Monoclonal Antibody Therapy in the Treatment of Non-Hodgkin Lymphoma

Monoclonal antibodies are revolutionizing the treatment of many illnesses. Some patients with coronary artery disease, Crohn disease, solid organ transplants, rheumatoid arthritis, or cancer have already experienced benefits from these engineered proteins. Monoclonal antibodies typically either harness the patient's own immune system to fight disease or suppress an errant immune system. Table 1 lists the monoclonal antibodies currently approved by the Food and Drug Administration (FDA); more than 50 others are in active clinical trials around the world. Monoclonal antibodies are currently used by cardiologists, gastroenterologists, nephrologists, and rheumatologists as well as oncologists. In this article, we focus on the use of monoclonal antibodies for the treatment of patients with non-Hodgkin lymphoma (NHL).

An estimated 56 000 people in the United States will develop NHL this year leading to more than 26 000 deaths.¹ Non-Hodgkin lymphomas range from slow-growing follicular lymphomas (historically grouped as low-grade NHL) to more aggressive large-cell lymphomas (intermediate- to high-grade NHL). Patients with either indolent or fast-growing lymphomas may achieve remissions with conventional chemotherapy, but most eventually succumb to their disease.

Monoclonal antibodies are used to treat both follicular and large-cell lymphomas using a variety of approaches. These approaches include using antibodies alone, linking antibodies with cellular toxins or radioisotopes, and combining antibodies with standard chemotherapy.

Monoclonal antibodies bind specific antigens, protein targets on the surfaces of cells. The overwhelming advantage of monoclonal antibodies compared with traditional pharmaceuticals is that they can be engineered to bind particular antigens. Antigen targets are selected based upon a variety of characteristics. First, the antigen should be expressed solely on the cells that are targeted, or at least be expressed to a much higher level than on cells not targeted. Second, even when the antibody binds to the antigen, the antigen should remain expressed at a high level on the target cells. Antigens that are modulated or decreased in number by antibody binding make less attractive targets for monoclonal antibody therapy.

The binding of antibodies to surface antigen on target cells can trigger cell death with little or no toxicity to nearby healthy cells. Monoclonal antibodies are thought to kill tumors through 3 different mechanisms: complement-mediated lysis, antibody-dependent cellular cytotoxicity, and activation of apoptosis.^{2 - 3} It is unknown to what degree each of these 3 mechanisms, or other unrecognized mechanisms, contributes to the overall tumor cell destruction. The extent of tumor cell destruction determines the response rate of patients receiving a particular therapy. A response may be complete, indicating that the tumor is no longer detectable, or it may be partial, indicating a significant (usually >50%) reduction in but not complete elimination of tumor cells. Monoclonal antibody administration may result in severe, usually short-lived reactions such as fevers, rigors, respiratory distress, and hypotension that may require antipyretics, antihistamines, or steroids for control.⁴ These reactions are often limited to the first few intravenous injections of the agent, and may be reduced by starting treatment with a low dose of the antibody and then escalating to the desired dose.

The anti-CD20 monoclonal antibody rituximab has found its widest application in the treatment of patients with follicular NHL. Rituximab is a partially humanized (murine and human components spliced together) antibody with only murine light and heavy chain variable regions. The CD20 antigen is an attractive target since it is found on most B-cell lymphomas and is not modulated by antibody binding.

As a single agent, rituximab may be effective in inducing long-term remissions in follicular NHL. The current standard dosing for rituximab is 375 mg/m² once weekly for 4 weeks, which resulted in a 46% overall response rate in patients with relapsed follicular lymphoma in 1 trial.⁴ Patients in this trial achieved maximal response within 4 months of therapy with a median duration of response of 10.2 months. Other schedules of rituximab administration, such as 3 times a week for 4 weeks, may be more efficacious in illnesses such as chronic lymphocytic leukemia.⁵ In addition to different schedules of rituximab infusion, doses higher than 375 mg/m² are also being investigated. Alterations in the dose and timing of rituximab infusions may result in even greater responses in patients with a variety of tumors expressing CD20.

Rituximab is also combined with immune modulators such as interferon α in the treatment of follicular lymphomas. A recent study by the Nordic Lymphoma Group demonstrated a 76% initial response rate for patients treated with rituximab as a single agent and a 100% initial response rate for patients treated with a combination of rituximab and interferon α.⁶ The duration of response in these patients remains to be determined.

The monoclonal antibody alemtuzumab is a humanized monoclonal antibody directed against the CD52 antigen. Alemtuzumab has proven effective in the treatment of chronic lymphocytic leukemia that is refractory to standard chemotherapy with fludarabine and alkylating agents. A 33% overall response rate has been reported.⁷ Currently, investigators are exploring the optimal duration of treatment and the role of maintenance therapy for patients with good initial responses. Similarly, single antibody therapy has been successful in the treatment of some other illnesses. Infliximab (a monoclonal antibody directed against tumor necrosis factor α) has been shown to be effective in the treatment of selected patients with Crohn disease.⁸

Some antibodies allow targeting of neoplastic cells, but may not induce cell death by themselves. Instead, they act as conduits for linked toxins or radioisotopes that require cell entry or close proximity to neoplastic cells to be effective. An immunotoxin that has been linked to a monoclonal antibody directed at the lymphoid marker CD19 shows antitumor activity in NHL. The combination of rituximab with this toxin may result in synergistic activity due to the ability of rituximab to damage the cell membrane, increasing the entry of the immunotoxin into neoplastic cells.⁹

Lymphoma cells tend to be very sensitive to radiation. Monoclonal antibodies can selectively deliver radiation to neoplastic cells with relative sparing of normal tissue. The combination of yttrium Y 90 with an anti-CD20 monoclonal antibody, ibritumomab tiuxetan, has been shown to increase delivery of radiation to neoplastic vs normal tissue by nearly 1000-fold.^{10 - 11} Similarly, an iodine I 131 labeled anti-CD20 antibody, tositumomab, has shown promising results. Gockerman et al¹² reported a 58% response rate for patients with follicular or transformed lymphomas treated with tositumomab; a median duration of response has not been reached after 17 months of follow-up. Some patients have remained in remission beyond 5 years.^{13 - 15}

Another unique approach uses antibodies to target the extracellular matrix that surrounds and supports tumor cells. This extracellular matrix contains laminin, type IV collagen, and tenascin at higher levels than normal tissue.¹⁶ Our group has developed a radiolabeled antibody to the extracellular glycoprotein tenascin, a key component for the adhesion of 1 cell to another and possibly a modulator of angiogenesis.¹⁷ This antibody is currently being evaluated to treat all types of NHL.

Initial data suggest concurrent administration of a monoclonal antibody with chemotherapy can be synergistic.¹⁸ Fludarabine, a chemotherapy agent used to treat follicular lymphoma, reduces expression of CD55, an antigen that inhibits complement-mediated lysis.¹⁹ This down-regulation may increase the sensitivity of lymphoma cells to complement-activating monoclonal antibodies. Preliminary data from a phase 3 trial of concurrent vs delayed combination therapy for patients with previously untreated follicular lymphoma suggest that the concurrent delivery of rituximab and chemotherapy provides a quicker response than does delayed exposure to the antibody.²⁰

Other combinations of monoclonal antibodies with conventional chemotherapy have been effective in preliminary studies, even in patients for whom high-dose chemotherapy with stem cell support has not been successful.^{21 - 24} Although most research on combinations of monoclonal antibodies with chemotherapy has focused on follicular lymphoma, combination therapy may be effective in more aggressive NHL as well. An interim analysis of the standard cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy regimen with or without rituximab has shown increased remission rates in patients with large-cell lymphoma treated with rituximab along with chemotherapy.²⁵

Similar multiple modality therapy is already used in the treatment of nonneoplastic illnesses. The combination of abciximab (a monoclonal antibody that binds to the platelet glycoprotein IIb/IIIa receptor) with angioplasty has been shown to decrease ischemia following coronary revascularization procedures.²⁶ The combination of disease-modifying antirheumatic drugs with infliximab has been shown to improve responses and quality of life in those with rheumatoid arthritis.²⁷

Several limitations of monoclonal antibodies are being investigated; overcoming these limitations should improve the efficacy of these new therapeutic agents. One limitation is that bulky disease tends to be more refractory to monoclonal antibody therapy.²⁸ This problem may be worse with antibodies that rely on the recruitment of immune system cells to kill tumor cells.²⁹

Another limitation of currently available monoclonal antibody therapy is that patients may develop immune reactions to murine or other nonhuman components of monoclonal antibodies, decreasing their circulatory half-life and limiting their overall effectiveness. There are no FDA-approved monoclonal antibodies that contain only human protein sequences.

Conversely, monoclonal antibody therapy may result in severe suppression of the immune system. While potentially beneficial in autoimmune disease and organ transplantation, this immunosuppression may reduce the ability of a patient to combat infections. This drawback may compound the risk of infections in patients who are already neutropenic. Additionally, bone marrow suppression and theoretically even secondary malignancies such as acute leukemias may result from the use of monoclonal antibodies linked to radioisotopes.¹⁵

One goal of current monoclonal antibody research is to modulate the expression of known tumor antigens, increasing the number of targets to which monoclonal antibodies could bind. This advance could allow improved targeting of tumor cells. The concept of combining monoclonal antibodies targeting different antigens on the same cell is also being explored. Investigators have hypothesized that a combination of antibodies might act synergistically and more effectively activate the host immune system or tumor cell apoptosis than any single antibody. Combinations of antibodies have proven more efficacious than single antibodies in cancer diagnostics and immunosuppression.^{30 - 31}

Monoclonal antibody therapy has improved outcomes in lymphoma and other malignancies. Much remains to be learned regarding the proper use of monoclonal antibodies alone or in combination with other therapeutic modalities. In what order should chemotherapy, radiation therapy, or monoclonal antibodies be used? How should antibodies be combined with high-dose chemotherapy and stem cell transplantation? How long can a patient safely be exposed to monoclonal antibodies and what are the long-term consequences? These questions need investigation before the full potential of this revolutionary new therapeutic approach for NHL and other diseases is realized.

Since monoclonal antibodies are used by physicians in a variety of medical specialties, information from additional research should lead to improvements in the use of monoclonal antibodies for many different applications. An antibody developed to treat rheumatoid arthritis, for example, may lead to the development of better antibodies for the treatment of coronary artery disease, graft-vs-host disease, or cancer.