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PD-L1 - Wikipedia checkpoint inhibition doesn't selectively target cancer cells. Rather, targeting PD-L1 with a PD-L1-specific monoclonal antibody (mAb) prevents it from engaging with its ligand, PD-1 (Programmed cell death protein 1 - Wikipedia), a cell-surface molecule largely, though not exclusively, expressed on the surface of immune cells such as T (both CD4 and CD8), B, NK (Natural Killer) T cells, monocytes and some DCs (dendritic cells) (1, 2).PD-L1 and PD-L2 are expressed on the cell-surface of a much wider variety of cells, being reported not just on T and B cells but also endothelial and epithelial cells, heart, lung, skeletal muscle, placenta, among others (2, 3). PD-L1 became relevant for cancers when multiple studies reported (3)Its high level expression by many types of cancers such as Breast, Cervix, Colon, Esophagus, Liver, Lung, Kidney, Ovary, Pancreas, Skin.Its expression by tumors correlated with poorer patient prognosis.At the same time, multiple studies also correlated high PD-1 expression levels on Tumor-infiltrating lymphocytes - Wikipedia (TILs) with poor prognosis of cancer patients as well as poor effector function (anti-tumor activity) of such TILs in in vitro studies (3).High PD-L1 expression on tumor cells is considered a tumor adaptation attempting to thwart effective anti-tumor immune responses by inhibiting PD-1-expressing TILs. Persistent T cell expression of PD-1 is interpreted as a sign of T cell exhaustion, a colorful description signifying the cell is or has become poorly capable of performing its antigen-specific effector functions.In the case of helper CD4 T cells, PD-1 expression implies poor capacity to help B and cytotoxic CD8 T cells perform their effector functions.In the case of cytotoxic CD8 T cells, PD-1 expression implies poor capacity to kill their target cells.The hope behind PD-L1 or PD-1 blockade is doing so would release from inhibition PD-1-expressing cancer-specific T cells present in the tumor (and maybe even anywhere else in the body), and thus render them capable of attacking and ridding of the tumor since blocking PD-1-PD-L1 engagement was found to reverse lymphocyte effector function inhibition, at least in preclinical (mouse model) studies.Ideally, the most optimal cancer immunotherapy approach would be cancer antigen-specific since they would likely be those with minimal collateral cost. For example, where an immune cell, say a cytotoxic CD8 T cell specific for a cancer cell antigen, bound its target antigen on the surface of a cancer cell and killed it.Obviously, PD-L1 or PD-1 blockade is a very different process, affecting not just tumor antigen-specific lymphocytes but others as well so it's not surprising to note then that it specifically and checkpoint inhibitors in general have at least two major drawbacks.They are not antigen-specific in the strict immunological sense, i.e., they do not target an antigen expressed only by the tumor but not by healthy cells. Thus there is scope for off-target effects (4), meaning attack on non-tumor tissue(s) as well. The hope there is that careful application of blockade dose and frequency would help focus the Rx more to cancer cells and help mitigate targeting of healthy tissue cells.Tumor-infiltrating and therefore presumably tumor-specific T cells could express not just PD-1 but multiple cell-surface inhibitory receptors such as LAG3 - Wikipedia (5) and TIM-3 (HAVCR2 - Wikipedia) (6). Blocking PD-1 alone on such T cells might not suffice to reverse their inhibition. May need to block these other inhibitory molecules as well.PD-L1 blockade also suffers from an additional drawback, namely, the lack of reliable identification, which means lack of reliable targeting. Identification of PD-L1 expressing cells was mired in technical difficulties since antibodies specific for human PD-L1 had a track record of poor validation. This made it hard to accurately and reliably ascertain whether a particular tumor sample expresses PD-L1 or not. This improved only in recent years after technically validated Immunohistochemistry - Wikipedia (IHC) assays using specific anti-human PD-L1 antibody clones such as Dako/BMS clone 28-8, Merck's mAb clone 22C3, and Ventana (Genentech/Roche) mAb clone SP142 appeared on the scene (7, 8).Bibliography1. Ishida, Yasumasa, et al. "Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death." The EMBO journal 11.11 (1992): 3887. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556898/pdf/emboj00096-0084.pdf2. Keir, Mary E., et al. "PD-1 and its ligands in tolerance and immunity." Annu. Rev. Immunol. 26 (2008): 677-704.3. Ohaegbulam, Kim C., et al. "Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway." Trends in molecular medicine 21.1 (2015): 24-33. https://pdfs.semanticscholar.org/8ff0/27fc0e5a1eded3bd4cc57850b6977e27639b.pdf4. Fay, André P., et al. "The management of immune-related adverse events associated with immune checkpoint blockade." Expert Review of Quality of Life in Cancer Care 1.1 (2016): 89-97. http://www.tandfonline.com/doi/pdf/10.1080/23809000.2016.1142827?needAccess=true5. Matsuzaki, Junko, et al. "Tumor-infiltrating NY-ESO-1–specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer." Proceedings of the National Academy of Sciences 107.17 (2010): 7875-7880. http://www.pnas.org/content/107/17/7875.full.pdf?with-ds=yes6. Du, Wenwen, et al. "TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action." International journal of molecular sciences 18.3 (2017): 645. TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action7. Herbst, Roy S., et al. "Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients." Nature 515.7528 (2014): 563. http://www.livewell-bioscience.com/uploads/2/9/4/0/29407049/2014_12_02-predictive_correlates_of_response_to_the_anti-pd-l1_antibody_mpdl3280a_in_cancer_patients.pdf8. Gandini, Sara, Daniela Massi, and Mario Mandalà. "PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis." Critical reviews in oncology/hematology 100 (2016): 88-98. https://www.researchgate.net/profile/Sara_Gandini/publication/294112615_PD-L1_expression_in_cancer_patients_receiving_anti_PD-1PD-L1_antibodies_A_systematic_review_and_meta-analysis/links/57061d9a08ae74a08e275661.pdfThanks for the R2A, Victor Lin.

Very, very different strategies to immunotherapy.CAR-T are T-cells engineered to express a chimaeric (the C) T-cell receptor onto which has been engrafted the ability to recognize a specific antigen (the A) on the tumor cells. So CAR-T is a cellular therapy.Chimeric antigen receptor - WikipediaAnti-PD-1 are antibody drugs that target as specific receptor or its ligand that are involved in immunotolerance.So in CAR-T you are introducing cells that are specifically targeting the tumor, whereas in Anti-PD-1 you are trying to generally upregulate T-cell immunity.

Yes there is. Although not common (4% at five years), it does occur. So far, I seem to be one of those. I was diagnosed with stage IV bladder cancer (with bone metastases) over two years ago and (after six months of chemotherapy and six weeks of radiation therapy (following a radical cystectomy), I have been disease free for over eighteen months (having had four clean PET scans since the end of treatment). If your father is receiving immunotherapy, he may have already failed chemo or other immunotherapy drugs, which doesn’t bode well, but there has been an explosion of new immunotherapy drugs, so there are probably still options.The standard first treatment for metastatic bladder cancer is combination chemotherapy with cisplatin and Gemcitabine for about six months. Some patients cannot take cisplatin for a variety of reasons so carboplatin may be substituted.Immunotherapy is usually used if disease persists after chemotherapy or if patients have medical reasons why they can’t have chemotherapy (renal failure, hearing loss or heart failure). Checkpoint inhibitors have shown activity in patients with metastatic bladder cancer in both the second line setting and the first-line setting (before chemotherapy).As in other areas of oncology, there are numerous immune drugs that have been recently approved.On April 17, the FDA granted approval for atezolizumab (Tecentriq) on an accelerated tract as a first line treatment for patients with locally advanced or metastatic urothelial carcinoma (the type most frequently occurring in the bladder) who are not eligible to receive cisplatin-based chemotherapy. It is an anti-PD-L1 drug.On May 1, the FDA granted approval for durvalumab (Imfinzi). It is also an anti-PD-L1 drug.May 9 , the FDA granted accelerated approval for avelumab (Bavencio). It is also an anti-PD-L1 agent.These were approved for treating patients with locally advanced or metastatic bladder cancer whose disease has progressed during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy.Pembrolizumab (Ketruda) was granted approval on May 18 for patients with locally advanced or metastatic bladder cancer who are not eligible for cisplatin-containing chemotherapy. It targets PD-1.Normally, binding of PD-L1 to PD-1 tamps down immune activity. By preventing the interaction between PD-L1 and PD-1, all four drugs can allow the immune system to be more active against tumor cells.Nivolumab (Opdivo) is another checkpoint inhibitor approved by the FDA for the treatment of patients with bladder cancer. It targets PD-1. (It is being used for a wide variety of cancers with moderate success,)For a more complete description of immune drugs for bladder cancer, see the NCI’s Immunotherapy Drugs Approved for Bladder Cancer .Localized radiation therapy is frequently used as well in Stage IV bladder cancer, both for palliation of pain and for treatment of oligometastatic disease (when there are only 1–4 sites of metastases). This may help patients have a complete response as well as killing cancer cells to spill their antigens into the blood, so the immune drugs can become even more sensitized to them.If you are interested in “No Nonsense” answers to serious medical questions, please follow me. (>400 answers on cancer, medicine and human behavior.)