Cancer Vaccines and Immunotherapy-2

How Cancer Vaccines Work

The immune system is capable of both specific and non-specific responses against tumor cells. However, successful cancer vaccines must stimulate the immune system to act largely in a tumor-specific fashion.

A successful cancer vaccine would present tumor antigens to immune cells and activate CD4 (also known as helper T cells) and CD8 T cells (also known as cytotoxic or killer T cells). CD8 T cells become activated and directly kill the tumor cells (Janeway CA, Jr et al. 1994), while CD4 T cells are indirectly activated by dendritic cells and macrophages (Grohmann U et al 1998) to produce messengers (cytokines) that boost CD8 (killer) T-cell activity (Seder RA et al 1994).

B cells are immune cells that produce antibodies to human tumors (Disis ML et al 1994; Sorokine I et al 1991). Cancer immunotherapy that generates a good antibody response produces a better clinical outcome for the patient (Hoover HC, Jr et al. 1993; Mittelman A et al 1994).

The immune system also has a range of non-specific tools that can be stimulated into action by cancer vaccines, including natural killer cells and macrophages (Klein E et al 1993; Mantovani A et al 1992).

Types of Cancer Vaccines

Therapeutic cancer vaccines are classified into two main categories:

Whole cell vaccines: self (autologous), donor (allogenic), or dendritic cell
Synthetic protein antigens (soluble vaccines).
Whole cell vaccines use inactivated whole tumor cells as the vaccine given to the cancer patient. These inactivated tumor cells have a range of abnormal tumor proteins to which the patient’s immune cells respond by generating an anti-tumor immune response and attacking any cancer cells persisting after surgery. Using the whole tumor cell as a vaccine eliminates the problem of having to identify the various key antigens, most of which remain unknown.

Self Versus Donor (Autologous Versus Allogenic) Vaccines. The tumor cells used in whole cell vaccines can be derived from the patient’s own (self or autologous) tumor (Lahn M et al 1997) after it has been removed during surgery. Alternatively, these tumor cells can be obtained from a tumor sample removed from another individual (donor or allogenic) with the same cancer type (Chan AD et al 1998).

Dendritic Cell Vaccines. Dendritic cells are finger-like cells that pick up proteins from tumor cells (antigens) or invading organisms (bacteria, viruses, and parasites), and process and present them to young lymphocytes (Avigan D 1999; Hajek R et al 2000), which then initiate immune responses (Bodey B et al 2004; Vieweg J et al 2005).

Dendritic cell-based cancer vaccines, prepared from blood samples taken from the cancer patient (Hajek R et al 2000; Tjoa BA et al 2000), have been used to treat prostate cancer (Murphy G et al 1996), colorectal cancer (Chen W et al 2000), non-small cell lung cancer (Hirschowitz EA et al 2004), breast cancer (Allan CP et al 2004), and B-cell cancers (Adema GJ et al 2005; Ragde H et al 2004; Reichardt VL et al 2004). Dendritic cells pulsed with tumor cells (lysate) are partially efficient in triggering effective anti-melanoma immunity in stage IV patients (Escobar A et al 2005). Dendritic cell cancer vaccines are safe and well tolerated in humans.

Synthetic protein antigens are mass-produced synthetic versions of abnormal proteins displayed by tumors, and can generate immune responses capable of destroying cells in the body that display these antigens (Schulz M et al 1991). This type of vaccination is given to patients with immune system boosters (adjuvants) or other messengers to further enhance immune system activity (Schulz M et al 1991). Dendritic cells, which coordinate the function of immune cells, are often used as a vehicle to deliver these synthetic proteins to the immune system (Liu KJ et al 2004).


Clinical Studies Using Different Types of Cancer Vaccines

Melanoma. Melanoma is perhaps the cancer that has been the central focus of cancer vaccine research.

Synthetic Proteins. Proteins that have been identified as tumor antigens for melanoma include tyrosinase, MART-1 (also known as Melan A), gp100 (Jager E et al 1996), and products of the MAGE gene family (Gaugler B et al 1994; Van Der BP et al 1991). These proteins are not unique to melanoma cells, but are normal body proteins that are overproduced by melanoma cells and therefore called melanoma-associated antigens (Jager E et al 1996).

Vaccines made up of MART-1, tyrosinase, and gp100 synthetic proteins were successfully used to vaccinate melanoma patients and induced objective tumor regression in all patients (Jager E et al 1996). Other melanoma cancer vaccines have used synthetic MAGE proteins and have been noted to cause complete tumor regression in some patients (Marchand M et al 1999; Weber JS et al 1999).

Gangliosides (GM2, GM3, GD2, and GD3). Gangliosides are cell surface molecules that are abnormally displayed or overproduced by all tumors. They are linked to an increased ability of tumors to spread, or metastasize (Bitton RJ et al 2002; Fredman P et al 2003), and to poor clinical outcomes (Hakomori S 2001). Therefore, they represent targets for vaccine-generated immune responses. Indeed, vaccination with purified gangliosides, prepared from laboratory-grown melanoma cells, showed that they were capable of generating an immune response in melanoma patients (Tai T et al 1985).

Another clinical study has shown that vaccination of melanoma patients (after surgery to remove skin, lymph node, and other metastases) with a concoction containing GM3, GD3, GM2, and GD2 generated strong immune responses that were associated with increased disease-free survival (Portoukalian J et al 1991). The successful use of ganglioside cancer vaccines is supported by improved survival of stage III melanoma patients who where treated with a GM2 vaccine following surgery to remove most of the tumor (Livingston PO et al 1994).

Heat Shock Proteins (HSPs). Heat shock proteins are abundant cell proteins known as molecular chaperones because they guide the assembly and eventual loading of proteins, prepared within the cell, into the external structures on which they are displayed to immune cells guarding the body (Przepiorka D et al 1998; Ren W et al 2004). Heat shock proteins from tumor cells therefore contain the perfect sample of tumor antigens for that particular tumor type and have proved effective as a basis for cancer vaccines, particularly for melanoma and renal cell carcinoma (Hoos A et al 2003; Huang XF et al 2003; Oki Y et al 2004).

A Phase III trial was performed with 300 patients with stage IV melanoma using heat shock protein (gp96)-peptide complexes derived from the patients’ own tumors (given once weekly for the first four weeks and every other week thereafter). The patients with skin and lymph node disease survived an estimated median of 626 days compared to 383 days in the control group (Srivastava PK 2006).

Non-Hodgkin’s Lymphoma. Other vaccine approaches (for example, anti-idiotype) have demonstrated clinical benefit in the treatment of non-Hodgkin’s lymphoma (Bendandi M 2004; Caspar CB et al 1997; Rodriguez CM et al 2004) and are being assessed for multiple myeloma treatment (Titzer S et al 2000).

Pancreatic, Lung, Colorectal, Breast, and Ovarian Cancers. Carcinoembryonic antigen (CEA). CEA is a glycoprotein (a protein attached to sugar groups) that is normally produced by cells only during fetal development. However, it is grossly overproduced by almost 50 percent of all human cancers (Huang EH et al 2002; Marshall J 2003; Ullenhag GJ et al 2004), including colon, rectal, breast, ovarian, lung, pancreatic, and gastrointestinal tract cancers (Marshall J 2003; Morse MA et al 1999). Indeed, CEA can be detected in blood samples from cancer patients and is therefore used to monitor cancer therapy and progression (Marshall J 2003).

CEA loaded into dendritic cells and used as a cancer vaccine generated (CD4 and CD8) anti-tumor responses that were associated with disease stabilization (Berinstein NL 2002; Liu KJ et al 2004; Ueda Y et al 2004). CEA delivered to the cancer patient’s immune system (by a poxvirus) brought about disease stabilization in up to 37 percent of treated patients (Berinstein NL 2002). A CEA-based vaccine (ALVAC-CEA) developed using vaccinia virus has also been shown to be safe in humans and capable of generating specific anti-tumor immune responses (Marshall J 2003).

Breast and Ovarian Cancer. Sialyl-Tn (STn). Sialyl-Tn is a carbohydrate that is overproduced by several types of cancer cells, including breast, ovarian, colorectal, gastric, and pancreatic cancer cells (Holmberg LA et al 2004). As a result, this tumor-associated antigen is a good candidate for a therapeutic vaccine for these cancers.

A sialyl-Tn-based cancer vaccine called Theratope®, developed by a Canadian company (Biomira Inc.), is effective in the treatment of breast and ovarian cancer patients (Holmberg LA et al 2000, 2001). In a clinical setting, this vaccine was safe and was associated with reduced risk of relapse (longer remission period) or death (Holmberg LA et al 2000, 2001).

Enhancing Immunotherapy Responses

Boosters for the Immune System. Tumor cells used as vaccine are often manipulated to produce and secrete messengers such as interleukin-2 and granulocyte macrophage colony stimulating factor (GM-CSF), which directly activate immune cells (Dranoff G et al 1997; Osanto S et al 2000; Sallusto F et al 1994). In the clinical setting, vaccines are often administered with immune system boosters (adjuvants), such as bacillus Calmette-Guerin (BCG) and DETOX, to make the immune system more responsive to the presented antigens (Harris JE et al 2000; Knutson KL 2002; Sondak VK et al 2003).

Cancer Vaccines in Clinical Trials (Phase III)

A variety of candidate cancer vaccines showed promise in early (phase I and II) clinical studies (Murphy G et al 1996; Weber JS et al 1999). However, most failed to translate this success to the larger phase III studies that examine the impact of the vaccine-induced immune response on the period of remission (or disease stabilization) enjoyed by the patient, and on overall survival. The former is also referred to as disease-free survival or progression-free survival (Kaufman HL 2005). Consequently, when making a balanced assessment of cancer vaccines as a treatment option, it is important to focus on vaccines that have reached phase III studies. With the exception of lung cancer, therapeutic cancer vaccines have progressed to phase III clinical studies for all the major cancer types.

Renal Cell Carcinoma. A cancer vaccine for renal cell carcinoma has recently been tested in a phase III setting using autologous (self-donated) cancer cells and lysates (prepared by breaking down cancer cells) (Doehn C et al 2003; Jocham D et al 2004). This study involved 558 renal cell carcinoma patients who were vaccinated (six injections in the skin once a month) with the autologous tumor cell vaccine after surgery (Jocham D et al 2004). After 70 months of follow-up, the progression-free survival of vaccinated patients was 67.8 percent compared to 59.3 percent in non-vaccinated patients (Jocham D et al 2004). These results support the use of this renal cell carcinoma vaccine following surgery (removal of a kidney) in renal cell carcinoma cases not larger than 2.5 cm (Jocham D et al 2004).

Melanoma. Several types of cancer vaccines for melanoma have progressed to phase III clinical assessment, including ganglioside and whole cell (allogenic and autologous)-based vaccines (Hsueh EC et al 1998; Knutson KL 2002; Sondak VK et al 2003).

A whole cell melanoma vaccine (CancerVax/Canvaxin) has been tested in a phase III clinical trial by comparing the outcomes of 935 vaccinated patients (after surgery) and 667 non-vaccinated patients (Hsueh EC et al 1998; Morton DL et al 2002). The five-year overall survival of vaccinated patients was 49 percent compared to 37 percent in the non-vaccinated group of patients (Morton DL et al 2002).

Melacine, a melanoma cancer vaccine prepared from allogenic (donor) tumor cells, has also progressed to phase III clinical evaluation (Sondak VK et al 2003; Sosman JA et al 2003). This vaccine is given to patients with an immunological booster and has been shown to confer vaccinated patients with survival benefits (Sondak VK et al 2003).

A ganglioside-based vaccine, developed for melanoma treatment and administered with an adjuvant, was initially shown to induce antibodies that could clear melanoma cells (Knutson KL 2002). However, evaluation of this vaccine in phase III studies produced somewhat disappointing results, as a standard treatment of high-dose interferon therapy generated better results in relation to relapse-free survival and overall survival (Kirkwood JM et al 2001).

Colon Cancer. Cancer vaccines for colorectal cancer that have progressed to phase III clinical studies have focused on the use of CEA proteins and whole cell autologous (self) tumor cells (Hanna MG, Jr. et al 2001; Harris JE et al 2000; von MM 2005). An autologous tumor cell vaccine used in combination with BCG as an adjuvant (immune booster) has been tested in a study of 412 stage II and III colorectal cancer patients who had undergone surgery to remove most of the tumor (Harris JE et al 2000). Vaccinations were given four weeks after surgery and patients who received this treatment showed benefits in disease-free survival and overall survival (Harris JE et al 2000).

Breast Cancer. The vaccine Theratope® (manufactured by Biomira Inc.), based on the tumor-associated antigen sialyl-Tn, is currently being evaluated in a large phase III study of 1000 metastatic breast cancer patients (Holmberg LA et al 2004; Ibrahim NK et al 2003). Findings from this study have yet to be published.

Note: Biomira Inc., a pharmaceutical company, does not treat patients. However, Biomira provides vaccines to physicians at various cancer clinics in North America and Europe where government-approved clinical trials are ongoing. The vaccines are provided only to physicians who are currently involved in vaccine exploration and who have extensive experience with these agents. To speak to Biomira's Medical Information Assistant, call 1-877-234-0444, ext. 500.

Prostate Cancer. Provenge®, a dendritic cell-based vaccine for prostate cancer, is being evaluated in phase III clinical studies by the US company Dendreon (Rini BI 2002). This vaccine involves loading synthetic prostate cancer cell proteins (recombinant protein antigens) into the patient’s dendritic cells (grown in the laboratory) and administering them as vaccine. Clinical studies have shown that this vaccine has activity in patients with hormone-independent prostate cancer (Schellhammer PF et al 2005). More recent media reports (NewsRX.com) have indicated that this vaccine improved survival in men with advanced prostate cancer in phase III studies; however, these results have not yet been published in the scientific literature.

Blood (Hematological) Cancers. The National Cancer Institute is currently overseeing a large phase III clinical study using an idiotype-based vaccine given to patients with follicular lymphoma after they have undergone chemotherapy (Kwak LW 2003).

Factors Affecting Immune System Status

Age. While cancer is more common in the elderly (Holmes FF et al 1991), immune strength gradually declines with age and can pose a problem for the successful use of immunotherapy in the elderly (Ginaldi L et al 1999; Pawelec G et al 2002). Although age-related decline in immune status is a natural feature of the immune system, it is also aggravated by lifestyle factors such as diet (Lesourd B et al 1999). Therefore, nutritional supplements to boost immune function may have even more significance in elderly cancer patients than in young adults.

Tumor-Induced and Surgery-Associated Immunosuppression. Two types of immunosuppression affect the successful outcome of immunotherapy: immunosuppression from the tumor and that associated with surgery to remove the tumor. Tumor-induced immunosuppression, due to the production of immunosuppressive factors by cancer cells, is overcome by surgical removal of the tumor mass (Morton DL 1978) and thus creates an environment in which immune cells can better respond to immunotherapy. However, the process of surgery and the associated use of particular anesthetic and analgesic drugs also dampens immune cell function, again reducing the effectiveness of any immunotherapy used (Vallejo R et al 2003). It is recommended that anesthetic and analgesic drugs be carefully selected to minimize immunosuppression, and that patients prepare for surgery by optimizing nutritional and immune status (Vallejo A et al 2002).

Nutritional Status. The production of immune-suppressing (immunosuppressive) agents by cancer cells presents a significant obstacle to cancer immunotherapy (Junker U et al 1996; Sarris AH et al 1999). Excessive production of pro-inflammatory cytokines and reactive oxygen species may damage the immune system, resulting in adverse immunotherapy outcome and cancer progression.

Therefore, nutritional supplements that improve the function of key immune cells will affect the efficacy of immunotherapy and could also be used to prepare patients for immunotherapy (Malmberg KJ et al 2002).

The impact of nutrition on the function of immune cells that play a key role in the efficacy of cancer immunotherapy is well established (Calder PC et al 2002b; Chandra RK 1999). Studies of cancer patients demonstrate that nutritional supplements can play a role in restoring immune status depleted by cancer and surgery to normal levels that would be more responsive to immunotherapy treatment (Malmberg KJ et al 2002).

Nutritional Therapy
Although the direct effect of nutritional supplements on the effectiveness of cancer immunotherapy has yet to be clinically evaluated, the impact of nutrition, particularly micronutrients, on immune cell function (that is, immunonutrition) is central to the success of any cancer treatment (Calder PC et al 2002b; Chandra RK 1999). Several nutrients are able to modulate immune response and counteract inflammatory processes. Zinc, omega-3 fatty acids, and glutamine all act differently to modulate immune response, but all appear to have the potential to protect against cancer progression (Grimble RF 2001).

Immunonutrition has gained recognition as an adjuvant cancer therapy and should be an integral part of cancer immunotherapy, particularly against cancers associated with chronic inflammation (Philpott M et al 2004), as it has beneficial effects on patient outcomes, enhances the immune response, and improves the prognosis of cancer patients (Chermesh I et al 2004).

Cells of the immune system that are essential for the success of cancer vaccines include:

1)Dendritic cells

2)CD4 T cells (lymphocytes)

3)CD8 T cells (lymphocytes)

4)B cells (lymphocytes)

5)Natural killer (NK) cells

6)Macrophages

7)Neutrophils.

Micronutrients that have been established as being essential to the optimal function of these immune cells include zinc, vitamins C and E, folic acid, and glutamine (Calder PC et al 1999; Calder PC et al 2002b).

Zinc. Zinc supplements improve immune cell function (Ibs KH et al 2003; Prasad AS et al 2002). Indeed, diets lacking in zinc are linked to reduced CD4 and CD8 T-cell function (Chandra RK 1999). While deficiencies in zinc also compromise the function of natural killer cells, macrophages, and neutrophils (Ibs KH et al 2003), this impairment of the immune system can be reversed by dietary zinc supplements (Chandra RK 1999; Ibs KH et al 2003). Zinc supplements should, however, be carefully monitored, as excessive intake (over 100 mg per day) is counterproductive and reverses any benefits seen with the suggested doses of 20 to 50 mg per day (Calder PC et al 2002b; Hercberg S et al 1998; Kohn S et al 2000).

Zinc supplements of 50 mg a day improve the structure of Langerhans’ cells (a type of dendritic cell found in the skin epidermis) by endowing them with a more dendritic (or finger-like) structure that improves their mobility and thus their ability to pick up antigens and transport them to lymphocytes (Kohn S et al 2000).