By Cathy Dunn

Jennifer Botten-Molina knows much more about cancer than the average person. As a licensed clinical social worker for Kansas City Internal Medicine‚ she counsels cancer patients daily‚ helping them along the often rocky road that follows diagnosis.

But in the Summer of 1999‚ when she noticed an uncharacteristic lack of energy and some mild symptoms‚ Botten-Molina did what most people would do: she convinced herself it wasn’t anything serious.

“I thought that my night sweats and stomach problems were early symptoms of menopause‚” says the 45-year-old mother of two from Kansas City‚ Missouri. “I felt that the exhaustion was the aftermath of a hectic schedule surrounding my daughter’s high school graduation. And the swollen glands in my neck? Just a minor infection.”

When the malaise continued and her glands remained swollen despite antibiotics‚ Botten-Molina’s physician recommended a biopsy. Despite her years of training‚ she was unprepared for the news that followed. She had stage IV non-Hodgkin’s lymphoma (NHL)‚ an aggressive form of the disease.

B Cell on the Attack
NHL is a broad term for a collection of cancers that affect B lymphocytes‚ one of the body’s main infection fighters. Approximately 300‚000 Americans have NHL‚ and that number is rapidly growing; about 50% of those have low-grade or “follicular” NHL. The disease is easy to distinguish from Hodgkin’s disease because NHL tissue biopsies lack the distinctive double-eyed cells described by Thomas Hodgkin more than a century ago.

B cells and their companions‚ T cells‚ are white blood cells that reside in the lymph system. B cells make antibodies‚ proteins that attach to corresponding antigens and help destroy them. T cells help regulate immune system activities. When B cells and T cells are working properly‚ they are an effective front line of defense against illness and infection. They circulate freely through the watery lymph system and bloodstream‚ ever alert to anything that threatens good health. Like well-trained soldiers‚ they quickly attack antigens—invaders such as viruses and bacteria—and destroy them.

When patients develop NHL‚ their B cells turn traitor‚ multiplying in abnormal ways and in excessive quantities. These mutants either do not follow the pattern of apoptosis (normal cell death) or multiply very rapidly‚ allowing cancerous cells to proliferate. Based on cell proliferation‚ NHL fits into classifications ranging from indolent (slow growing) to aggressive. Sometimes neither chemotherapy nor other traditional cancer treatments will stop the onslaught of this puzzling disease‚ leaving patients with few options.

Botten-Molina completed the standard treatment‚ a six-month course of CHOP (a powerful chemotherapy concoction containing cyclophosphamide‚ doxorubicin‚ vincristine‚ and prednisone). The side effects took their toll.

“I had trouble sleeping‚ lost my hair‚ gained weight from prednisone‚ and was very nauseated‚” she recalls. “And when it was all over‚ I still had traces of cancer.”

That’s when her physician recommended a new cancer-fighting option that targets tumors with a precision akin to a laser-guided missile. This new weapon in the oncologist’s arsenal is called monoclonal antibody therapy‚ a tongue-twister term that packs a powerful lifesaving punch for those with NHL.

Monoclonal antibodies are genetically engineered proteins that mimic those made by the body’s own infection-fighting white blood cells. Because they are man made‚ they can be produced in great quantities in laboratories‚ making them available to many patients. They may comprise murine (mouse)‚ chimeric (human and mouse)‚ or humanized (human only) components. They can be used alone (“naked”) or in tandem with a toxin or radioactive isotope. When injected into the bloodstream of patients with a particular type of non-Hodgkin’s lymphoma‚ these manmade copies lock onto a specific antigen (protein on a cell surface) present on cancerous B cells and destroy them‚ leaving cells of other types virtually untouched.

Rituxan's Stellar Debut
“In 1997‚ the Food and Drug Administration [FDA] approved the first cancer-fighting monoclonal antibody‚ Rituxan®[the trade name of the monoclonal antibody rituximab] to treat lymphatic malignancy. It is more effective for certain types of lymphoma than others‚” says Bruce D. Cheson‚ MD‚ Division of Cancer Treatment and Diagnosis of the National Cancer Institute (ctep.cancer.gov).

According to Dr. Cheson‚ “Rituxan is a genetically engineered chimeric antibody that has been successful in patients with low-grade B-cell NHL who have not responded to more traditional treatments.”

“In a groundbreaking clinical study on Rituxan (www.rituxan.com)‚ 48% of the 166 participants with advanced‚ low-grade indolent [follicular] NHL who completed the treatment course had tumor shrinkage of 50% or more‚” Dr. Cheson notes. “Six percent of those had a complete remission.”

“Rituxan is a product that has actually exceeded our expectations sinceits FDA approval‚ particularly in patients with follicular NHL‚” says Robert O. Dillman‚ MD‚ medical director of the Hoag Cancer Center in Newport Beach‚ California. “It continues to gain favor with hematologists and oncologists.”

Botten-Molina had done her research‚ and she knew that if she didn’t choose antibody therapy‚ her only other option may have been a bone marrow transplant. She agreed to receive Rituxan’s standard treatment course of four infusions—once a week for four weeks.

“I was afraid to take Rituxan because it was new and virtually unknown‚” she admits. “I’d already been through so much‚ and I didn’t know what to expect from this therapy.”

Traditional chemotherapy can produce a plethora of unpleasant side effects‚ including nausea‚ vomiting‚ mouth sores‚ dizziness‚ fatigue‚ weakness‚ hair loss‚ infections‚ bruising‚ and poor appetite. Some patients might also experience more serious complications such as heart problems or neurological difficulties.

In contrast‚ those treated with Rituxan seem to fare much better overall because this targeted treatment is generally easier on the body. Most physical discomforts reported by patients were related to the intravenous infusion and usually occurred only during the first treatment. Some people experienced flu-like symptoms‚ including fever‚ chills‚ and respiratory symptoms‚ but even those side effects diminished with subsequent infusions.

“With Rituxan‚ our studies showed that participants had fewer‚ less severe side effects because the medication targets and destroys only B cells‚ leaving other types of cells undamaged‚” Dr. Cheson says. “In addition‚ Rituxan requires a total of four infusions‚ where traditional chemotherapy treatments might be needed for six months or longer.”

What she went through with Rituxan was “a breeze” compared to CHOP‚ Botten-Molina says. Her side effects were minor; she didn’t have hair loss‚ nausea‚ or fatigue. In a few weeks‚ she learned that her cancer was in remission. And‚ almost three years later‚ it still is.

The Radioactive Edge
While Botten-Molina carries on with her busy life‚ researchers are continuing their investigations into the effectiveness of Rituxan and its new companions‚ Bexxar® (tositumomab) and Zevalin™(ibritumomab tiuxetan). Bexxar‚ still awaiting FDA approval‚ is a combination of mouse antibody and radioactive iodine I-131. Zevalin (www.idecpharm.com)‚ which received FDA approval in February 2002‚ links radioactive yttrium to a mouse version of the antibody rituximab.

“Unlike Rituxan‚ both Bexxar and Zevalin contain a radioactive isotope that delivers powerful radiation directly to cancer cells‚” Dr. Cheson explains. “These are exciting‚ innovative treatments for lymphoma.”

In phase II clinical trials‚ patients received a trace dose of Bexxar followed by a therapeutic dose one or two weeks later. After both infusions‚ most patients experienced more than a 50% shrinkage in the size of their tumors. Phase III clinical trials are now underway to further study Bexxar’s potential.

“Because iodine I-131 emits powerful gamma rays up to several feet from the source‚ treatment with Bexxar requires extra safety precautions‚” says Dr. Dillman. “Patients are free to go home but should be partially isolated for a day or two to prevent exposing others to radiation.”

In a phase III pivotal trial‚ patients who had progressive disease after traditional therapy showed an 80% overall response rate on the Zevalin regimen.
“Unlike Bexxar‚ Zevalin emits only beta particles‚ which extend millimeters from the source‚” Dr. Dillman adds. “Patients do not have to be isolated after treatment because the radiation risk is minimal.”

On the Fast Track With Campath
Campath® (alemtuzumab)‚ another new antibody‚ binds to an antigen that is present on both normal and malignant B and T lymphocytes. Campath (www.campath.com) is approved for the treatment of B-cell chronic lymphocytic leukemia (CLL)‚ a slow-growing cancer of the blood that affects the lymphocytes.

CLL‚ the most prevalent form of adult leukemia‚ is characterized by an accumulation of malignant lymphocytes. These tumor cells congregate in bone marrow and other tissues‚ causing damage to the marrow and enlargement of the lymph nodes‚ liver‚ and spleen. CLL symptoms include fatigue‚ bone pain‚ night sweats‚ decreased appetite‚ and weight loss.

In a landmark clinical trial‚ patients with advanced CLL who failed to improve when treated with traditional chemotherapy responded when given Campath antibody.

“In the initial study of 93 CLL patients who had failed previous therapies‚ one third of them showed improvement when treated with Campath‚” says Kanti R. Rai‚ MD‚ chief of the division of hematology and oncology at Long Island Jewish Medical Center in New Hyde Park‚ New York‚ and a principal investigator in the drugœs clinical trials.

“Those patients lived longer and experienced a better quality of life. The downside‚ though‚ is that Campath‚ like many other cancer-fighting medications‚ cannot discriminate between normal cells and leukemic ones. The destruction of normal B and T lymphocytes opens the door to a wide range of infections‚ which was one of the main drawbacks in our early studies‚” Dr. Rai notes. “In this pivotal clinical trial‚ we’ve added antibiotics to guard against infections.

“Now that Campath is approved‚ we’re looking into new ways to use it effectively. For example‚ we’re starting to investigate its impact as a treatment for lymphoma and acute leukemia‚ how it reacts in combination with other medications like Fludara® [fludarabine]‚ and what type of results we get when we pair it with other monoclonal antibodies‚” adds Dr. Rai. “Without a doubt‚ Campath is a drug with outstanding potential.”

A Bright Future for Targeted Therapies
In fact‚ a variety of antibody therapies now being tested hold great promise. One recent‚ significant study compared the effectiveness of pairing Rituxan and CHOP against CHOP alone. Bertrand Coiffier‚ MD‚ University Hospital of Lyon‚ France‚ was principal investigator and part of the Groupe d’Etude des Lymphomes de l’Adulte (GELA)‚ a cancer cooperative from Belgium‚ France‚ and Switzerland.

Final results from the study were recently published in The New England Journal of Medicine (www.nejm.com). The 399 elderly patients (ages 60 to 80) in the study had an aggressive form of NHL. The results showed that combining conventional therapy with Rituxan significantly improved participants’ survival rates. This group is particularly difficult to treat because patients often have other diseases‚ including diabetes‚ hypertension‚ and cardiac disease‚ so they often do not tolerate CHOP therapy as well as younger patients.

In addition‚ Rituxan‚ when combined with CHOP‚ increased remission rates by 15% over those receiving only CHOP chemotherapy.

The success of the GELA clinical trial is an encouraging development for researchers conducting similar studies in the United States. In fact‚ Rituxan‚ Bexxar‚ Zevalin‚ and Campath are now being tested extensively nationwide in combination with traditional chemotherapies and with each other. Other new monoclonal antibodies‚ such as epratuzumab‚ are also joining the ranks.

Epratuzumab‚ a humanized antibody‚ is being tested in clinical trials to treat indolent and aggressive forms of NHL in patients who may not respond to Rituxan. The new treatment binds to a different antigen (CD22) than does its predecessor‚ Rituxan‚ which binds to antigen CD20.

Clinical trials continue to affirm the success of Rituxan and its companions. “However‚ we’ve only just reached the tip of the iceberg in the study of antibody therapy‚” Dr. Dillman notes. “It’s an exciting time to be involved in cancer research‚ particularly with the applications of these new developments.

“Because we’ve had such positive results so far‚” he adds‚ “we’ve started to use antibodies earlier and earlier in the treatment regimen. Alone and in combination‚ the use of antibodies has opened the door to a new era in the treatment of cancer. Someday‚ targeted therapies may well be the gold standard to fight NHL. Perhaps by then‚ chemotherapy will no longer be needed at all.”