Case 32

Published on 18/02/2015 by admin

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Last modified 18/02/2015

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CASE 32

You are looking after a patient with B cell chronic lymphocytic leukemia (CLL). There are a number of conventional chemotherapeutic regimens available to treat this disease and a number of other investigational ones. Included among the investigational therapies is one involving infusion of antibodies made artificially (ex vivo) to the patient’s own tumor cells. There is, in fact, a major accepted immunologic dogma behind this treatment and why it might be expected to work, although thus far in practice such therapy has not been as effective as we might have hoped.

QUESTIONS FOR GROUP DISCUSSION

1. In B cell CLL, membrane immunoglobulin (B cell antigen receptor) is considered a tumor-specific antigen. Explain.

2. There are two major types of CLL. Explain how these populations differ.

3. In what types of cells is ZAP-70 normally found? In general terms, what is its role?

4. How does CLL typically present clinically? How is it diagnosed?

5. Assuming that an antibody can be generated that is specific for the tumor-specific antigen (question 1), the immune complex that is formed on the cell surface could activate a number of immunologic processes to destroy these malignant cells. Explain how each of the following could be recruited to destroy the malignant B cells: (a) complement, (b) neutrophils, and (c) NK cells.

6. One would expect that the infusion of tumor-specific antibodies would lead to the effective killing and elimination of malignant cells. However, this approach has not been particularly effective. Explain why that might be the case (see Tumor Immunology, Section IV).

7. Describe the “Jerne idiotypic network theory.” How would these networks produce the normal homeostasis in both T and B lymphocytes within the immune system?

8. Assuming that you could develop the appropriate anti-idiotypic antibody to target a particular population of T cells, what in vitro experiments could you perform that would provide information as to the potential efficacy of this approach?

9. The generation of antibodies specific for the idiotype on B cells would, in effect, represent the “magic bullet” therapy so long sought. The effectiveness of this therapy relies on the individual uniqueness (magic bullet) of the treatment. Yet, this is also its major limitation as a therapeutic approach in clinical practice. Explain.

10. Why would the use of T cell or B cell differentiation molecules as targets for antibodies tagged with toxins/radioactive material be more attractive for therapy than similarly labeled anti-idiotypic antibodies in clinical practice?

RECOMMENDED APPROACH

Implications/Analysis of Family History

B cell CLL is a monoclonal tumor, resulting from the proliferation and expansion of a single clone of B cells at a “frozen” point in time in their development. Studies of CLL and family history have shown an elevated risk of CLL for offspring and siblings of patients with CLL, as well as first- and second-degree relatives. However, no specific gene has been identified that is the cause of the disease per se. Recent literature reports have focused on the fact that patients with CLL can be divided into two major groups: those that have mutations in the variable region of the immunoglobulin heavy chain (VH) and those that do not have mutations in this gene. Patients with the mutated gene have a better prognosis than those without the mutation. It is now known that there are about 244 genes that are differently expressed in these two types of CLL. Of these 244 genes, ZAP-70 has been determined to be the best prognostic marker. ZAP-70, a tyrosine kinase, is a key signaling molecule in T cells and NK cells. It is not normally expressed in B cells. However, it is expressed in most patients with unmutated immunoglobulin VH gene, where it is recruited to the B cell receptor and enhances signaling.

Implications/Analysis of Clinical History

More than half the patients diagnosed with CLL are asymptomatic. For these patients diagnosis is made after a blood test for other reasons, including a yearly physical examination. Patients who are symptomatic will present with fatigue, weight loss, and generalized lymphadenopathy. The median age of CLL diagnosis is 64 years.

Implications/Analysis of Laboratory Investigation

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