Casey loved the outdoors - hiking, boating, sports, he was outside as much as he could be. He never felt it was summer until he had his first sunburn. When Casey was 25, his girlfriend noticed that a mole on his shoulder was spreading and turning darker in the center. Casey pooh-poohed her worry, but eventually agreed to visit the free skin cancer screening clinic being held at work. The dermatologist looked carefully at the mole and arranged for Casey to come in for further testing; the mole was diagnosed as malignant melanoma.
Figure 1. Melanoma: left, as it appears on the skin; right, a tissue section (the melanoma cells are black).
Melanoma is a tumor of the melanocytes, the melanin pigment-producing cells of the skin. It is a tumor that often metastasizes, making it hard to treat because many small metastatic tumors cannot be seen and removed surgically. As tumors grow, they secrete growth factors that cause new blood vessel growth to nourish the tumor. In metastatic cancer, some cells break through the blood vessel walls and spread in the circulation to other parts of the body, where they adhere to the vascular endothelium and extravasate into the tissues to form metastatic tumors.
Melanoma has several tumor-associated antigens. MART, tyrosinase, and gp100 are all proteins that are required for melanin synthesis and are expressed in normal and tumor melanocytes. MAGE is expressed in melanoma cells and in testis, but not in normal melanocytes.
Casey's skin tumor was removed surgically, as were his draining lymph nodes (two of which had melanoma metastases). Imaging using radioactive monoclonal mouse anti-MAGE antibody detected numerous small metastases in Casey's lungs. Since melanoma is often resistant to chemotherapy, Casey's oncologist suggested they use immunotherapy against the tumor metastases.
1. (15 points) In 1891 a young New York physician named William Coley observed that a patient with a large sarcoma on his neck developed a severe erysipelas (Streptococcus pyogenes) infection. When he recovered from his infection, his tumor also healed and he remained cancer-free. Coley developed a mixture of killed S. pyogenes (a Gram + coccus) and Serratia marcescens (a Gram - rod) that he called Coley's Toxins; this mixture of dead bacteria and their toxins was injected into cancer patients multiple times for weeks or months. Following the first injection, the patients developed fever and chills. Several cases of complete remission (absence of tumor) followed treatment. Injections were given into the tumor and into the buttocks. Coley's Toxin is no longer used, but BCG (the attenuated Mycobacterium bovis used in the tuberculosis vaccine) infused into the bladder is a successful treatment for early stage bladder cancer.
How could Coley's Toxin or BCG help the immune system eliminate tumor cells? [HINT: How do bacteria affect the innate immune system? How will this affect adaptive immunity?]
2. (25 points) Table 2 above shows the cell surface markers found on TAA-specific T cells from six HLA-A2 positive patients with metastatic melanoma. The melanoma antigens used were tyrosinase and MART, proteins required for the production of the skin pigment melanin. T cells specific for peptides Tyr368-376, MART27-35 and Tyr368-376 (the numbers represent the amino acid locations in the protein sequence of these antigens) were tested for the presence of several cell surface markers, including the β chain of CD8, CD16 (FcR found on neutrophils, macrophages and NK cells), CD28, markers for naive (CD45RA) or memory T cells (CD45RO and CD44), and CD11a (integrin LFA-1).
3. (60 points) Brainstorm an immunotherapy to treat melanoma or a vaccine to prevent melanoma. The goal of your therapy/vaccine is to generate effector cells and memory cells that will attack and kill melanoma cells. Use the skills you have learned from the vaccine proposal project and previous cases. Decide what antigen you will use, whether you need an adjuvant, how you will give the treatment, how it will stimulate the immune system, what immune effectors it will generate, and how it will overcome at least one of the mechanisms tumors employ to evade immune elimination. What possible side effects might this treatment or vaccine cause?
Additional Sources
Lee, P. P. et al. Characterization of circulating T cells specific for tumor-associated antigen in melanoma patients. Nature Medicine 5 (June 1999), 677-685.
Lollini, P-L., F. Cavallo, P. Nanni and G. Forni. Vaccines for tumour prevention. Nature Reviews Cancer 6 (March 2006): 204-216