PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify ...factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.
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•High mutational loads may predict better survival, but not response to anti-PD-1•BRCA2 mutations are enriched in melanomas responsive to anti-PD-1•A transcriptional signature is related to innate anti-PD-1 resistance (IPRES)•IPRES defines a transcriptomic subset across distinct types of advanced cancer
High mutational loads are associated with improved survival in melanoma patients but are not predictive of response to anti-PD-1 therapy, suggesting that other genomic and non-genomic features also contribute to response patterns on PD-1 checkpoint blockade therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
CTLA4 blocking monoclonal antibodies provide durable clinical benefit in a subset of patients with advanced melanoma mediated by intratumoral lymphocytic infiltrates. A key question is defining ...whether the intratumoral infiltration (ITI) is a differentiating factor between patients with and without tumor responses.
Paired baseline and postdosing tumor biopsy specimens were prospectively collected from 19 patients with metastatic melanoma, including 3 patients with an objective tumor response, receiving the anti-CTLA4 antibody tremelimumab within a clinical trial with primary endpoint of quantitating CD8(+) cytotoxic T-lymphocyte (CTL) infiltration in tumors. Samples were analyzed for cell density by automated imaging capture and further characterized for functional lymphocyte properties by assessing the cell activation markers HLA-DR and CD45RO, the cell proliferation marker Ki67, and the regulatory T-cell marker FOXP3.
There was a highly significant increase in ITI by CD8(+) cells in biopsy samples taken after tremelimumab treatment. This included increases between 1-fold and 100-fold changes in 14 of 18 evaluable cases regardless of clinical tumor response or progression. There was no difference between the absolute number, location, or cell density of infiltrating cells between clinical responders and patients with nonresponding lesions that showed acquired intratumoral infiltrates. There were similar levels of expression of T-cell activation markers (CD45RO, HLA-DR) in both groups and no difference in markers for cell replication (Ki67) or the suppressor cell marker FOXP3.
CTLA4 blockade induces frequent increases in ITI by T cells despite which only a minority of patients have objective tumor responses.
Whole-exome sequencing was performed on four patients' tumors before exposure to pembrolizumab and after disease progression following a response to treatment. Acquired mutations involving antigen ...presentation and interferon response were noted.
Durable responses in metastatic cancers have been achieved with a variety of immunotherapies such as interleukin-2, adoptive cell transfer of tumor-infiltrating lymphocytes, antibodies that block cytotoxic T-lymphocyte–associated antigen 4 (CTLA4),
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and antibodies that block programmed death 1 (PD-1).
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However, in a recent study, approximately 25% of patients with melanoma who had had an objective response to PD-1 blockade therapy had disease progression at a median follow-up of 21 months.
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The mechanisms of immune-resistant cancer progression are mostly unknown. Previous studies involving humans examined the loss of beta-2-microglobulin as a mechanism of acquired resistance to several forms of cancer . . .
Purpose: Tumor antigen–loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated
antigen 4 (CTLA4)–blocking antibodies should release a key ...negative regulatory pathway on T cells. The combination was tested
in a phase I clinical trial in patients with advanced melanoma.
Experimental Design: Autologous DC were pulsed with MART-1 26-35 peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued
to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point.
Results: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab
at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all
melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients
with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related
gene signatures, in particular for B-cell function, may be important in predicting response.
Conclusion: The combination of MART-1 peptide–pulsed DC and tremelimumab results in objective and durable tumor responses at the higher
range of the expected response rate with either agent alone. (Clin Cancer Res 2009;15(19):6267–76)
Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues ...limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, ...an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed by multicolor flow cytometry using two computational approaches to resolve the leukocyte phenotypes at the single-cell level. There was a statistically significant increase in the frequency of T cells in patients who responded to therapy. The frequency of intratumoral B cells and monocytic myeloid-derived suppressor cells significantly increased in patients' biopsies taken on treatment. The percentage of cells with a regulatory T-cell phenotype, monocytes, and natural killer cells did not change while on PD-1 blockade therapy. CD8(+) memory T cells were the most prominent phenotype that expanded intratumorally on therapy. However, the frequency of CD4(+) effector memory T cells significantly decreased on treatment, whereas CD4(+) effector T cells significantly increased in nonresponding tumors on therapy. In peripheral blood, an unusual population of blood cells expressing CD56 was detected in two patients with regressing melanoma. In conclusion, PD-1 blockade increases the frequency of T cells, B cells, and myeloid-derived suppressor cells in tumors, with the CD8(+) effector memory T-cell subset being the major T-cell phenotype expanded in patients with a response to therapy.
Highlights • Few treatments for metastatic melanoma provide long term tumor regressions. • Response rate of 15.6% observed in 143 patients treated with tremelimumab. • Patients with tumor response to ...tremelimumab very likely to have durable responses. • Ten and 12.5 year estimated survival rates of 16% observed in these patients. • Anti-CTLA-4 memory immune responses against tumors can last beyond a decade.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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