Distinct immunological mechanisms of CTLA-4 and PD-1 blockade revealed by analyzing TCR usage in blood lymphocytes.

Targeting immune inhibitory receptors has brought excitement, innovation and hope to cancer patients. Our recent work revealed the immunological effects of blocking the CTLA4 and PD-1 immune checkpoints on T cell receptor usage among peripheral blood cells, and further uncovers how the expansion of the T cell repertoire matches the immunotoxicity profile of the therapy.

CTLA4 blockade broadens the peripheral T-cell receptor repertoire.

PURPOSE: To evaluate the immunomodulatory effects of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC). EXPERIMENTAL DESIGN: We used next-generation sequencing to study the complementarity-determining region 3 (CDR3) from the rearranged T-cell receptor (TCR) variable beta (V-beta) in PBMCs of 21 patients, at baseline and 30 to 60 days after receiving tremelimumab. RESULTS: After receiving tremelimumab, there was a median of 30% increase in unique productive sequences of TCR V-beta CDR3 in 19 out of 21 patients, and a median decrease of 30% in only 2 out of 21 patients. These changes were significant for richness (P = 0.01) and for Shannon index diversity (P = 0.04). In comparison, serially collected PBMCs from four healthy donors did not show a significant change in TCR V-beta CDR3 diversity over 1 year. There was a significant difference in the total unique productive TCR V-beta CDR3 sequences between patients experiencing toxicity with tremelimumab compared with patients without toxicity (P = 0.05). No relevant differences were noted between clinical responders and nonresponders. CONCLUSIONS: CTLA4 blockade with tremelimumab diversifies the peripheral T-cell pool, representing a pharmacodynamic effect of how this class of antibodies modulates the human immune system.

New drug targets in metastatic melanoma.

Over the past 30 years, and despite extensive clinical research, the treatment options for metastatic melanoma have been limited. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes have failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma have contributed in the development of new agents and to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. Since the discovery of activating mutations in the BRAF oncogene, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma, with unprecedentedly high response rates. Inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided clinically validated targets for cancer immunotherapy, resulting in durable tumour responses. The combination of both approaches may result in additional benefits. Here we discuss current molecular targeted treatment options, immunotherapy and promising ongoing research to develop new strategies to treat melanoma.

Update on the diagnosis of cancer of unknown primary (CUP) origin.

The cancer of unknown primary (CUP) concept encompasses a heterogeneous group of cancers that are difficult to diagnose and that show diverse clinical and histopathological features. Currently, CUP is the fifth most frequent cancer diagnosis in women and the eighth in men. The ongoing development of new therapies specific to the various cancer types makes mandatory the identification of the primary tumour in CUP patients, so that they may benefit from advances in therapy and improvements in prognosis. Molecular detection techniques provide very useful tools in the prediction of primary tumour types and must be used together with clinical, histopathological and IHC diagnostic techniques. Steady collaboration and fluid communication between oncologists and pathologists is of the utmost importance for the correct interpretation of tests and the personalised approach required by each individual case. Work in multidisciplinary teams will result in significant changes in the diagnosis and treatment of these patients.

Diagnosis of unknown primary cancer based on molecular techniques may influence therapeutic approach and improve survival.

Unknown primary cancer (UPC) is a common clinical syndrome classically associated with a poor prognosis. Pathological examination including immunohistochemistry continues to be essential in tumour origin characterization, although in many cases primary tumour site remains unknown. Gene expression based analysis may offer important diagnostic information that could lead to therapeutic decisions.