Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castrationresistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drugrelated adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1200690

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

Background Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Methods In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. Results As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The media...

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Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

MicroRNA (miRNA ) alterations are involved in the initiation and progression of human cancer. The causes of the widespread differential expression of miRNA genes in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the miRNA processing machinery. MiRNA-expression profiling of human tumours has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify miRNA genes that might represent downstream targets of activated oncogenic pathways, or that target protein- coding genes involved in cancer.

MicroRNA signatures in human cancers

MicroRNA (miRNA) alterations are involved in the initiation and progression of human cancer. The causes of the widespread differential expression of miRNA genes in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the miRNA processing machinery. MiRNA-expression profiling of human tumours has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify miRNA genes that might represent downstream targets of activated oncogenic pathways, or that target protein- coding genes involved in cancer.

Successful engineering cancer immunotherapy

The relationship between neoantigen recognition by T cells and the clinical success of cancer immunotherapy is beyond doubt.1,2 Personalized neoantigen-based cancer vaccines and neoantigen-specific T-cell therapy represent promising cancer treatments.3 Challenges yet remain to unleash the full potential of mutanome-based cancer immunotherapy. Among them, the identification and validation of clinically-relevant neoantigens require a complex, individualized and costly approach which only yields a limited number of neoepitope per patient.4,5 We recently reported a novel method that enables the sensitive detection of tumour neoantigens in highly enriched in vitro-expanded tumour-infiltrating lymphocytes (TILs).6 This strategy, dubbed NeoScreen, is based on the early exposure of patients’ tumours to private sets of selected neoantigens loaded on competent autologous B cells. NeoScreen demonstrated a considerable enrichment in neoepitope-specific T cells by several orders of magnitude and increased by threefold the breadth of tumour antigens found with conventional methods, thus enabling the sensitive identification of rare patientspecific neoantigens. By increasing the frequency of existing tumour-specific T-cell receptor (TCR) clonotypes but also by recruiting additional clonotypes that can be newly detected with markedly enhanced sensitivity, NeoScreen

/pdf/towards-next-generation-til-therapy-tils-enriched-in-1f274l65.pdf

Towards next‐generation TIL therapy: TILs enriched in neoepitope‐specific T cells

Peptide major histocompatibility complex (pMHC) multimers have been used since decades to identify, isolate and analyze antigen-specific T cells by flow (and more recently mass) cytometry. Yet well established as a standard technology, improvements are still required to face the growing needs of personalized immune monitoring. Here we review the latest developments about (i) the quality of pMHC class I and II monomers, (ii) the importance of the multimeric scaffold, (iii) the staining conditions and (iv) the high-throughput synthesis of pMHC monomers. Finally, innovative multiplexed, combinatorial strategies for parallel detection of antigen-specific T cells in a single sample are discussed.

High-throughput identification of human antigen-specific CD8+ and CD4+ T cells using soluble pMHC multimers.

Dendritic cells are the most efficient antigen-presenting cells. They capture, process and present antigens to T cells, thus initiating specific immune responses. Taking into account this capability, dendritic cells have been proposed as therapeutic agents against tumors. In recent years other properties of dendritic cells have surfaced. In particular, dendritic cells have been shown to have immunosuppressive properties in some settings and were also capable of inducing proliferation of regulatory T cells. Moreover, it has been shown that dendritic cells are able to generate angiogenic factors and might be able to participate in the angiogenic process. Thus, for tumor therapeutic purposes, further studies on the biology of dendritic cells are necessary in order to generate cells with optimized immunogenic properties, but avoiding a pro-angiogenic profile.

Dendritic Cells: From Inducers of Specific T-Cell Responses to Promoters of Angiogenesis

Adoptive immunotherapy offers opportunities to reprogram T cells and the tumor microenvironment. Orthogonal engineering of adoptively transferred T cells with an IL-2Rβγ-binding IL-2 variant, PD1-decoy and IL-33 led to cell-autonomous T-cell expansion, T-cell engraftment and tumor control in immunocompetent hosts through reprogramming of both transferred and endogenous CD8+ cells. Tumor-infiltrating lymphocytes adopted a novel effector state characterized by TOX suppression and specific expression of multiple effector molecules, most prominently granzyme C. While the IL-2 variant promoted CD8+ T-cell stemness and persistence, and was associated with downregulation of TOX, the combination with IL-33 was necessary to trigger the novel polyfunctional effector state. Rational T-cell engineering without host lymphodepletion enables optimal reprogramming of adoptively transferred T cells as well as mobilization of endogenous immunity into new functional CD8+ states mediating tumor control.

George Coukos

Papers

Successful engineering cancer immunotherapy

Towards next‐generation TIL therapy: TILs enriched in neoepitope‐specific T cells

High-throughput identification of human antigen-specific CD8+ and CD4+ T cells using soluble pMHC multimers.

Dendritic Cells: From Inducers of Specific T-Cell Responses to Promoters of Angiogenesis

Orthogonal Gene Engineering Enables CD8+ T Cells to Control Tumors through a Novel PD-1+TOX-indifferent Synthetic Effector State