Nearly 100 years ago, Ehrlich described the concept of harnessing the immune system to treat cancer. This idea motivated many scientists and clinicians with the appeal of developing treatments for patients with cancer that are more tumor-specific and less toxic to the host. This did not become possible until the development of hybridoma technology by Kohler and Milstein, which allowed for the production of large quantities of a single antibody with defined specificity (monoclonal antibody). Many clinical trials quickly ensued, however, the application of antibody-based treatments from clinical trials into accepted clinical practice has been discouragingly slow.
The recent approval by the US Food and Drug Administration (FDA) of rituximab(Drug information on rituximab) (Rituxan), an unconjugated chimeric antibody against the CD20 antigen, for the treatment of relapsed low-grade or follicular B-cell non-Hodgkins lymphoma marked a milestone in the development of these antibody-based treatments. Other new drug applications to the FDA are pending using both unconjugated and radiolabeled monoclonal antibodies, and it is anticipated that further new treatment options based on monoclonal antibody technology will soon be available for the treatment of patients with non-Hodgkins lymphoma. The most promising of these treatments and the comparison of these strategies are reviewed here.
Two types of treatment have emerged and have been explored widely. These are based on the use of either native or modified unconjugated monoclonal antibodies, or on the use of monoclonal antibodies, to target radionuclides, drugs, or toxins to the tumor. The first approach utilizes unconjugated monoclonal antibodies. Early trials employed murine or rat antibodies, whereas more recent studies have used chimeric or humanized monoclonal antibodies. These monoclonal antibodies contain mostly human antibody sequences with only the variable region or the actual antibody binding sites coming from the original murine antibody structure. These modified monoclonal antibodies have a longer half-life in vivo, are less immunogenic, and have increased clinical activity. In general, treatment with unconjugated monoclonal antibodies is well-tolerated with minimal infusion-related symptoms and often no dose-limiting toxicity (certain exceptions apply). A closely related approach to unconjugated monoclonal antibody therapy is the use of a tumor vaccine based on the idiotype to induce tumor-specific immunity directly in B-cell non-Hodgkins lymphoma patients, eliminating the need to produce and administer a custom anti-idiotype monoclonal antibody
The second strategy uses the monoclonal antibody as a carrier to specifically target a radionucleotide or toxin to the tumor cells. This approach has clearly demonstrated increased antitumor activity but must be dosed carefully and is associated with dose-limiting toxicity. Results from clinical trials of both approaches using unlabeled or radionucleotide conjugated monoclonal antibody-based therapies are strongly affected by the types of monoclonal antibody used, the characteristics of the target antigen, and the type of non-Hodgkins lymphoma treated.
Monoclonal antibody-based treatments have resulted in documented antitumor responses in many patients with B- and T-cell non-Hodgkins lymphoma. However, there have also been many failures and anecdotal responses that have not led to treatments that are applicable for general therapy. Indeed, over the past 20 years we have learned that there are important antigen and antibody as well as tumor characteristics that are critical in the successful application of monoclonal antibody-based therapies for the treatment of cancer. Progress has been made, and the approval of rituximab as the first of these new agents ushers in the beginning of a new era in cancer therapy by providing tumor specificity with less host toxicity.
Characteristics of Tumor Antigens
Identification and characterization of the cell-surface antigen for immunotherapeutic attack is critical. Desirable antigen characteristics are different for each type of monoclonal antibody-based therapy and are detailed in Table 1. In general, the ideal tumor antigen should be present in high density on the surface of all of the tumor cells and not be expressed on normal cells. In reality, true tumor specificity is rare and often makes it difficult to apply the treatment to more than a single patient. As an example, the antigen receptor idiotype is tumor-specific but requires a custom antibody to be made for each patient with lymphoma, whereas antigens such as CD19 or CD20 are lineage-specific, and expression is limited to malignant and normal B lymphocytes. Thus, although absolute tumor specificity is often a goal of immunotherapy, most antigens are only relatively tumor-specific with the antigen expressed on some normal host cells. Expression on critical host cells or tissues must be avoided.
Other important antigen characteristics that should be considered include:
secretion or shedding of antigen from the cell into the circulation
modulation or internalization of the antigen into the cell upon monoclonal antibody-binding
antigen mutation or inhomogeneous expression on the malignant clone, and
the biologic function of the antigen that may be blocked, augmented, or triggered by monoclonal antibody-binding.
Treatments with unconjugated monoclonal antibodies or monoclonal antibodies targeting toxins or radionuclides differ in which of these characteristics are critical for the successful application of antibody therapy.
Mechanisms of Anti-Tumor Effect
Unconjugated monoclonal antibodies depend on either immune-mediated effects due to complement or antibody-dependent cell-mediated cytotoxicity (ADCC) or direct effects to cause tumor cell kill or growth inhibition. Over the past years there has been an increasing recognition of the direct effects of monoclonal antibodies binding to tumor cells. These effects range from the blocking of a growth factor receptor (eg, the interleukin-2 [IL-2] receptor),[3,4] to the stimulation of the immunoglobulin (Ig) receptor (anti-idiotype monoclonal antibodies). These effects are often diverse and depend on the antigen that is targeted and on the stage of differentiation of the tumor cell. Monoclonal antibodies may effect cells directly by growth inhibition and cell-cycle arrest and by the induction of apoptosis. Synergy of monoclonal antibodies with conventional treatments such as chemotherapy drugs and irradiation may also occur and is currently a major focus of investigation.
The mechanism of tumor cell kill using conjugated monoclonal antibodies may include the antitumor activity of unconjugated monoclonal antibodies (if sufficient monoclonal antibody is administered), but also the antitumor effects due to the targeting of the drug, toxin, or radionuclide to the tumor tissues. In most trials there is insufficient evidence to identify the true contribution of tumor cell kill to the monoclonal antibody alone vs the specific and nonspecific antitumor effect of the monoclonal antibody and the targeted agent. However, it appears that the majority of the effect is due to targeted effects of the radioisotope.
Lymphoma Tumor Antigens
A large number of antigens have been targeted for monoclonal antibody-based therapy for non-Hodgkins lymphoma. The general characteristics of selected tumor antigens are shown in Table 2. For the most part, these antigens are lineage-specific and expressed by B-cell or T-cell malignancies as well as the normal host lymphocytes at a given stage of differentiation. Issues such as modulation, antigen shedding, and secretion have been identified as critical negative characteristics for unconjugated monoclonal antibody-based treatments, while modulation and internalization is required for the success of immunotoxin-based approaches. To date, few monoclonal antibody-based treatments have been able to reliably induce complete remissions in the majority of patients, and the generation of antigen-negative tumor cell variants has not been a problem. As treatments continue to improve, this is likely to become a greater issue.
Antigens range from truly tumor-specific (anti-idiotype) to lineage-specific (such as anti-CD19, 20, or 22 for B cells or anti-CD3, 4, or 8 for T cells) or more broadly expressed antigens (such as CD52 [target for CAMPATH]) that may be expressed on multiple cell lineages. The selection of the target antigen plays a major role in the success of monoclonal antibody-based therapy. Over the past years, the CD20 antigen has emerged as an excellent target antigen for unconjugated and radiolabeled monoclonal antibody therapy. In retrospect, this may be predicted by many of the characteristics of this antigen. In a similar fashion, the failure of many monoclonal antibody-based treatments can be traced to shortcomings of the target antigen and the selected monoclonal antibody-based treatment.