Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8+CCR9+ naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8+ T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches.
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PMID:Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma. 2685 30

Immune surveillance plays a critical role in preventing the development and progression of cancer. Immune modulators, such as interferon-gamma or interleukin-2, have been a part of the cancer treatment armament over the past few decades. However, new understandings regarding the role of the costimulatory and coinhibitory molecules associated with T-cells and antigen-presenting cells as well as tumor necrosis factor receptors and ligands have ushered the new era of immunotherapy for cancer treatment. We now know that primary cancer cells evade screening by the innate immune system, proliferate, and form metastases by upregulating immune inhibitory pathways referred to as immune checkpoints. The recent development of therapies that target immune checkpoints, such as cytotoxic T lymphocyte antigen 4, programmed cell death 1, programmed cell death ligand 1, indoleamine 2,3-dioxygenase, T-cell immunoglobulin and mucin domain 3, and lymphocyte activation gene 3 precisely target the immune system and give new hope for treating various types of cancer. In select marker-enriched populations, immunotherapies provide high response rates as well as durable responses in terms of progression-free survival and overall survival. Numerous factors, such as patient's immune system, the expression of targets on both immune and cancer cells, maintenance of an effective drug exposure, and tolerability to these agents may play a role in this unique observation.
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PMID:Role of Clinical Pharmacology in the Development and Approval of Immunotherapies Targeting Immune Checkpoints. 2750 Aug 94

Small-cell lung cancer (SCLC) is distinguished from non-small-cell lung cancer by its rapid growth and more frequent metastases. Although patients with SCLC are highly responsive to chemotherapy and radiation therapy, long-term prognosis remains poor, with relapse and disease recurrence occurring in almost all cases. Whereas combination chemotherapies continue to be the standard of care in extensive-stage SCLC, there is value in exploring whether immune-checkpoint inhibition is an effective treatment strategy, given the durable responses in non-small-cell lung cancer. Data from SCLC trials have shown clinical activity and response to cytotoxic T-lymphocyte antigen-4 protein and programmed cell death-1 blockade, suggesting that antibodies targeting these pathways may be effective in improving survival outcome. However, data on clinical activity by programmed cell death-1 ligand expression in SCLC are not widely available. Limited data indicate that programmed cell death-1 ligand expression may not be an ideal biomarker for patient selection. Continued research is necessary to better optimize patient selection and response to therapy.
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PMID:Recent Advances and Future Strategies for Immune-Checkpoint Inhibition in Small-Cell Lung Cancer. 2752 Jun 30

A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours.
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PMID:Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy. 2776 31

Despite the success of anti-programmed cell death protein 1 (PD1), anti-PD1 ligand 1 (PDL1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA4) therapies in advanced cancer, a considerable proportion of patients remain unresponsive to these treatments (known as innate resistance). In addition, one-third of patients relapse after initial response (known as adaptive resistance), which suggests that multiple non-redundant immunosuppressive mechanisms coexist within the tumour microenvironment. A major immunosuppressive mechanism is the adenosinergic pathway, which now represents an attractive new therapeutic target for cancer therapy. Activation of this pathway occurs within hypoxic tumours, where extracellular adenosine exerts local suppression through tumour-intrinsic and host-mediated mechanisms. Preclinical studies in mice with adenosine receptor antagonists and antibodies have reported favourable antitumour immune responses with some definition of the mechanism of action. Currently, agents targeting the adenosinergic pathway are undergoing first-in-human clinical trials as single agents and in combination with anti-PD1 or anti-PDL1 therapies. In this Review, we describe the complex interplay of adenosine and adenosine receptors in the development of primary tumours and metastases and discuss the merits of targeting one or more components that compose the adenosinergic pathway. We also review the early clinical data relating to therapeutic agents inhibiting the adenosinergic pathway.
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PMID:Targeting immunosuppressive adenosine in cancer. 2916 46

Monoclonal antibodies that block the programmed death-1 (anti-PD-1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4) immune checkpoint receptors (pembrolizumab, nivolumab, ipilimumab, or the combination of nivolumab with ipilimumab) are approved treatment option for patients with advanced melanoma. Over half of all patients are refractory to these immunotherapies and are in need of alternative or complementary treatment options. Talimogene laherparepvec (T-VEC) is a first-in-class intralesionally delivered oncolytic immunotherapy, which has proven efficacy in the treatment of advanced melanoma. A proportion of patients treated with T-VEC will benefit from an abscopal response of noninjected metastases indicative of a systemic antitumor immune response elicited by the intratumoral injections. At present it remains unknown whether the systemic antitumor responses elicited by T-VEC are nonredundant with immune-checkpoint blockade. Recent data on potential synergy between T-VEC and both PD-1 and CTLA-4 blockade suggest that the mechanism of action may be complementary. We report on the successful treatment with intralesional T-VEC of two female patients with locoregionally advanced BRAF V600 wild-type melanoma who previously progressed on anti-PD-1 and anti-CTLA-4 inhibitors.
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PMID:Successful treatment with intralesional talimogene laherparepvec in two patients with immune checkpoint inhibitor-refractory, advanced-stage melanoma. 3021 12

Intracardiac metastases in the absence of inferior vena cava involvement is a rare occurrence in patients with metastatic renal cell carcinoma (mRCC). There is limited evidence regarding the efficacy and safety of standard treatment modalities for mRCC patients with intracardiac metastases. Presence of intracardiac metastases is known to indicate poor prognosis and may potentially increase risk of treatment-related complications. Recent advances in RCC management have integrated nivolumab, a programmed death-1 (PD-1) receptor inhibitor, as a preferred treatment option in the second-line setting after failure of prior anti-angiogenic therapy; or in combination with ipilimumab, an anti-Cytotoxic T-lymphocyte antigen-4 antibody as first-line therapy for intermediate to poor risk patients with mRCC. The efficacy and toxicity of nivolumab in patients with mRCC and intracardiac metastases has never been reported previously. We herein present the first reported case of mRCC with intracardiac metastasis and a resultant excellent response to nivolumab treatment and discuss the imaging techniques and treatment options for this rare presentation.
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PMID:Rare Case of Intracardiac Renal Cell Carcinoma Metastasis with Response to Nivolumab: Case Report and Literature Review. 3068 63

Until immunotherapy was developed, a diagnosis of metastatic melanoma was most often fatal. Programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies have been shown to work synergistically to treat metastatic disease throughout the body and brain. Today, over half of patients diagnosed with stage IV disease are alive after 3 years. In the adjuvant setting, 70% patients remain disease free with PD-1 blockade after 1 year. These treatments are generally safe and well tolerated. However, treatment-related endocrinopathies require long-term medications. With better therapies producing more durable responses, advanced cutaneous melanoma is dramatically more manageable now than ever before.
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PMID:Revolutionizing treatment of advanced melanoma with immunotherapy. 3069 91

The common adverse effects of immune checkpoint blockade therapy are well recognised. However, neurological adverse effects of checkpoint inhibitor therapy are less widely appreciated, and their clinical management remains challenging. Therefore, we report our experience of managing acute, life-threatening neurological toxicity during immune checkpoint inhibitor therapy. Five male patients with stage IV melanoma underwent anti-programmed cell death protein 1 therapy (monotherapy or combination therapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies) and developed severe neurological symptoms and signs including headache, hemiparesis and dysarthria. The initial diagnosis of brain metastases actually occurred after initiation of checkpoint inhibitor therapy in three of the patients, whereas two patients had pre-existing central nervous metastases and developed cerebral oedema and haemorrhage during immunotherapy. A rapidly fatal outcome occurred in two patients treated with immunotherapy following the development of BRAF-inhibitor and MEK-inhibitor resistance. Four of the patients died owing to neurological complications, and one achieved a complete cerebral response. Immunotherapy and tumour progression can both result in the development of neurological symptoms and signs, making it difficult to determine causality. However, the temporal relationship between the development of neurological symptoms and the first administration of therapy means that patients should be closely monitored for the development of neurological sequelae, which may even herald the presence of occult brain metastases. The decision on whether to continue immunotherapy must balance the risks of symptom - versus disease progression. However, in our case series, it is encouraging to note that the initial acute neurological symptoms were often transient. Nevertheless, pretherapeutic brain imaging to exclude occult brain metastases and stratify the risk of intracerebral oedema and haemorrhage should be considered.
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PMID:Acute neurological adverse events during immune checkpoint inhibition therapy in patients with melanoma brain metastases. 3087 Feb 72

Effective therapeutic strategies to precisely eradicate primary tumors with minimal side effects on normal tissue, inhibit metastases, and prevent tumor relapses, are the ultimate goals in the battle against cancer. We report a novel therapeutic strategy that combines adjuvant black phosphorus nanoparticle-based photoacoustic (PA) therapy with checkpoint-blockade immunotherapy. With the mitochondria targeting nanoparticle, PA therapy can achieve localized mechanical damage of mitochondria via PA cavitation and thus achieve precise eradication of the primary tumor. More importantly, PA therapy can generate tumor-associated antigens via the presence of the R848-containing nanoparticles as an adjuvant to promote strong antitumor immune responses. When combined with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4, the generated immunological responses will further promote the infiltrating CD8 and CD4 T-cells to increase the CD8/Foxp3 T-cell ratio to inhibit the growth of distant tumors beyond the direct impact range of the PA therapy. Furthermore, the number of memory T cells detected in the spleen is increased, and these cells inhibit tumor recurrence. This proposed strategy offers precise eradication of the primary tumor and can induce long-term tumor-specific immunity.
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PMID:Photoacoustic-immune therapy with a multi-purpose black phosphorus-based nanoparticle. 3290 46


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