. Most cancer vaccines are therapeutic, in that they are intended to treat existing cancer rather than to prevent it (Dalgleish AG 2004; Hellstrom KE et al 2003). The cancer patient would initially undergo surgery to remove most of the tumor. Vaccination would then be undertaken to generate a specific immune response capable of clearing any residual cancer, thus preventing relapse (Hellstrom KE et al 2003; Hodge JW 1996; Reinartz S et al 2004) and extending the period of remission or survival in the patient.

The manner in which therapeutic cancer vaccines are used in the clinic is summarized in Table 3.

Table 3: The use of therapeutic cancer vaccines in the clinic