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Cancer Vaccines and Immunotherapy

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.

Drug

Molecular Target

Mechanism of Action

Cancer Type

References

Herceptin® (trastuzumab)

HER2/neu (human epidermal growth factor receptor)

mAb, BRM, STI

Breast (metastatic)

(Baselga J et al 2001)

Erbitux™ (cetuximab)

EGFR (epidermal growth factor receptor)

mAb, BRM, STI

Colorectal (advanced), head and neck, and pancreatic

(Bonner JA et al 2006; Moroni M et al 2005; Xiong HQ et al 2004)

Tarceva® (erlotinib)

EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor)

mAb, BRM, STI

Non-small cell lung and pancreatic (advanced)

(Johnson JR et al 2005; Moore MJ 2005)

Iressa® (gefitinib)

EGFR-TKI

BRM, STI

Non-small cell lung (restricted access)

(Fukuoka M et al 2003)

Avastin™ (bevacizumab)

Humanized antibody to VEGF (vascular endothelial growth factor)

BRM, anti-angiogenic

Colorectal (metastatic), clear-cell renal carcinoma (metastatic)

(Hainsworth JD et al 2005; Jubb AM et al 2006)

Rituxan® (rituximab) (see chapter on Lymphoma)

Monoclonal antibody to CD20, a B-cell antigen

mAb, BRM

B-cell non-Hodgkin's lymphoma (NHL)

(van Heeckeren WJ et al 2006)

Thalidomide

Anti-TNF-a (tumor necrosis factor- alpha)

Anti-angiogenic, TNF modifier

Multiple myeloma, renal cell carcinoma (not FDA approved;restricted to clinical trials)

(Rajkumar SV et al 2006; Srinivas S et al 2005)

Table 2. Targeted Therapies (mAb = monoclonal antibody; BRM = biologic response modifiers; STI = signal transduction inhibitors)

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).