Immunological Research: A multi-faceted approach to curing disease

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Animal models of human disease have been a tremendous asset to the development of cures for disease. Unfortunately, animal physiology is often not identical to human and more appropriate models are needed. Enter stem cell technology and tissue banking.

The culture of human cells, or xenotransplantation into mice with impaired immune responses provides a platform to test new drugs or culture protocols. To achieve this, an ongoing supply of human cells must be obtained and processed.

Kimera Labs sources human tissue and then processes it for research purposes.

Our group was born out of a tragedy millions of Americans are facing on a daily basis. Cancer.

Through fund raising, education, banking, research and distribution we have developed a number of tools to advance the state of health care in the oncology field.

Funding: By creating the Kimera Society Inc, we are developing a private operating foundation currently applying for 501(c)3 status with the IRS, allowing donors to target funds directly to research labs performing promising investigations.

Education: Kimera Labs and the Kimera Society supports the development of dotcure.org and cancerfocus.org.

Launched in 2006, cancerfocus.org is a patient education site and forum which allows our scientists to come directly into contact with patients that need the most concrete information available. Dotcure.org is a new intiative of the Kimera Society to crowd source research funds.

Banking: By soliciting tissues from cancer centers around the world, we are building a library of disease tissues to facilitate new drug discovery and testing in the future. Our pioneering work in cord blood banking, will bring new discoveries and uses to the rich and under-utilized cord blood cell industry.

Research: Through ongoing collaborations with the University of Miami, Johns Hopkins and other research centers, we participate in research projects for academic publications.

Distribution: As promising therapies and drugs are developed, we aid in the distribution of materials through our network of South American pharmacies and clinics.

http://kimeralabs.com/

Duncan Ross, PhD. has started a tumor immunotherapy service out of his lab in Miami. When anyone gets a biopsy or surgical tumor removed, they overnight it to him and then he tries to extract the T-cells and grow them against their tumors and reinject. He is working within an ambulatory center there with two surgeons.

Animal models of human disease have been a tremendous asset to the development of cures for disease. Unfortunately, animal physiology is often not identical to human and more appropriate models are needed. Enter stem cell technology and tissue banking.

Antigen and Lymphopenia-Driven Donor T-Cells

http://cancerfocus.org/forum/showthread.php?t=4015

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Larry Weisenthal, M.D., PhD.
Medical and Lab Director
Weisenthal Cancer Group; Huntington Beach, CA

Clinical trials are warranted to test macrophage-activating biologic response modifiers administered following chemotherapy of ovarian and breast cancers. This is based on (1) striking in vitro findings in fresh human tumor cell culture assays, (2) supportive data from pilot clinical trials, and (3) a sound mechanistic rationale. I would advocate sequential administration of (1) assay-directed chemotherapy, (2) "non-specific" immunotherapy (e.g. antigens derived from bacteria), and (3) more "specific" cytokine therapy (e.g. interferon gamma).

In 1991, my colleagues and I published a study (1,2) in the Journal of the National Cancer Institute which I hoped would receive scrutiny and follow-up. This was a tumor immunology study which grew out of a contract research project. Continuing this research was at the time not an option, as my priorities were to establish a clinical laboratory to provide cell culture drug resistance testing.

In the 1991 study, we presented the concept of "in situ vaccination," based upon our studies of biologic response modifiers in the DISC assay. We found that there was a striking association between the activity of biologic response modifiers which activate macrophages and the prior treatment status of patients with breast and ovarian cancers. Color photomicrographs illustrating method.

http://weisenthal.org/jnci83_38_91f1.jpg

The following agents were dramatically more active in fresh tumor specimens from previously-treated breast and ovarian cancer patients than against specimens from untreated patients:

1. ImuVert (a potent macrophage activator derived from Serratia marcescens)
2. Interferon gamma, and
3. Tumor necrosis factor

This greater activity in specimens from treated versus non-treated patients was not observed in adenocarcinomas known to be relatively resistant to chemotherapy (colon cancer, non-small cell lung cancer, etc.). Graphs showing representative results.

http://weisenthal.org/jnci83_39_91.jpg

This differential activity was also not observed in agents which are not potent macrophage activators (interleukin-2 and interferon alpha).

Based on these findings (and supported by anecdotal studies in the clinical trials literature), we proposed that effective chemotherapy produces massive release and processing of tumor antigens, which leads to a state in which the human immune system is primed (via "in situ vaccination") to respond to exogenous macrophage-activation signals with potent, specific antitumor effects.

In the above-quoted study (1), I reviewed a diverse clinical trials literature which supported this concept. More recently published was a randomized trial in previously untreated ovarian cancer (3) , in which cisplatin/cyclophosphamide was compared to the same chemotherapy plus interferon gamma, administered subcutaneously three times a week, every other week, for the duration of chemotherapy (6 plannned treatment cycles). The study was prematurely closed because chemotherapy standard treatment had changed from platinum/cyclophosphamide to platinum/Taxol, but, even with the low power of the small numbers of patients accrued to show a difference, there was a significant advantage to combined treatment in progression-free survival and a soft trend for improved overall survival. The authors quoted our earlier work1 in providing a mechanism for their positive results and called for follow-up clinical trials. Progression-free survival curves.

http://weisenthal.org/bjc82_1138_00.jpg

As noted above, my preferred trial design would be (1) first complete (preferably assay-directed) chemotherapy, then (2) administer non-specific immunotherapy to responders, then (3) provide more specific cytokine therapy, e.g. interferon gamma.

Literature Citation:

1. Weisenthal LM, Dill PL, Pearson FC (1991) Effect of prior cancer chemotherapy on human tumor-specific cytotoxicity in vitro in response to immunopotentiating biologic response modifiers. J Natl Cancer Inst 83: 37-42

2. Weisenthal LM (1991) Effect of prior chemotherapy on biologic response modifier activity. J Natl Cancer Inst 83: 790-791

3. Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, et al. (2000) Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase 3 trial. Br J Cancer 82:1138-1144, 2000.

Method for detecting immune-mediated cytotoxicity

ABSTRACT

A method for detecting the sensitivity of tumor cells to immune effector substances by using an assay that distinguishes living tumor cells from dead cells in mixed populations of cells. Acquired resistance to immune effectors used in therapy may be determined and used to identify methods to circumvent such resistance using the method.

http://www.google.com/patents/US4996145

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Preclinical, laboratory studies suggest immunotherapy could potentially work like a vaccine against metastatic cancers.

Results from the recent study show the therapy could treat metastatic cancers and be used in combination with current cancer therapies while helping to prevent the development of new metastatic tumors and train specialized immune system cells to guard against cancer relapse.

The study detailed the effects of a molecule engineered by lead author Xiang-Yang Wang, Ph.D., of Virginia Commonwealth University Massey Cancer Center, on animal and cell models of melanoma, prostate and colon tumors. The Flagrp-170 molecule consists of two distinct proteins, glucose-regulated protein 170 (Grp170), known as a "molecular chaperone," and a "danger signal" derived from flagellin, a protein commonly found in bacteria. The researchers used modified viruses, or adenoviruses, that can no longer replicate to transport Flagrp-170 directly to the tumor site to achieve localized vaccination. The novel therapy caused a profound immune response that significantly prolonged survival in animal models.

Grp170 is currently being explored for its potential as a "cancer vaccine" because it has been shown to help the immune system recognize cancer antigens. Antigens are molecules from foreign objects such as bacteria, viruses or cancer that, when detected, provoke an immune response aimed at attacking them. However, because cancer cells can alter the microenvironment surrounding a tumor, they are able to suppress immune responses and continue replicating without being attacked by the body's natural defenses.

The chimeric chaperone Flagrp-170, created by strategically fusing a fragment of flagellin to Grp170, not only enhances antigen presentation, it also stimulates additional immune signals essential for functional activation of specialized immune cells, including dendritic cells, CD8+ T lymphocytes and natural killer (NK) cells. Dendritic cells act as messengers between the innate and adaptive immune systems.

Once activated in response to a stimulus such as Flagrp-170, dendritic cells migrate to lymph nodes where they interact with other immune cells such as T lymphocytes to shape the body's immune response. CD8+ T lymphocytes and NK cells are known to respond to tumor formation and kill cancer cells by triggering apoptosis, a form of cell suicide.

"Overcoming cancer's ability to suppress the body's natural immune responses and restore or develop immunity for tumor eradication is the goal of cancer immunotherapy," says Wang. "More experiments are needed, but we are hoping Flagrp-170 may one day be used in formulating more effective therapeutic cancer vaccines."

Moving forward, the researchers are working to better understand the molecular mechanisms responsible for Flagrp-170's therapeutic effects.

Additional studies are underway to more efficiently target and deliver Flagrp-170 to tumor sites in order to provoke a more robust and durable immune response.

Source: Cancer Research

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Tumor cell evolution enables cancer cells to evade destruction by the immune system. Cells that can be destroyed are destroyed. What is left is resistant to immune destruction. The mechanisms of escape are extremely diverse.

Tumor cells can lose the antigens (a molecule that the immune system reacts against and attacks) that trigger an immune response. In addition, tumor cells can inhibit the immune response, or develop resistance to the killing mechanisms involved.

For a tumor to grow and cause disease in the first place, it must evade destruction bv the immune system. The immune response is therefore a major selective pressure that directs the flow of tumor cell evolution.

This is one reason that immunotherapy has had so little success in the cure or chronic control of cancer in patients.

Tumor cells evolve that not only escape destruction by immune attack, but also that subvert normal immune cells to enhance tumor growth. Tumors recruit normal white blood cells to help in the process of tissue invasion.

Tumors also can release soluble factors that stimulate normal cells to produce enzymes that digest connective tissue and facilitate invasiveness. It's like renting bulldozers to clear space for new apartment houses.

The limitations of narrowly targeted therapy are also seen with cancer vaccines and immunotherapy. The earliest approaches at targeting tumor-specific molecules involved attempts to turn the immune system against proteins that are unique to cancer cells.

Certain types of lymphoma have a unique, patient-specific antibody on the surface of the lymphoma cells. The lymphoma cells make this antibody, which is absent from normal cells. Patients have been treated with antibodies targeted to the particular antibody on their lymphoma cells.

This antibody-against-an-antibody was prepared specially for each patient. In a study of 45 patients, eight responded. Only six patients had long-term control of their disease. The problem is that lymphoma cells can and do evolve without the surface antibody marker (Blood. 1998 Aug 15;92(4):1184-90).

Dr. Steven A. Rosenberg, Chief of Surgery at the National Cancer Institute (NCI) and a leading cancer immunologist, published a review of clinical trials on cancer vaccines. His analysis revealed that the overall response rate among 765 patients in a large number of different trials was only 3% (Nat Med. 2004 Sep;10(9):909-15).

Reference: "Cure: Scientific, Social and Organizational Requirements for the Specific Cure of Cancer" A. Glazier, et al. 2005

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Immunotherapy (also called biologic therapy or biotherapy) is a type of cancer treatment designed to boost the body's natural defenses to fight the cancer. It uses materials either made by the body or in a laboratory to improve, target, or restore immune system function. Although it is not entirely clear how immunotherapy treats cancer, it may work by stopping or slowing the growth of cancer cells, stopping cancer from spreading to other parts of the body, or helping the immune system increase its effectiveness at eliminating cancer cells.

There are several types of immunotherapy, including monoclonal antibodies, non-specific immunotherapies, and cancer vaccines.

Monoclonal antibodies

When the body’s immune system detects antigens (harmful substances, such as bacteria, viruses, fungi, or parasites), it produces antibodies (proteins that fight infection). Monoclonal antibodies are made in a laboratory, and when they are given to patients, they act like the antibodies the body produces naturally. Monoclonal antibodies are given intravenously (through a vein) and work by targeting specific proteins on the surface of cancer cells or cells that support the growth of cancer cells. When monoclonal antibodies attach to a cancer cell, they may accomplish the following goals:

Allow the immune system to destroy the cancer cell.

The immune system doesn't always recognize cancer cells as being harmful. To make it easier for the immune system to find and destroy cancer cells, a monoclonal antibody can mark or tag them by attaching to specific parts of cancer cells that are not found on healthy cells.

Prevent cancer cells from growing rapidly.

Chemicals in the body called growth factors attach to receptors on the surface of cells and send signals that tell the cells to grow. Some cancer cells make extra copies of the growth factor receptor, which makes the cancer cells grow faster than normal cells. Monoclonal antibodies can block these receptors and prevent the growth signal from getting through.

Deliver radiation directly to cancer cells.

This treatment, called radioimmunotherapy, uses monoclonal antibodies to deliver radiation directly to cancer cells. By attaching radioactive molecules to monoclonal antibodies in a laboratory, they can deliver low doses of radiation specifically to the tumor while leaving healthy cells alone. Examples of these radioactive molecules include ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar).

Diagnose cancer.

Monoclonal antibodies carrying radioactive particles may also help diagnose certain cancers, such as colorectal, ovarian, and prostate cancers. Special cameras identify the cancer by showing where the radioactive particles accumulate in the body. In addition, a pathologist (a doctor who specializes in interpreting laboratory tests and evaluating cells, tissues, and organs to diagnose disease) may use monoclonal antibodies to determine the type of cancer a patient may have after tissue has been removed during a biopsy.

Carry powerful drugs directly to cancer cells.

Some monoclonal antibodies carry other cancer drugs directly to cancer cells. Once the monoclonal antibody attaches to the cancer cell, the cancer treatment it is carrying enters the cell, causing the cancer cell to die without damaging other healthy cells. Brentuximab vedotin (Adcetris), a treatment for certain types of Hodgkin and non-Hodgkin lymphoma, is one example.

Other monoclonal antibodies approved by the U.S. Food and Drug Administration (FDA) to treat cancer include:

Bevacizumab (Avastin)
Alemtuzumab (Campath)
Cetuximab (Erbitux)
Trastuzumab (Herceptin)
Rituximab (Rituxan)
Panitumumab (Vectibix)
Ofatumumab (Arzerra)

Side effects of monoclonal antibody treatment are usually mild and are often similar to an allergic reaction. Possible side effects include rashes, low blood pressure, and flu-like symptoms, such as fever, chills, headache, weakness, extreme tiredness, loss of appetite, upset stomach, or vomiting.

Although monoclonal antibodies are considered a type of immunotherapy, they are also classified as a type of targeted treatment (a treatment that specifically targets faulty genes or proteins that contribute to cancer growth and development). Learn more about targeted treatments.

Non-specific immunotherapies

Like monoclonal antibodies, non-specific immunotherapies also help the immune system destroy cancer cells. Most non-specific immunotherapies are given after or at the same time as another cancer treatment, such as chemotherapy or radiation therapy. However, some non-specific immunotherapies are given as the main cancer treatment.

Two common non-specific immunotherapies are:

Interferons. Interferons help the immune system fight cancer and may slow the growth of cancer cells. An interferon made in a laboratory, called interferon alpha (Roferon-A [2a], Intron A [2b], Alferon [2a]), is the most common type of interferon used in cancer treatment. Side effects of interferon treatment may include flu-like symptoms, an increased risk of infection, rashes, and thinning hair.

Interleukins. Interleukins help the immune system produce cells that destroy cancer. An interleukin made in a laboratory, called interleukin-2, IL-2, or aldesleukin (Proleukin), is used to treat kidney cancer and skin cancer, including melanoma. Common side effects of IL-2 treatment include weight gain and low blood pressure, which can be treated with other medications. Some people may also experience flu-like symptoms.

Cancer vaccines

A vaccine is another method used to help the body fight disease. A vaccine exposes the immune system to a protein (antigen) that triggers the immune system to recognize and destroy that protein or related materials. There are two types of cancer vaccines: prevention vaccines and treatment vaccines.

Prevention vaccine. A prevention vaccine is given to a person with no symptoms of cancer to prevent the development of a specific type of cancer or another cancer-related disease. For example, Gardasil is a vaccine that prevents a person from being infected with the human papillomavirus (HPV), a virus known to cause cervical cancer and some other types of cancer. It was the first FDA-approved vaccine for cancer. Cervarix is another vaccine that is approved to prevent cervical cancer in girls and women. Learn more about HPV vaccination for cervical cancer and the role of HPV in other cancers. In addition, the U.S. Centers for Disease Control and Prevention recommends that all children should receive a vaccine that prevents infection with the hepatitis B virus, which may cause liver cancer.

Treatment vaccine. A treatment vaccine helps the body's immune system fight cancer by training it to recognize and destroy cancer cells. It may prevent cancer from coming back, eliminate any remaining cancer cells after other types of treatment, or stop cancer cell growth. A treatment vaccine is designed to be specific, which means it should target the cancerous cells without affecting healthy cells. At this time, sipuleucel-T (Provenge) is the only treatment vaccine approved in the United States. It is designed for treating metastatic prostate cancer.

Source: Cancer.Net

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If you're considering monoclonal antibody therapy as part of your cancer treatment, learn about these drugs and carefully weigh the benefits against the potential side effects.

By Mayo Clinic staff

Monoclonal antibody drugs are a relatively new innovation in cancer treatment. While several monoclonal antibody drugs are available for treating certain cancers, the best way to use these new drugs isn't always clear.

If you and your doctor are considering using a monoclonal antibody as part of your cancer treatment, find out what to expect from this therapy. Together you and your doctor can decide whether a monoclonal antibody treatment may be right for you.

What is a monoclonal antibody?

A monoclonal antibody is a laboratory-produced molecule that's carefully engineered to attach to specific defects in your cancer cells. Monoclonal antibodies mimic the antibodies your body naturally produces as part of your immune system's response to germs, vaccines and other invaders.

How do monoclonal antibody drugs work?

When a monoclonal antibody attaches to a cancer cell, it can:

Make the cancer cell more visible to the immune system. The immune system attacks foreign invaders in your body, but it doesn't always recognize cancer cells as enemies. A monoclonal antibody can be directed to attach to certain parts of a cancer cell. In this way, the antibody marks the cancer cell and makes it easier for the immune system to find.

The monoclonal antibody drug rituximab (Rituxan) attaches to a specific protein (CD20) found only on B cells, one type of white blood cell. Certain types of lymphomas arise from these same B cells. When rituximab attaches to this protein on the B cells, it makes the cells more visible to the immune system, which can then attack. Rituximab lowers the number of B cells, including your healthy B cells, but your body produces new healthy B cells to replace these. The cancerous B cells are less likely to recur.

Block growth signals. Chemicals called growth factors attach to receptors on the surface of normal cells and cancer cells, signaling the cells to grow. Certain cancer cells make extra copies of the growth factor receptor. This makes them grow faster than the normal cells. Monoclonal antibodies can block these receptors and prevent the growth signal from getting through.

Cetuximab (Erbitux), a monoclonal antibody approved to treat colon cancer and head and neck cancers, attaches to receptors on cancer cells that accept a certain growth signal (epidermal growth factor). Cancer cells and some healthy cells rely on this signal to tell them to divide and multiply. Blocking this signal from reaching its target on the cancer cells may slow or stop the cancer from growing.

Stop new blood vessels from forming. Cancer cells rely on blood vessels to bring them the oxygen and nutrients they need to grow. To attract blood vessels, cancer cells send out growth signals. Monoclonal antibodies that block these growth signals may help prevent a tumor from developing a blood supply, so that it remains small. Or in the case of a tumor with an already-established network of blood vessels, blocking the growth signals could cause the blood vessels to die and the tumor to shrink.

The monoclonal antibody bevacizumab (Avastin) is approved to treat a number of cancers, not including breast cancer. Bevacizumab targets a growth signal called vascular endothelial growth factor (VEGF) that cancer cells send out to attract new blood vessels. Bevacizumab intercepts a tumor's VEGF signals and stops them from connecting with their targets.

Deliver radiation to cancer cells. By combining a radioactive particle with a monoclonal antibody, doctors can deliver radiation directly to the cancer cells. This way, most of the surrounding healthy cells aren't damaged. Radiation-linked monoclonal antibodies deliver a low level of radiation over a longer period of time, which researchers believe is as effective as the more conventional high-dose external beam radiation.

Ibritumomab (Zevalin), approved for non-Hodgkin's lymphoma, combines a monoclonal antibody with radioactive particles. The ibritumomab monoclonal antibody attaches to receptors on cancerous blood cells and delivers the radiation.

A number of monoclonal antibody drugs are available to treat various types of cancer. Clinical trials are studying monoclonal antibody drugs in treating nearly every type of cancer.

How are monoclonal antibody drugs used in cancer treatment?

Monoclonal antibodies are administered through a vein (intravenously). How often you undergo monoclonal antibody treatment depends on your cancer and what drug you're receiving. Some monoclonal antibody drugs may be used in combination with other treatments, such as chemotherapy and hormone therapy. Others are administered alone.

Monoclonal antibody drugs were initially used to treat advanced cancers that hadn't responded to chemotherapy or cancers that had returned despite treatment. However, because these treatments have proved to be effective, certain monoclonal antibody treatments are being used earlier in the course of the disease. For instance, rituximab can be used as an initial treatment in some types of non-Hodgkin's lymphoma, and trastuzumab (Herceptin) is used in the treatment of some forms of early breast cancer.

Many of the monoclonal antibody therapies are still considered experimental. For this reason, these treatments are usually reserved for advanced cancers that aren't responding to standard, proven treatments.

FDA-approved monoclonal antibodies for cancer treatment
Name of drug Type of cancer it treats

Alemtuzumab (Campath) Chronic lymphocytic leukemia
Bevacizumab (Avastin) Brain cancer
Colon cancer
Kidney cancer
Lung cancer

Cetuximab (Erbitux) Colon cancer
Head and neck cancers

Ibritumomab (Zevalin) Non-Hodgkin's lymphoma

Ofatumumab (Arzerra) Chronic lymphocytic leukemia
Panitumumab (Vectibix) Colon cancer

Rituximab (Rituxan) Chronic lymphocytic leukemia
Non-Hodgkin's lymphoma

Tositumomab (Bexxar) Non-Hodgkin's lymphoma

Trastuzumab (Herceptin) Breast cancer
Stomach cancer

Source: Food and Drug Administration (FDA), Center for Drug Evaluation and Research

What types of side effects do monoclonal antibody drugs cause?

In general, monoclonal antibody treatment carries fewer side effects than do traditional chemotherapy treatments. However, monoclonal antibody treatment for cancer may cause side effects, some of which, though rare, can be very serious. Talk to your doctor about what side effects are associated with the particular drug you're receiving.

Common side effects

In general, the more-common side effects caused by monoclonal antibody drugs include:

Allergic reactions, such as hives or itching
Flu-like signs and symptoms, including chills, fatigue, fever, and muscle aches and pains
Nausea
Diarrhea
Skin rashes

Serious side effects

Serious, but rare, side effects of monoclonal antibody therapy may include:

Infusion reactions. Severe allergy-like reactions can occur and, in very few cases, lead to death. You may receive medicine to block an allergic reaction before you begin monoclonal antibody treatment. Infusion reactions usually occur while treatment is being administered or soon after, so your health care team will watch you closely for a reaction.

Dangerously low blood cell counts. Low levels of red blood cells, white blood cells and platelets may lead to serious complications.

Heart problems. Certain monoclonal antibodies may cause heart problems, including heart failure and a small risk of heart attack.

Skin problems. Sores and rashes on your skin can lead to serious infections in some cases. Serious sores can also occur on the tissue that lines your cheeks and gums (mucosa).

Bleeding. Some of the monoclonal antibody drugs are designed to stop cancer from forming new blood vessels. There have been reports that these medications can cause bleeding.

What should you consider when deciding on monoclonal antibody drug treatment?

Discuss your cancer treatment options with your doctor. Together you can weigh the benefits and risks of each treatment and decide whether a monoclonal antibody treatment is right for you.

Questions to ask your doctor include:

Has the monoclonal antibody drug shown a clear benefit? Some monoclonal antibody drugs are approved for advanced cancer, though they haven't been shown to extend lives. Instead, some drugs are more likely to slow a cancer's growth or stop tumor growth temporarily.

What are the likely side effects of monoclonal antibody treatment? With your doctor, you can determine whether the potential side effects of treatment are worth the likely benefit.

How much will monoclonal antibody treatment cost? Monoclonal antibody drugs can cost thousands of dollars per treatment. Insurance doesn't always cover these costs.

Is monoclonal antibody treatment available in a clinical trial? Clinical trials, which are studies of new treatments and new ways to use existing treatments, may be available to you. In a clinical trial, the cost of the monoclonal antibody drug may be paid for as a part of the study. Also, you may be able to try new monoclonal antibody drugs. Talk to your doctor about what clinical trials may be open to you.