Abstract A89: Loss of HLA molecules as melanoma resistance mechanism in immune checkpoint blockade therapy.

Melanoma immunotherapy based on immune checkpoint blockade, by targeting of CTLA-4 or PD-1, has markedly improved the treatment of advanced disease, as shown by several recent trials. Monotherapy with CTLA-4-specific antibody (Ipilimumab) prolongs overall survival, while PD-1-specific antibodies (Nivolumab and Lambrolizumab) induce durable tumor regression in a large fraction of patients. Moreover, a recent trial based on combination checkpoint blockade (Ipilimumab plus Nivolumab) has shown an objective response rate of 53%, with tumor reduction of 80% in responding patients, without escalation of toxic effects. In spite of these highly relevant results, clinical benefit by immunotherapy targeting CTLA-4 or PD-1 remains limited to a fraction of patients. This points to the existence of immune escape mechanisms, which, in some tumors, may prevent effective elimination of neoplastic cells, in spite of the reactivated T cell immunity. This hypothesis was tested in a melanoma patient, treated with Ipilimumab, and that we recently reported (J. Clin. Oncol. 29:e783-8, 2011) to have a strong T cell infiltrate and evidence of T cell maturation/activation only in a regressing right adrenal metastasis, but not in the progressing controlateral lesion. To this end, we carried out DASL whole genome gene expression analysis and extensive immunohistochemistry (IHC) on paraffin-embedded neoplastic tissues. The results indicated that, in comparison to the progressing metastasis, the regressing lesion had a distinct gene expression profile characterized by enhanced expression of several genes involved in T cell differentiation to cytolytic effector stage. Most importantly, the regressing lesion retained expression of HLA molecules on neoplastic cells. In contrast, the progressing lesion showed almost complete loss of HLA class I and Class II molecules by the tumor, as documented by IHC. Taken together, these results suggest that lack/loss of expression of HLA molecules, by tumor cells, may represent a highly effective tumor resistance mechanism to immune checkpoint blockade. Moreover, pre-therapy IHC on tumor samples may allow to test whether HLA antigen expression/loss is a predictive marker for response/resistance to therapy targeting CTLA-4 or PD-1. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A89. Citation Format: Andrea Anichini, Filippo G. de Braud, Roberta Montarini, Ilaria Bersani, Gabrina Tragni, Loris de Cecco, Silvana Canevari, Lorenza Di Guardo, Lorenzo Pilla, Michele Del Vecchio. Loss of HLA molecules as melanoma resistance mechanism in immune checkpoint blockade therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A89.