Review

The anti-cancer wave

Divya Pamnani

A 52 year old man, who was given just a year to live as he was diagnosed with stage IV melanoma, the deadliest of all skin diseases, had complete remission after being treated by his own blood. With the use of cancer immunotherapy, researchers in the US who were treating the patient, extracted white blood cells and cultured the infection-fighting CD4+T cells in the laboratory. The cloned T cells, which had been vastly expanded, were then re-infused to the patient to fight the cancer.

After previously undergoing unresponsive drug treatment, the man has remained free of the disease for two years now. This 52 year old's dramatic turnaround lends promise to cancer immunotherapy. More good news—there were no harmful side effects.

What is immunotherapy?

Immunotherapy, also known as biological therapy, biotherapy or biological response modifier therapy, is a relatively new addition to the family of cancer treatments. This type of treatment uses the body's immune system, directly or indirectly, to fight the disease. Immunotherapy is being designed to stimulate the patient's immune system to work harder or smarter and to enhance the immune system response by administering immune system components such as man-made proteins. The basic idea of cancer immunotherapy is to try to get the immune system to react to cancer cells as if they are foreign.

Cancer immunotherapy is a growing area of research which has proved to be successful in treating melanomas, the deadliest form of skin cancer, and some other cancers including kidney cancer, gall bladder cancer, breast cancer, and prostate cancer—as an alternative route to treatment. The aim is to develop less toxic treatments which are at least as effective as chemotherapy and radiation.

The immune system—key players

The response to antigens is a highly coordinated process that uses many types of cells of the immune system. Most cells of the system are lymphocytes, (type of white blood cell). Several types of lymphocytes work together to attack cancer cells:

• B cells (B lymphocytes): These mature into plasma cells that secrete proteins called antibodies (immunoglobulins). Antibodies recognise and attach to foreign substances known as antigens; each type of B cell makes one specific antibody, which recognises one specific antigen.
• T cells (T lymphocytes): They work primarily by producing signalling proteins called cytokines, which allow immune system cells to communicate with each other and include lymphokines, interferons, interleukins, and colony-stimulating factors. Some T cells, called cytotoxic T cells, release pore-forming proteins that directly attack infected, foreign, or cancerous cells. Other T cells, called helper T cells, regulate the immune response by releasing cytokines to signal other immune system defenders.
• Natural killer (NK) cells: These cells produce powerful cytokines and pore-forming proteins that bind to and kill many foreign invaders, infected cells, and tumour cells. Unlike cytotoxic T cells, they are poised to attack quickly, upon their first encounter with their targets.
• Antigen-presenting cells (APCs) are not lymphocytes but work closely with them to fight cancer. The two main groups of antigen-presenting cells are monocytes and macrophages, which swallow and digest microscopic organisms and particles in a process known as phagocytosis; and dendritic cells, which work by finding unwanted cells in the body, perform phagocytosis and present their antigens on their surfaces. They then travel to an area with many lymphocytes, such as the lymph nodes or spleen, for an immune response.

How immunotherapy works

Cancer immunotherapy is the technique of harnessing the body's immune system to attack cancer. The immune system normally responds to threats to the body by distinguishing between itself and foreign invaders. In case of cancer, this is difficult because most tumours consist of the body's own cells growing out of control. However, many cancer cells display unusual antigens or receptors on their surface that allows them to be identified. Antibodies and cancer vaccines to stimulate the immune system are being developed to attack these tumour cells.

There are two main types of immunotherapy—active immunothera-pies stimulate the body's own immune system to fight the disease, and passive immunotherapies do not rely on the body to attack the disease; instead, they use immune system components (such as antibodies) made in the lab.

Monoclonal Antibodies: Presently monoclonal antibodies (mAbs) are the most widely used form of cancer immunotherapy. Monoclonal antibody therapy uses antibodies made outside the body (in the lab) rather than by a person's own immune system. This type of treatment is considered a form of passive immunotherapy. These treatments often do not require the person's immune system to take an ‘active’ role in fighting cancer.

The first mAbs were made entirely from mouse cells, by fusing a myeloma (a type of bone marrow cancer) cell from a mouse with a mouse B cell that makes a specific antibody. One problem with this is that the human immune system can see these antibodies as foreign (because they are from a different species) and can mount a response against them. In the short term, this can sometimes cause allergic-type reactions. In the long term, it means that the antibodies may only be effective the first time they are given; after that, the body's immune system is primed to destroy them before they can be helpful. Over time, researchers have learned how to replace some parts of these mouse antibody proteins with human parts. Depending on how much of the mAb is human, these are called chimeric or humanised antibodies. Some mAbs are now fully human, which means they are likely to be safer and may be more effective than older mAbs.

Cancer Vaccines: Cancer vaccines are a form of active biological therapy currently under study. Researchers are developing vaccines that may encourage the patient's immune system to recognise cancer cells. Cancer vaccines come in two types—therapeutic, which are aimed at treating an existing cancer, and prophylactic, which are designed to prevent disease.

Therapeutic vaccines are injected in a person after cancer is diagnosed. These vaccines may stop the growth of existing tumours, prevent cancer from recurring, or eliminate cancer cells not killed by prior treatments. Cancer vaccines given when the tumour is small may be able to eradicate the cancer. On the other hand, prophylactic vaccines are given to healthy individuals before cancer develops. These vaccines are designed to stimulate the immune system to attack viruses that can cause cancer. By targeting these cancer-causing viruses, doctors hope to prevent the development of certain cancers.

At present, two vaccines have been licensed by the US Food and Drug Administration (FDA) as prophylactic vaccines—the hepatitis B vaccine, which prevents infection with hepatitis B virus, a known risk for liver cancer; and Gardasil, which prevents infection with the two types of human papillomavirus (HPV)—HPV 16 and 18--that together cause 70 percent of cervical cancer cases worldwide. Although no treatment vaccines are approved, there are many in research trials. The FDA recently rejected a treatment vaccine in 2007, known as Provenge to treat prostate cancer. Dendreon, the company sponsoring the vaccine, had presented clinical data that suggested a benefit of slowed tumour growth among treated patients. However, researchers could not prove beyond doubt that the difference was not just chance.

Beyond antibodies and vaccines

Researchers are looking at ways to induce apoptosis, or cell death, in a tumour cell. Unlike all other antibodies, which bind to receptors to either turn them off or signal an immune response, this tactic activates so-called ‘death receptors’ on the outside of cancer cells, resulting in cell death. This strategy focuses on death receptors known as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) receptors. TRAIL is part of the Tumor Necrosis Factor (TNF)-super family of receptors and ligands that regulate normal cell death; researchers have tried to use TNF itself as an agent to induce cancer cells to die, but it was proved to be too toxic.

So, now research is focused on pharmaceutical agents that can provoke TRAIL to do its work. Researchers in Germany studied bortezomib as a therapeutic option in patients with glioma and found a significant response at the cellular level. In prostate cancer, low-dose 12-O-tetradecanoylphorbol-13-acetate showed activity as well.

Indian companies

There are an estimated 2.5 million cases of cancer in India at any given time; it is easily one of the ten leading causes of death in the country. Nearly 8,00,000 cases were diagnosed in 2000 and there were 5,50,000 deaths due to cancer in that same year. Tobacco-related cancers account for almost one-third of all cancers in India—predominantly head and neck, lung, and oesophageal cancers. The two most common cancers among Indian women are those of the cervical and breast. What is most disheartening is that many of these cancers can either be prevented altogether or treated effectively if detected early. More than 70 percent of all cancers in India are found when the disease is so advanced that treatment is much less effective. With such statistics, Indian companies have realised the potential that this segment has to offer. Following is a brief overview of what some indigenous companies have been up to on the cancer front:

Biocon: Biocon launched BIOMAb EGFR, a therapeutic monoclonal antibody-based drug for treating solid tumours of epithelial origin, such as head and neck cancers, in 2006. The drug is the first of its kind to be clinically developed in India and is the first anti-epidermal growth factor receptor (EGFR) humanised monoclonal antibody for cancer to be made available anywhere in the world. This drug is engineered to specifically target and block EGFR responsible for the proliferation of cancer cells. The product has shown consistent response in clinical trials initiated both in India and globally and is produced at its manufacturing facility in India.

Nicholas Piramal India Limited (NPIL): The company commenced clinical studies of its main anti-cancer drug molecule. The new chemical entity, called P276-00, has entered phase I and II clinical studies, which are being held in Canada. The clinical trials involve patients being infused intravenously with P276-00, which is the first in a series of compounds from NPIL's research centre to go into clinical trials. It is an inhibitor of the key protein that is required by cells to multiply. Since cancer cells have an unbridled growth pattern, P276-00 is effective as it blocks the key enzyme at the 'entry stage'. This prevents the cells from synthesising other necessary elements before they divide, which forces the cells to embark on the path of programmed cell death.

Dabur Pharma: Dabur launched nanoxel in January 2007, a new version of an existing anti-cancer drug paclitaxel, which is a nanoparticle-based formulation. It is a chemotherapeutic agent that inhibits mitotic division, and falls under the drug category of 'taxanes'. Nanoxel can be delivered in higher doses while reducing side effects associated with chemotherapy. Dabur also has a strong focus on developing cancer vaccines, and redevelopment of anti-cancer drugs using nanoparticle/nanocell technology, etc.

Panacea Biotec: So far, five cancer drugs, namely Paclitrust, Docetrust, Gemtrust, Zoletrust, and Temotrust have been launched by Panacea in 2007, to provide treatment for breast cancer, brain tumour, ovarian cancer, pancreatic cancer, prostate cancer and colorectal cancer. These are also chemotherapeutic drugs, administered via intravenous injections.

Dr Reddy's Laboratories (DRL): The company launched Redituxa in 2007, its brand of rituximab, a mAb used in the treatment of Non-Hodgkin's Lymphoma (NHL). In an effort to strengthen its oncology business, DRL has also launched an anti-cancer product named Cantop, a lyophilised form of topotecan hydrochloride. Currently, DRL markets anti-cancer products such as Mitotax (paclitaxel), Dacotin (oxaliplatin), and Docetere (docetaxel). Mitotax is indicated for ovarian and breast cancer after the failure of first line therapy. Dacotin is for colorectal cancer, while Docetere is for lung and breast cancer.

Merck, Sharpe and Dohme: The Indian subsidiary of Merck announced the introduction of ERBITUX at the end of 2006, a gold standard targeted therapy for the treatment of colorectal cancer (CRC) in India. ERBITUX works by targeting EGFR which is found on the surface of cells and is involved in the stimulation of cellular growth, replication and/or differentiation when stimulated by growth factors. EGFR has been shown to be involved in the development and progression of many common types of cancers.

MAbs—The next big thing

According to a market research report—Global Protein Therapeutics Market Analysis—in April 2008, the protein therapeutic market valued in excess of $57 billion, projecting a growth rate of 12.83 percent. Protein therapeutics is dominated by monoclonal antibodies, currently worth $20 billion, and expected to have a future growth rate in double digits. Since 2001, mAbs-based therapies have been posting the fastest growth within the protein therapeutics market. The mAbs market is classified as one of the most lucrative sectors of pharma industry. It is forecasted that mAbs will act as the key growth segment of the prescription pharma market. According to a Datamonitor report, mAbs revenues are projected to grow at a compounded annual growth rate (CAGR) of 14.2 percent over the period 2006-12.

Leveraging on the strengths and opportunities, about 40 companies in the Asia Pacific region are focusing on product development from mAbs. Companies in India, Japan, Korea, and China, doing research and development, are entering into deals with major pharma companies to catch up with the pace of development and for early entry into the market. In some cases it may be other way also. The lower development costs in the Asia Pacific region on the clinical side allow for cheaper access to this billion dollar market of therapeutics.

Humanised antibodies trend

Beginning with murine antibody in 1986, companies are now focusing more towards humanised and human antibody, and, in particular, fully human technologies. Human antibody products are expected to dominate the next wave of approvals. The market is expected to continue to evolve as antibody engineering capabilities advance further, including more efficient manufacturing and alternative delivery methods, broadening the commercial viability of antibodies treatments in a wider range of diseases. A wave of fully human products is expected to launch from 2007 onwards, accounting for 12 of the 20 launches between 2007 and 2010. More good news about the mAbs market—antibodies currently face no prospect of generic competition, which further enhances the industry's mAbs approval potential.

(The author has done her Bachelor of Science in Psychology and Biology at the University of Texas at Austin. She can be contacted at pamnani.divya@gmail.com)