Case 37

Published on 18/02/2015 by admin

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CASE 37

WT has been a “sun worshipper” all his life. Over the past several months he has noticed some worrisome changes in some freckles on his legs and arms, and one in particular seems to have grown substantially, with a significant change in coloration and an irregular contour. You recognize all of these signs as being potentially indicative of malignant melanoma and send him to a local dermatologist for biopsy. The results come back positive. WT has heard about some recent positive data using immunotherapy in melanoma and asks your advice.

QUESTIONS FOR GROUP DISCUSSION

1. Melanoma is one of the cancers for which “spontaneous” remissions are reported. Discuss possible mechanisms for this remission.

2. Tumor-specific antigens (TSAs) derived from melanoma DNA libraries have been cloned. What is the TSA on melanoma cells?

3. Immunity directed to melanoma can often be monitored by following evidence for anti-melanocyte reactivity. Explain how this would present clinically. What is the clinical term for this reaction?

4. Explain why normal melanocytes are destroyed after supposedly targeting of TSAs on the melanoma.

5. Discuss the rationale for therapy using dendritic cells that have been pulsed with cloned melanocyte-associated epithelial antigens (MAGE) proteins (referred to as vaccines).

6. Explain why granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 are used to culture CD34+ peripheral blood cells in question 5.

7. What approach could one use to ensure that the re-infused dendritic cells receive a constant supply of cytokines, without putting the patient at risk for complications normally experienced when administering cytokines?

8. Provide a rationale for these steps in generating a therapeutic vaccine for melanoma: culture of tumor infiltrating lymphocytes ex vivo with (a) MAGE-pulsed dendritic cells and (b) IL-2 before re-infusion.

9. Explain the rationale for introducing IL-2, tumor necrosis factor (TNF) or interferon gamma (IFNγ) as sole therapy (or adjunctive therapy) in melanoma patients.

10. In extension of the work on melanoma, breast cancer therapies have also been developed. What tumor antigens would one target in breast cancer patients?

RECOMMENDED APPROACH

Implications/Analysis of Family History

Low-risk alleles (e.g., melanocortin 1 receptor gene [MC1R]) may increase the risk of melanoma in the general population, when that population has a high sun exposure. These individuals have enhanced sun sensitivity, and so their risk of developing melanoma is increased.

We are not provided with any family history, but hereditary melanoma is rare. In such cases, melanoma transmission occurs along either the paternal or the maternal lineage but not both. Mutations in two genes—CDKN2A (cell cycle regulator) and CDK4 (cyclin-dependent protein kinase 4)—are associated with hereditary melanoma. CDKN2A is a cell cycle regulator that is often mutated or deleted in cancer, particularly melanoma. (Patients with a defect in CDKN2A also have an increased risk of developing pancreatic cancer.) Based on the information given in the case, this patient does not have hereditary melanoma but rather an idiopathic case of disease (related to environmental/behavioral risk factors).

Implications/Analysis of Clinical History

We need to consider the fact that no family history is provided as a significant negative. Although we have not determined that WW has one of the risk alleles for MC1R (see earlier), the fact that he has been a sun worshipper and that he has scattered freckles in sun-exposed areas puts him in a higher risk group than someone who has a low-risk sun exposure.

Implications/Analysis of Laboratory Tests

A biopsy specimen of the pigmented lesions indicated that WW has malignant melanoma.

Additional Laboratory Tests

To test for metastatic disease, a chest radiograph was requested but shown to be normal. Patients with malignant melanoma often show distant metastases (lungs, brain, kidney).

DIAGNOSIS

WW was diagnosed with malignant melanoma (Fig. 37-1). The most widely used measurement system (after skin biopsy) to predict 5-year survival is the “Breslow” measurement. In this system a defined melanoma thickness is associated with a 5-year survival in 97% of patients. At the other end of the scale a 10-fold increase in thickness is associated with a 5-year survival of only 32% of the patients. Another system, the “Clark Level of Invasion” can also be used to determine prognosis. There are five Clark levels of invasion, with level one indicating that the melanoma is confined to the outermost layer of skin and level five indicating penetration of the melanoma into fat cells beneath the dermis. This is then correlated with 5-year survival rate after surgical removal of the melanoma.

FIGURE 37-1 Skin lesion on patient with documented malignant melanoma.

THERAPY

The lesion was excised with a large margin, and WW was shown how to perform routine self-examination and advised to seek professional examination every 6 months.

ETIOLOGY: MALIGNANT MELANOMA

Melanoma is indeed a bright spot on the horizon for those interested in the immunotherapy of cancer. It is indeed one of the cancers for which “spontaneous remissions” are reported, which may in turn reflect an autologous antitumor reaction (immunologically derived) in the natural host.

Tumor-Specific Melanocyte-Associated Epithelial Antigens

When laboratories first attempted to derive evidence for a host (human) antitumor response, and indeed for tumor antigens that could elicit these, melanoma was the first target used. The so-called MAGE antigens have been cloned from tumor-derived DNA libraries and represent molecules subtly different from the endogenous molecules. Because the MAGE antigen is different, albeit subtly, from normal melanocytes, it can function as a tumor-specific antigen and induce tumor-cell specific immunity. Interestingly, immunity directed to melanoma can often be monitored by following evidence for anti-melanocyte reactivity (which presents as patchy loss of pigmented cells in the normal skin, or “vitiligo”).

Innovative Therapies

Current therapy in melanoma includes use of cloned MAGE proteins for pulsing dendritic cells (grown from autologous CD34+ peripheral blood lymphocytes in vitro in the presence of GM-CSF and IL-4) before infusion back into the patient as a tumor vaccine. Other vaccines have also been used, including these same cells (also transfected with GM-CSF/IL-4 to promote their growth in vivo) or tumor-infiltrating lymphocytes (TILs) cultured ex vivo with MAGE-pulsed dendritic cells and IL-2 before re-infusion in vivo.

IL-2 and other cytokines (TNF, IFNγ) have also been used as solo therapy (or adjunctive therapy) in melanoma patients, again with the express view of engaging the host immune response in protection against malignant growth.

Other Malignancies

In extension of the work on melanoma, other tumor antigens (e.g., BRCA [breast]; MUC-1 [breast/other adenocarcinomas]) have been used in similar trials in other human malignancies.

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