Faculty Bibliography

Background Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells. Methods We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients. Results Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab. Conclusions These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti-CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund and others.).

The goals of any cancer therapy are to improve disease control, palliate pain and improve overall survival. We are fortunate to have in our cancer armamentarium two new immune-directed therapies which not only impact on disease control but also on overall survival. The first, sipuleucel-T, a cellular-based vaccine, was approved for prostate cancer and was shown to be safe with minimal toxicity. The second, ipilimumab, a monoclonal antibody directed to an immunologic checkpoint molecule, showed a survival benefit in patients with advanced melanoma. Benefit appeared to correlate in some cases with the development of autoimmune events, signaling that the immune system is in overdrive against the cancer. Where we are and where we will likely go are the topics to be discussed in this review.

Vascular neoplasms are uncommon and pose a diagnostic and treatment challenge to the pathologist and surgeon, respectively. Epithelioid hemangioendothelioma is a rare neoplasm of vascular origin with an unknown etiology. Its biologic behavior lies somewhere between that of a benign hemangioma and that of a malignant angiosarcoma; however, it is unpredictable at best. Intravascular epithelioid hemangioendotheliomas have been described more often in veins than arteries, and there are only about 30 reports in the English literature. We report here the case of an epithelioid hemangioendothelioma of the inferior vena cava, which presented with abdominal pain, ascites and pedal edema.