US Pharm
. 2013;38(9)(Oncology suppl):8-11.

ABSTRACT: The recent approval of sipuleucel-T (Provenge) as an autologous cellular immunotherapy for asymptomatic hormone refractory prostate cancer has generated tremendous interest in the development of cell-based immunotherapy for cancer. The ability of cancer cells to specifically evade the immune system, survive, and thrive has been identified as one of the hallmark features of malignant tumors. Cell-based immunotherapy is using strategies to help immune cells recognize tumor antigens and then destroy the cancer cells. These promising immunotherapy strategies for cancer treatment have been extensively studied by academic research institutions and the pharmaceutical industry in clinical trials. This review highlights the common tumor antigens and the strategy of using dendritic cell–based immunotherapy to enhance tumor antigen recognition for cancer treatment.

Surgery, radiation therapy, chemotherapy, and hormone therapy are four traditional modalities for cancer treatment. Many traditional cytotoxic chemotherapeutic agents have a very narrow therapeutic index (NTI), low overall response rate, rapid and severe systemic toxicity, unpredictable efficacy, and frequent resistance. There is an urgent need for more targeted, less toxic, and more individualized therapies to improve the efficacy and safety of cancer treatments. It is particularly critical for those hard-to-treat cancers that are refractory to chemotherapy or hormonal therapy, such as advanced melanomas and prostate, breast, colorectal, and lung cancers.

With the recent approval of several novel immunotherapy agents for cancer treatment within the past 5 years, immunotherapy has become an emerging strategy in oncology. Cell-based immunotherapy offers a unique strategy to trigger or boost a patient’s own immune defenses to fight cancer by enforcing tumor recognition, improving the survival and functions of T cells and other immune effector cells, and modifying dendritic cells to present specific tumor antigens to activate T lymphocytes.1

Evading Attack From the Immune System Is a Hallmark Feature of Cancer

Human tumors generally apply two mechanisms to evade the host immune attack. These mechanisms: 1) take advantage of an already suppressed host immune system; and 2) avoid host immune system recognition.2 Clinical evidences indicates that the immune system plays a critical role in cancer development and treatment, especially for those patients with deficient T-cell function. Patients with compromised immune function (e.g., HIV patients), or suppressed immune function (e.g., transplant patients on immunosuppressants) have substantial and clinically significant higher risk of cancer development compared to individuals with normal immune function.3,4 Human tumors can also escape immune system attack through the growth of antigen-negative tumor variants, down-regulation of major histocompatibility complex (MHC) class Ia molecule expression, human leukocyte antigen (HLA) under-expression in tumor cells, and by underexpressing costimulatory molecules or blocking costimulatory pathways in cancer cells.

Without a significant presence of tumor antigens, tumor cells can easily evade the host immune system because of poor targets for cytotoxic T lymphocytes. New evidence also indicates that adenosine-producing regulatory T cells (Tregs) and expression of toll-like receptors (TLRs) on the tumor cell surface can also play an important role in helping tumor cells evade the host immune system.5,6 As such, the ability of cancer cells to specifically evade the immune system, survive, and thrive has been identified as one of the hallmark features of malignant tumors.7,8

The goal of antitumor immunotherapies is to inhibit tumor-induced immune evasion and enforce tumor recognition by improving survival and functions of T cells and other immune effector cells, as well as to modify dendritic cells to present tumor-specific antigens (TSAs) to activate T lymphocytes. Unlike tumor-associated antigens (TAAs), which are not unique to tumors and are also seen on normal cells, TSAs generally only present on tumor cells and can be recognized by cytotoxic T lymphocytes.9,10 A good example of a TSA is HPV (E7), which is a viral transforming gene product uniquely expressed in tumor cells of cervical cancer patients.11 A common example of a TAA is human epidermal growth factor receptor 2 (HER2/neu). This growth factor receptor is overexpressed in over 30% of breast cancer patients, but it can also be found on normal breast and ovary cells.12

Both TSA and TAA can be potential targets for antitumor immunotherapy; however, recent developments in the field of immunology suggest that many antigens originally thought to be tumor specific can also be detected in normal cells.13 As such, most tumor antigens are categorized by their sources and molecular structures.

TABLE 1 summarizes some examples of tumor antigens that can be potentially targeted for cancer immunotherapy and diagnosis and prognosis of malignancies.14-16 Many tumor vaccines and immunotherapy drugs are being developed that target these tumor antigens.

Dendritic Cell–Based Immunotherapy

The host immune system includes: 1) an antigen-nonspecific innate immune response, which is mediated by phagocytic cells, natural killer (NK) cells, complement (cytokine involved in immune reactions), interferons (IFNs) and other cytokines; and 2) an antigen-specific adaptive immune response, which is mediated by antigen-presenting cells (APCs), plasma cells, cytotoxic T cells, memory B cells, and T cells. Compared to innate immune response, the adaptive immune system response provides a more specific and stronger defense for future recurring tumor attacks. The major function of APCs (i.e., dendritic cells, macrophages, B lymphocytes) in an antigen-specific adaptive immune response is to capture antigen and present it to T lymphocytes.

One of the primary types of APCs is the dendritic cell. Dendritic cells are distributed widely in many kinds of tissues, such as the skin, respiratory tract, genitourinary tract, gastrointestinal tract, lymphoid tissues, and most solid organs. Their progenitors are produced in the bone marrow and have high phagocytic capacity. Dendritic cells express both major histocompatibility-I and II (MHC-I and MHC-II) molecules that allow them to present antigens to T-cell receptors (TCR) on both naive T8 lymphocytes and naive T4 lymphocytes, respectively. Presentation of antigen to T8 and T4 lymphocytes leads to their activation, proliferation, and differentiation into immune effector cells. This process is essential for inducing antigen-specific T-cell responses (FIGURE 1).17,18

Although the regulatory mechanism of antigens presenting on dendritic cells is still not clear, studies suggest that major antigens associated with MHC presenting to the TCR on the surface of the T cell needs a costimulatory pathway to generate sufficient signals for T cell activation and effector functions. Research has indicated that CD80:CD28 is an essential activating costimulatory pathway for antigen presentation. In contrast, it was discovered that the antigen CTLA-4 (cytotoxic T-lymphocyte–associated antigen 4) found on T cells has a negative regulatory effect on T-cell activation, which inhibits CD80:CD28 costimulatory pathway for antigen presentation and stops the immune system from attacking cancer cells. There was also evidence that blocking antibody to CTLA-4 combined with a cancer vaccine releases the physiological brake on the immune system and elicits a potent immune attack at tumors (FIGURE 1).18 In March 2011, the FDA approved ipilimumab (Yervoy), the human monoclonal antibody blocking CTLA-4, to treat unresectable or metastatic melanoma.19


Modifying dendritic cells to present tumor antigens to activate T lymphocytes is one of the most successful strategies to induce a host immune system response capable of destroying tumors. For dendritic cell–based cancer immunotherapy, the cancer patient’s dendritic cells are collected. The TSA can be pulsed or genetically engineered into the autologous dendritic cells. These activated dendritic cells, which present TSA, are then transfused back to prime the adaptive immune response against the cancer cells expressing the TSA. Extensive clinical research has been developed to identify the ideal source and type of dendritic cell for immunotherapy. Tremendous efforts have also been spent on discovering novel tumor antigens and optimizing the technology to activate dendritic cells to efficiently present the tumor antigen to T lymphocytes. Rigorous clinical protocols regarding the appropriate dose, duration, clinical setting, and criteria for clinically significant immune response also need to be established.20,21

One of the critical issues in the development of dendritic cell–based immunotherapy is to maximize and stabilize the antigen-presented dendritic cells. In vivo and in vitro strategies for tumor antigen loading to dendritic cells have been developed. The tumor antigen can be delivered in vivo by infusing the tumor antigen to patients’ circulating dendritic cells. To maximize the antigen presentation, the tumor antigen can be coupled to dendritic cell–specific antibodies before they are infused in patients. To enhance the antigen loading to dendritic cells, many in vitro strategies have been developed recently using tumor- or viral-derived antigens.22

Sipuleucel-T (Provenge)

Provenge was approved in April 2010 to treat hormonal refractory asymptomatic or minimally symptomatic metastatic prostate cancer.23,24 It is the first and so far the only cell-based and individualized immunotherapy approved by the FDA, which represents a milestone for cancer immunotherapy.

There are two major components to Provenge, an active component comprised of APCs harvested from prostate cancer patients by leukapheresis, and a tumor antigen, which in this case is a recombinant fusion protein combining prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). As described in TABLE 1, PAP is a cell type-specific differentiation tumor antigen highly expressed on the surface of prostate cancer cells (PAP is known to be present in 95% of prostate cancers). GM-CSF is an immune cell activator that regulates the recruitment and function of dendritic cells and macrophages.23

Interestingly, the dose of the drug is determined in part by measuring the expression of CD54 molecule (also known as ICAM-1) on the surface of APCs after culture and pulsed with PAP-GM-CSF. CD54 is a marker of immune cell activation that plays an essential role in antigen-specific, cell-mediated immune response.25,26 Three days prior to the infusion date, the patient’s peripheral blood mononuclear cells are obtained via a standard leukapheresis. Then during day 2 and 3, the collected APCs are expressly delivered to the drug manufacturer (Dendreon), where Provenge is produced by culturing collected APCs with the treatment of PAP-GM-CSF recombinant fusion protein. On day 3 or 4, the activated APCs will be sent back to the physician’s office for infusion.23

Each dose of Provenge should contain a minimal 50 million autologous CD54+ cells activated with PAP-GM-CSF suspended in 250 mL of Lactated Ringer’s Injection, USP, and be infused over 60 minutes without a cell filter. Three complete doses of Provenge treatment with an approximately 2-week interval is recommended for hormonal therapy refractory asymptomatic or minimally symptomatic metastatic prostate cancer patients.23

The FDA’s approval of Provenge was based on the clinical evidence from a randomized, double-blind, multicenter phase III trial (IMPACT), which indicated that the drug significantly improved overall survival (OS) in men with metastatic castrate-resistant prostate cancer, although the time to progression (TTP) was not significantly different.27 In the study, 1,512 patients were randomized in a 2:1 ratio to receive three Provenge infusions (n = 341) or control autologous peripheral blood mononuclear cells that had not been activated (n = 171). Provenge extended the OS by a median 4.1 months (Provenge arm: 25.8 months; Control arm: 21.7 months; hazard ratio (HR): 0.775; 95% CI: 0.614, 0.979; P = .032). In addition, 52.1% of patients survived after 48 months compared to 41.2% patient survival in the control arm, and 31.7% of patients in the Provenge arm survived after 36 months compared to 23% of patients in the control arm. However, no significant effect on the TTP was observed in this clinical trial. Although the adverse events, mainly infusion reactions such as chill, fever, and headache, were more common in the Provenge arm, they were generally mild and can be managed by premedication with acetaminophen and diphenhydramine.27

The efficacy was confirmed by a second smaller, randomized, double-blind, multicenter phase III trial (Provenge arm: n = 82; Control arm: n = 45). Provenge extended the OS by a median of 4.5 months (Provenge arm: 25.9 months; Control arm: 21.4 months; HR: 0.586; 95% CI: 0.388, 0.884; P = .010).28

Since Provenge is autologous cell therapy, the treatment will only be available at 50 approved clinical sites around the country, and both patients and physicians must adhere to the personalized leukapheresis and infusion schedules. Three complete doses of Provenge treatment with an approximately 2-week interval is recommended for hormonal therapy refractory asymptomatic or minimally symptomatic metastatic prostate cancer patients.23 The three infusions of the drug can cost up to $93,000, but it will be covered by Medicare if the treatment plan is approved.24

Conclusions and Future Prospects

With the approval of Provenge, the first cell-based cancer immunotherapy, the concept of cancer treatment and pharmacotherapy has been redefined. There is an urgent need for pharmacists to understand these novel strategies for cancer treatment, such as cell-based cancer immunotherapy. With the discovery of more novel tumor antigens and clinically efficient and cost-effective technologies to engineer APCs and immune effector cells to enhance the recognition of tumor antigen and improve the survival of immune cells, additional cell-based immunotherapies like Provenge should be available in the market soon.

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