Immune checkpoint blockade in hematologic malignancies. Upon further investigation, they were able to show that androgen receptor engagement inhibits CD8+ T cell production of IFN. They also support the notion that hormones contribute to sex bias in cancer, and should be more thoroughly considered for their contributions to differential responses to immunotherapy. Interestingly, the patient experienced ICANS on this recent round of treatment. 24. Cooper DS, Meriggioli MN, Bonomi PD, Malik R. Severe exacerbation of myasthenia gravis associated with checkpoint inhibitor immunotherapy. One approach is diagnostic testing. The site is secure. To determine what might be sufficient for CAR T cell activation, they replaced the CD3 chain and costimulatory regions with these proximal signaling molecules. Immune Checkpoint Therapy as a Weapon against Cancer - PMC When mice treated with wild-type T cells were started on ENZA halfway through infection, reflecting a more realistic disease treatment setting, an intermediate result was observed. A large Phase III trial has been launched with a primary endpoint of overall survival. Therefore, ICIs were considered a novel treatment option in 2011 with the approval of ipilimumab [ 14 ], revolutionizing cancer treatment. Vitiligo is an AE that is directly related to antitumor responses through the antitumor T cells in the skin, with lots of supporting evidence. CISH knock out in T cells increased PD-1 expression and the adoptive transfer of CISH knock out T cells synergistically combined with PD-1 antibody blockade resulting in durable tumor regression and survival in a preclinical animal model. In patients with melanoma treated with ipilimumab, the presence of irHypophysitis was associated with better outcomes, and treatment with high-dose steroids for the irHypophysitis mitigated outcomes. eCollection 2022. Accessibility Immune Checkpoint Inhibitors in Cancer Therapy - PubMed This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical . Before Immune Checkpoint Blockade in Cancer Therapy. Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. Learn more about Mailchimp's privacy practices here. In this model, 2-HC-activated TCR-T cells yielded a dramatic change in cell neighborhoods, with a significant increase in the size and breadth of distribution of productive interaction zones between tumor cells and TCR-T cells, while for canonically activated cells, such zones were more sparsely distributed. Building 9, Jing Dongbei Technology Park, No.18 Kechuang 10th St, BDA, Beijing, 100176, P.R.China, Pennsylvania Office: 1400 Liberty Ridge Drive, Suite 101, Wayne, PA 19087, Texas Office: 10101 Southwest Freeway, Suite 100. PSAT342 Hypothyroidism After Use Of Immune Checkpoint Inhibitor Therapy There are at least 3 broad possible ways to approach combination for immune checkpoint therapy in cancer. Many factors will affect the risk of IMDC, including the type of ICI used, the type of underlying cancer, and patient characteristics. In males, a Tcf7 transcription program drove the T cell exhaustion. Multiple markers were found to be upregulated and downregulated in these zones, and given the thousands of interactions (experiments) analyzed, rules for how cells change in the presence of other cells could be inferred and used to construct and compare tissue structures. PD-1, like CTLA-4, has two ligands, PD-L1 and PD-L2, which are expressed on many cell types. Trials targeting particular immune modulators such as TNF or IL-6, rather than using broadly active immunosuppressants such as corticosteroids, are underway as novel attempts to balance benefit and toxicity. Ann Intern Med. The first patient, CRI-3061, who had metastasis to the lung and liver, was treated with TCR-transduced T cells following lymphodepletion with cyclophosphamide and fludarabine. [23] A lower incidence of hypothyroidism was observed in a trial of combined B cell depletion and immune checkpoint inhibitor treatment compared with studies of immune checkpoint inhibitor monotherapy. Unfortunately, this patient did not achieve a clinical response by RECIST, and despite additional treatment with PD-1 blockade and chemotherapy, the patient progressed and died of disease. More importantly, a subset of patients who received ipilimumab has durable responses lasting more than a decade, which drives optimism that a cure may truly be possible. Immune Checkpoint Inhibitor Cancer Therapy: Spectrum of Imaging Smith also noted that while their research has focused on the taxa, their influence on outcomes may be more closely related to the metabolites they produce.Engineering CAR T cells for enhanced efficacy and specificity-Robbie Majzner - Stanford University School Medicine, Stanford, California.Robbie Majzners talk focused on a new approach to CAR T cell engineering. However, only a subset of patients with advanced tumors currently . An ad hoc analysis suggested a potential clinical benefit, and tumor tissues from these patients showed that a higher IFN signature was associated with partial response at the population level, but not at the individual level. #ACLC22 @IASLC #LCSM . Following treatment, this patient did not experience ICANS, and analysis showed that cytokine production spiked at day 1 in this patient, versus day 4 in the previous patient. 2018 Sep;62:29-39. doi: 10.1016/j.intimp.2018.06.001. Piecing together an AR/IFN/antigen presentation axis, Moran used TCGA data to show that increased AR activity correlated with reduced IFN pathway activity and with reduced antigen processing and presentation. Alpha diversity (diversity between taxa) at baseline was lower in patients compared to a healthy volunteer cohort, whereas the beta diversity (diversity within taxa) was much higher in patient samples, suggesting that patients with cancer are more likely to present with dysbiosis prior to therapy. Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood. HHS Vulnerability Disclosure, Help The vast majority of CAR T cell designs rely on CD3, taking advantage, albeit crudely, of TCR signaling machinery to induce T cell activity. The .gov means its official. Abstract. In vivo, the ZAP70 CAR dramatically outperformed a 4-1BB CAR, inducing complete tumor clearance and cures in several models, likely due to enhanced proliferation and persistence. The future of immune checkpoint therapy. However, the ZAP70 CARs showed reduced tonic signaling and induced fewer exhaustion markers, including Lag3, Tim3, and PD-1. immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy. 8600 Rockville Pike Antigens work like a mask to hide cancer cells from the immune system. This program is designed to raise awareness and close knowledge gaps for medical oncologists, surgeons, dermatologists, oncology nurses, and oncology pharmacists regarding the expanding use of ICIs to treat patients with melanoma. Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy Accumulating evidence suggests that as a molecular imaging modality, positron emission tomography/computed tomography (PET/CT) can play a vital role in the management of ICIs therapy by using different molecular probes . 2022 Aug 31;27(17):5607. doi: 10.3390/molecules27175607. Immune checkpoint inhibitors (ICIs)-anti-programmed death-1 (PD-1) and their ligands (PD-L1 and PD-L2) have become widely used in the treatment of several malignancies. CC is also known as T-cell inflammatory cancer. An official website of the United States government. Personalization of neoadjuvant immunotherapy can occur at multiple time points prior to, during, or after therapy, including looking for baseline markers prior to treatment, making on-treatment therapy adjustments based on pathological analysis of the resected tumor, or performing risk-adapted follow-up. This site needs JavaScript to work properly. 31 Oct 2022 12:23:02 Immune checkpoint inhibitors in advanced and recurrent/metastatic The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. In this setting, transferred antigen-specific T cells with the AR CRISPRd out were maintained at higher levels and resisted exhaustion, producing IFN at higher levels than their wild-type counterparts. Nolan first focused on what happens at boundary areas between cell types to understand how the phenotype of the cells changed when interacting in these perturbation zones. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor. In this context, immunotherapy and immune checkpoint inhibitors (ICIs) are particularly likely to play a role in the treatment of cervical tumors in a variety of disease settings. In TCR signaling, multiple ITAM-containing domains within the TCR, the most important of which are in CD3, are phosphorylated by the kinase LCK, allowing for the ZAP70 kinase to come in and dock on the phosphorylated ITAMs, become activated, and go on to phosphorylate LAT and SLP76. Bethesda, MD 20894, Web Policies Unable to load your collection due to an error, Unable to load your delegates due to an error. Immune checkpoints are regulators of the immune system. In the past decade we also witnessed a paradigm-shift in cancer immunotherapy as we learned to unleash anti-tumor immune responses to eradicate tumors. Immune checkpoint blockade therapy - PubMed Nolan speculated that cancers may be attracted to or excluded from certain lymphatic structures due to unique permissive or non-permissive rule sets. Bethesda, MD 20894, Web Policies Robust prediction of response to immune checkpoint blockade therapy in Evaluating the role of the cytokine cocktail versus IL-2, the researchers found that T cells manufactured in the cocktail showed a more tissue-resident memory-like phenotype, preservation of markers of a less differentiated T cells, more effector cytokine production, and increased in vitro killing at low effector:target cell ratios compared to T cells manufactured with IL-2 alone. Two inhibitory molecules, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers. Biomarkers in immune checkpoint inhibition therapy for cancer patients Opportunistic infections are not included in typical databases of immune-mediated causes of death and thus may be underrecognized. Surgically related morbidities were all reduced, and quality of life markers were improved when TLND was not required. In more recent clinical data, higher alpha diversity has been associated with favorable effector:target ratios. METHODS This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. LRRC15+ fibroblasts are enriched in active fibrotic lesions of Idiopathic pulmonary fibrosis lungs and in sites of active fibrosis in human Crohns disease.Sex bias and cancer immunotherapy: Time has come-Zihai Li - The Ohio State University, Pelotonia Institute for Immuno-Oncology, Columbus, Ohio.Zihai Li highlighted sex as an important biological determinant in cancer immunology and how sex bias suppresses T cell immunity and immune tolerance. 2019 Apr 15;115(5):869-877. doi: 10.1093/cvr/cvz025. Finally, Sharma described a pilot safety trial in stage 4 metastatic clear cell renal cell carcinoma (ccRCC) in which immune checkpoint blockade prior to debulking surgery of a larger lesion (or lesions) provided good safety data. LRRC15+ CAF depletion potentiated antitumor immunity in response to anti-PD-L1 checkpoint blockade in subcutaneous and orthotopic settings. What is Immune Checkpoint | Sino Biological The 2022 Updated European Association of Urology Guidelines on the Use of Adjuvant Immune Checkpoint Inhibitor Therapy for Renal Cell Carcinoma https://buff.ly/3TGTca5 @AlbigesL @u_capitanio @milanhoraplzen @Lorenzo_marconi @Dr_Klatte @foxal72 @Yasminabugh @tompowles1 . Knockout of PKC in the bone marrow of mice was found to improve tumor control, and further investigation revealed that while priming and early recruitment remained unchanged in PKC knockouts, there was an increase in activated T cell accumulation over time, a shift from an M2-like to an M1-like macrophage phenotype, and a beneficial change in neutrophil subsets. Interestingly, irPneumonitis appears more common in diseases associated with chronic lung injury and tobacco use, suggesting criticality of other factors. Houston, TX 77074, Dsseldorfer Str. In a BRCA/P53-deficient tumor model, anti-CSF-1R enhanced PARP inhibitor efficacy in a CD8+ T cell-dependent manner and overcame resistance to PARP inhibition. The discovery of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 represents a significant breakthrough in the field of cancer immunotherapy. Zev Wainbergs talk summarized approaches targeting the production and activity of the broadly immunosuppressive molecule adenosine. By blocking them, these drugs allow immune cells to respond more strongly to cancer. Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. However, clinical trials combining PARP inhibitors with ICB failed to demonstrate superior activity compared to PARP inhibitor monotherapy. Cancers | Free Full-Text | Immunotherapeutic Approaches for Treating A major (mPR) or a partial pathological response (pPR) at 6 weeks (after ipi/nivo neoadjuvant therapy) is a strong predictor of good overall survival, with weak responses indicating poor outcomes. MeSH BRCA1-associated triple-negative breast cancers (TNBC) have higher levels of cytosolic DNA and an active STING pathway, and are highly infiltrated with macrophages and T cells. Males also have higher mutational burdens and mortality across several cancers. Immune checkpoint blockade (ICB) therapy provides remarkable clinical gains and has been very successful in treatment of melanoma. Further evaluation confirmed that exposure to P-I-M was not merely a surrogate for sicker patients, as exposure to cefepime, a broad-spectrum antibiotic given to similarly sick patients, was not associated with worse progression-free or overall survival, while piperacillin/tazobactam exposure was. As is true of other types of immunotherapies, checkpoint inhibitor therapy attempts to tweak your body's natural immune system to improve its ability to fight off infections and diseases. Li defined sex as a biological determinant based on anatomy, sex chromosomes, sex hormones, and their interactions, as opposed to gender, which is a social and behavioral determinant. Among PD-L1 functions is a key regulatory role on T cell activities. The side effects you may have and how they make you feel will depend on how healthy you are before treatment, your type of cancer, how advanced it is, the type of immune checkpoint inhibitor you are receiving, and the dose.. Doctors and nurses cannot know for sure when or if side effects will occur or how . Checkpoint inhibitor therapy is a form of cancer immunotherapy. Drugs that inhibit checkpoint antigens effectively unmask cancer cells, allowing the . This approach has been demonstrated in murine models, which showed that survival was dependent on NK, CD4+ T, and CD8+ T cells and on IFN signaling and perforin production. Blank then described assays to identify compounds that enhance cross-presentation, as well as the use of IL-2 to improve anti-PD-1 responses, which was identified in the work of Daniella Thommen using patient-derived tumor fragments. While clinical trials demonstrated benefits of ICIs over chemotherapy, variation in outcomes across patients has been observed and trial populations may not be . T cell therapiesEric TranMelody SmithRobbie MajznerTumor microenvironmentZev A. WainbergGarry P. NolanZihai LiShannon J. TurleyAmy MoranMyeloid cellsJennifer L. GuerrieroThomas F. GajewskiCheckpoint therapyRyan J. SullivanPadmanee SharmaChristian Blank. Data in a high-dose IL-2 trial also led to the conclusion that steroid treatment eliminated treatment efficacy. Immune Checkpoint Inhibitors: Mesothelioma Immunotherapy Careers, The publisher's final edited version of this article is available at. In particular, the combination therapy with atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) significantly improved survival benefits compared with sorafenib as a single agent, a finding that has stimulated . Using an in vivo genetic approach, Turley and colleagues further demonstrated that universal Dpt+ fibroblasts gave rise to LRRC15+ CAFs in a TGFBR2-dependent manner in PDAC. PARP inhibition directly modulated human macrophages, leading to differentiation of CD14+ monocytes into macrophages with increased expression of CSF-1R ex vivo. In mice with bone tumors, the combination of anti-CTLA-4 and anti-TGF led to an increase in Th1 CD4+ T cells, clonal expansion of CD8+ T cells, tumor regression, and improved survival. The .gov means its official. Some cancers can protect themselves from attack by stimulating immune checkpoint targets. doi: 10.1053/j.gastro.2017.06.017. Another approach may be more aggressive tapering (kidney nephritis as an example). In addition to cancer, LRRC15+ fibroblasts were found to emerge in multiple human inflammatory diseases, including pulmonary fibrosis, COVID19, ulcerative colitis, and rheumatoid arthritis. The future of immune checkpoint therapy | Science Single-cell RNAseq data analysis of day 10 MB49 tumors showed that androgen-responsive genes were expressed in progenitor-exhausted CD8+ T cells; this was further confirmed across multiple datasets. This therapy is now built into a neoadjuvant trial in melanoma. To understand the role of TGF-activated fibroblasts in lack of response to ICB, Turleys team analyzed the stromal compartment of pancreatic ductal adenocarcinoma (PDAC) a highly aggressive and treatment-refractory disease in which fibroblasts and TGF are implicated in tumor progression. Here, anti-PD-1 monotherapy showed a pCR rate of 25%, while the combination of anti-PD-1 and anti-CTLA-4 showed a pCR rate of 45%, showing the potential benefit of combination therapy. This is well supported by deep epidemiological evidence of higher rates of autoimmunity in females, and higher rates of cancer and cancer mortality in males for a number of cancer types not associated with reproduction. For example, individual lymph nodes and tonsils were examined, and although there were some key, perhaps primordial, rules that were similar among all such lymphatic tissues, a number of differences were found, likely reflecting tissue specificity. Single-cell RNAseq and proteomic analysis of PARP inhibitor-treated macrophages revealed that these macrophages were dependent on lipid metabolism. In this setting, more tissue can be obtained for analysis and interventions may be attempted before the major immunosuppressive mechanisms set in with metastatic disease. Approves an Immunotherapy Drug for Bladder Cancer", "Enrolling the immune system in the fight against cancer", "International Nonproprietary Names for Pharmaceutical Substances (INN)", "Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance", "The Cish SH2 domain is essential for PLC-1 regulation in TCR stimulated CD8+ T cells", "Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade", "The effects of B cell depletion on immune related adverse events associated with immune checkpoint inhibition", "Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in immune checkpoint blockade treatment of metastatic melanoma", "Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients", https://en.wikipedia.org/w/index.php?title=Checkpoint_inhibitor&oldid=1106910644. will also be available for a limited time. In order to enhance the response rate of immune-checkpoint blockade . However, many of the antibiotics that were evaluated in this cohort had a limited effect on the intestinal microbiome, so Smith decided to look more closely at stronger antibiotics that targeted obligate anaerobes, which were classified as P-I-M. Another observation in this study was that patients with bone metastases were less responsive to immune checkpoint blockade than patients with soft tissue metastases. A2AR & A2BR: The Adenosine A2A receptor is regarded as an important checkpoint in cancer therapy because adenosine in the immune microenvironment, leading to the activation of the A2a receptor, . Management of Immune-Related Adverse Events in Patients Treated With CME: Integrating Immune Checkpoint Therapy Into the Management of In a study in metastatic gastric cancer combining CTX030 with chemotherapy and an anti-PD-1 antibody (budigalumab), the response rate was perhaps higher compared to prior studies without CTX030, but again there was the suggestion that patients with low PD-L1 expression may benefit more, particularly regarding durability, and could be a targeted population. Blocking immune checkpoints is also efficient in non-small-cell lung cancer, renal cell cancers, hypermutated gastrointestinal cancers, and others. These checkpoints are a normal part of the immune system and keep immune responses from being too strong. metastatic melanoma, non-small cell lung cancer, head and neck cancer, Hodgkin's lymphoma, urothelial carcinoma, Merkel cell carcinoma, urothelial carcinoma, renal cell carcinoma, non-small cell lung cancer, small cell lung cancer, This page was last edited on 27 August 2022, at 03:32. Jennifer Guerriero described how macrophages are heterogeneous and highly abundant in a majority of solid tumors, and a high density of macrophages is associated with poor prognosis and resistance to chemotherapy. During tumorigenesis, tumor cell-derived factors recruit monocytes into the tumors, where they differentiate into tumor-associated macrophages (TAMs). As explained by Christian Blank, neoadjuvant immunotherapy aims to utilize checkpoint blockade while significant tumor tissue is still present to provide a greater antigen source for T cell expansion than the limited micrometastases present after surgical removal of the tumor. Altering the hinge and transmembrane domain regions between constructs (CD28 and CD8) to prevent homodimerization, and introducing 2CA mutations into the CD28 transmembrane domain to prevent heterodimerization both helped to clean up the system, but some leakiness persisted. 40, 65760 Eschborn, Germany, 213-00123-2-1 KSP2Tech-Pot, 2007-2022 Sino Biological, Inc. All rights reserved, SARS-CoV-2 Prefusion Trimeric Spike Variant, Immunodetection for Pan Influenza NP Antigens, Common Cytokine Receptor Signaling Pathway, Nanobodies: An Important Tool for the Next Generation of Tumor Diagnostics and Therapeutics, Universal Vaccine Advancement through AI and Recombinant Technology, ExpertAnswers: Yuning Chen on Antibody Production, Industry Insights with Yuning Chen on Recombinant Proteins, Sino Biological Europe: A New Face in the European Life Science Market, Producing Challenging Proteins in the Golden Age of Protein Engineering, Free Sample of Premium Quality Cytokines and Growth Factors, Special Offer: Custom Recombinant Antibody Production Service, Immune checkpoint therapy-adverse effects, Immune checkpoint blockade: blocking antibodies. 8600 Rockville Pike In a trial in lung cancer, anti-PD-1 and anti-CTLA-4 led to a number of major pathological responses (mPR). Focusing on CD4+PD-1+ cells, which are known to be predictive of outcome, Nolan found that the location of such cells was predictive only when in association with granulocytes. Atezolizumab, avelumab and durvalumab are immune checkpoint inhibitors that block PD-L1 and are used to treat several cancer types, including: Bladder cancer. Programmed cell death-1 (PD-1) was shown in 2000 to be another immune check-point that limits the responses of activated T cells (20). As a result, clinical trials ensued and the first FDA-approval of a drug to help . However, compensatory inhibitory pathways, such as VISTA and PD-L1 (expressed in CD68+ macrophages with mutual exclusivity) were upregulated in these tumors as well. Similarly, the establishment of a cancer Moon Shots Program, first at the University of Texas MD Anderson Cancer Center in 2013 by Dr. Ron DePinho, and now a Cancer Moonshot on a national level as called for by President Obama and Vice President Biden, provides an opportunity to take a giant leap forward by applying cutting-edge science and technology in our fight against cancer. In untargeted effect size analysis, Ruminococcus, Bacteroides, and Faecalibacterium were associated with day 100 complete responses, while Akkermansia was the top enriched dominant taxon in these patients . Fundamental Mechanisms of Immune Checkpoint Blockade Therapy The emergence of tumor-infiltrating lymphocytes in nasopharyngeal carcinoma: Predictive value and immunotherapy implications. Immune Checkpoint Inhibitors (ICIs) ICIs are cancer immunotherapies that boost anti-cancer immune responses by targeting immunologic receptors on the surface of T-lymphocytes ( Table 1) [ 13 ]. Advantages of Immune Checkpoint Therapy | Sino Biological In particular, the SREBP1-mediated fatty acid synthesis pathway was shown to be associated with pro-tumor macrophages. To check if the failure of ICB in this TNBC clinical trial was due to the high number of macrophages in the TNBC TME, Guerriero and colleagues analyzed macrophages in BRCA/P53-deficient GEMM after PARP inhibitor treatment and found increases in suppressive tumor macrophages. 4. Interestingly, rather than preventing LAT and SLP76 from interacting, interrupting GADS instead led to a completely clean system, with no response to single antigen-expressing cells, but robust killing of dual antigen-expressing targets. T-cell transfer therapy, which is a treatment that boosts the natural ability of your T cells to fight . An official website of the United States government. Ryan Sullivan presented his thoughts on how to uncouple antitumor immunity from immune toxicity following immunotherapy, and began by discussing a case study of a melanoma patient who developed a late brain recurrence, presumably from an initial skin lesion 10 years earlier. Immune checkpoint inhibitor monotherapy is associated with less cardiac It addresses investigational neoadjuvant and adjuvant therapy with ICIs, especially in the earlier stages of the disease. An unexpected role for androgens in limiting cancer immunotherapy efficacy-Amy Moran, Oregon Health & Science University, Portland, Oregon. Jim Allison's seminal paper on immune checkpoint therapy was published in 1996, which demonstrated that blockade of a T cell inhibitory pathway, CTLA-4, could lead to enhanced anti-tumor immune responses and tumor rejection with long-term survival of mice. Inhibition of CTLA-4 or PD-1 was first studied in and approved for patients with metastatic melanoma. Breast Cancer Res Treat. Further evidence of this can be found in patients that saw reversal of immune toxicity following fecal microbiome transplant from healthy donors. Investigating this, Sharma and others found that soft tissue metastases show increased Th1 and INF responses, while bone metastases show increased Th17 responses. Looking at clinical responses to PD-1 checkpoint blockade in patients with advanced prostate cancer who were progressing on ENZA, Moran and colleagues found that patients had differential responses. For example, the first neoadjuvant clinical trial of anti-CTLA-4 in patients with bladder cancer (n=12), done in 2006 (prior to FDA approval), provided important safety data and signals of clinical efficacy.