Abstract IA05: Selective pressure by activated T cells identifies de novo and adaptive resistance mechanisms in melanoma
Authors: Flaherty Keith T. 
Published: May 2019

Abstract
Melanoma has been the tumor type in which immune checkpoint antibodies have been directed for the longest time in clinical trials and clinical practice. Compared to many other advanced solid tumors, a significant minority of patients have manifestations of metastatic disease that are amenable to minimally invasive biopsies to fuel translational research. With CTLA-4 blocking antibodies, the response rate was only 10% and insights into predictive biomarkers only began to emerge once large numbers of patients had been treated and with long-term follow-up. However, with PD-1/PD-L1 blocking antibodies response rates as high as 40% have been observed in previously untreated melanoma patients, making it far more tractable to glean insights into differences between responders and nonresponders in smaller number of patients.
Emerging data from analysis of pretreatment tumor biopsies strongly support the greater, but still not high, likelihood of patients responding to PD-1/PD-L1 antibody-based therapy if there are robust numbers of CD8+ T cells infiltrating into a tumor prior to the start of therapy. Response prediction appears to be improved by assessment of T-cell infiltration into tumors early in the course of therapy. Modest improvement in response prediction appears to be achieved by accounting for the presence of regulatory T cells, with those tumors having the highest effector CD8+/Treg ratio being the most likely to respond. Additional predictive accuracy is contributed by a marker of T-cell activation, such as granzyme B, which would only be scored as positive if there are T cells present in the first place. While many additional modulators of T-cell entry and function have been implicated as mechanistically related to immune checkpoint antibody efficacy/resistance, none have been shown to have add predictive accuracy for response.
A parallel body of evidence has developed indicating that the presence of predicted mutated neoantigens can predict response to immune checkpoint antibodies in melanoma. It is notable that melanoma has the highest number of mutations per megabase of any common solid tumor, which is thought to associate with the high response rate (40%) compared to other cancers in which PD-1/PD-L1 antibodies have demonstrated efficacy leading to regulatory approvals (15-20% response rates). The current state-of-the-art approach for predicting the presence of mutated antigens is algorithm-based, matching altered peptide sequences with a patient's HLA type to rank potential high-affinity binders. A very small number of such antigens have been validated by the presence of specific T-cell clones that recognize those antigens in patients. Nonetheless, response prediction appears robust and roughly compared to that achieved with phenotypic markers of tumor recognition described above, particularly when predicted mutated neoantigens are clonal.
The most recent area of active investigation pertains to the phenotype of tumors with de novo resistance to immune checkpoint antibodies and mechanisms of acquire resistance. Early work suggests that the same phenotype of resistance associated with MAP kinase pathway targeted therapy (tumor cells that lose expression of melanocyte markers in favor of neural crest markers) predicts nonresponse to PD-1 antibodies. Very few patients with progression following response have been interrogated to date, but genetic loss of components of the MHC complex and inactivating mutations in the interferon signaling pathway in tumor cells appear to account for a significant proportion of cases.
Citation Format: Keith T. Flaherty. Selective pressure by activated T cells identifies de novo and adaptive resistance mechanisms in melanoma [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA05.