Checkpoint Inhibitor Immunotherapy Research Articles

Role of checkpoint inhibitors immunotherapy in non-muscle invasive bladder cancer: current methods and future perspectives

Immuno-therapy involvement in bladder urothelial malignancies is growing very fast. The use of Immuno-therapy with check-point inhibitor has greatly developed since it was first approved as a second-line treatment for cases who had formerly failed platinum-based chemotherapy. There are recognized applications for first-line metastatic illness in platinum-ineligible or cisplatin-ineligible PD-L1 diagnosed cases, as well as a label for BCG-refractory high-risky non-muscle invasive bladder cancer (NMIBC). It is now being studied in neo-adjuvant and adjuvant muscle invasive bladder cancer (MIBC) clinical trials. This review discusses the clinical trials that led to these FDA agreements, as well as prospective and ongoing trials. Current clinical guidelines support Bacillus Calmette-Guérin (BCG) as the primary treating option for intermediate to high-risk NMIBC. Despite the intra-vesical BCG-instillation, intra-vesical relapse occurs in a considerable number of individuals with intermediate to high risk NMIBC. Furthermore, treating BCG-nonresponsive NMIBC is still difficult. For these individuals with BCG-nonresponsive NMIBC, there are no viable therapy alternatives other than radical cystectomy, which has been shown to have excellent oncological results. In this regard, for the care of BCG-nonresponsive NMIBC, safe and reliable noninvasive or lesser-invasive therapeutic alternatives with adequate oncological results are needed. Regarding the latest introduction of immuno-therapeutic medications, the treatment of progressive or metastatic urothelial cancer has substantially advanced. These developments have sparked a surge in interest in immuno-therapeutic medications for NMIBC, particularly BCG-nonresponsive NMIBC. The goal of this literature review is to provide and debate the most up-to-date information on the function of Immuno-therapy in BCG-nonresponsive NMIBC and the presently accessible treatment options. Furthermore, this page highlights the current research in this topic. We wanted to convey the current state of Immuno-therapy in NMIBC and discuss future directions.

A Multi-Institution Analysis of Relapsed Lymphoma Occurring during Pregnancy Including Pharmacokinetics with Antenatal Checkpoint Inhibitor Therapy

Introduction: Lymphoma (LYM) diagnosed during pregnancy is an uncommon occurrence. There are significant ethical and management challenges that involve maternal and fetal risks associated with delayed intervention vs antenatal therapy. Moreover, there are a scarcity of available data regarding relapsed/refractory LYM occurring during pregnancy, which may guide practitioners and patients (pts) on treatment options, prognosis, maternal complications, and fetal outcomes.Methods: We performed a detailed retrospective analysis of pts diagnosed with relapsed LYM during pregnancy 1989-2021 across 10 academic centers worldwide. Data on disease characteristics, treatment, obstetric complications and fetal outcomes were examined. Survival analyses were performed using Kaplan-Meier. In addition, via an IRB approved protocol for a pt receiving antenatal checkpoint inhibitor therapy, we analyzed blood during gestation for measurement of nivolumab (NIVO) concentrations for comparison of pt serum concentrations to expected/predicted, as well as cord blood, and placenta concentrations for NIVO. All aliquots were run on a CLIA-level certified and validated ELISA assay (range 10-250 ng/mL, with dilutions up to 1000-fold [250 ug/mL]).Results: Overall, 23 cases of relapsed LYM during gestation were identified. 18 (78%) pts had Hodgkin LYM (HL), 2 (9%) peripheral T-cell LYM, and 1 pt each diffuse large B-cell LYM, follicular LYM, and marginal zone LYM. The median age of pts at time of relapse during pregnancy was 31 years (21-35). The median time from initial LYM diagnosis to pregnancy relapse was 24 months (7-229). Overall, 19 (82%) pts were White and there was 1 each Hispanic, Black, American Indian, and Asian. At time of relapse, 3 (13%) pts had stage I, 10 (44%) stage II, 4 (17%) stage III, and 4 (17%) stage IV disease; 12 (52%) pts presented with B-symptoms. Therapy was deferred to post-partum in the majority of pts; however, 5 (22%) pts received antenatal therapy (due to tumor burden, etc) between 20-32 weeks' gestation (Table). Among these, 4 achieved a complete response (CR), with 1 pt who had antenatal progressive disease (PD) requiring change to NIVO as detailed below.This 31-year-old female presented at 13 weeks' gestation with biopsy-proven relapsed HL (6 ABVD cycles 3 years prior). By 18 weeks, her ECOG PS was 3, and she developed bulky pelvic adenopathy >10cm, and severe hypercalcemia, hyponatremia, and progressive non-hemolytic anemia (5.4 gm/dL). Modified ESHAP was started at week 19 with brisk subjective improvement and resolution of lab abnormalities; however, she had PD at week 25. Single-agent NIVO was started after counseling about potential risks/benefits. She received 240 mg IV q 2 weeks for 6 cycles (through week 37) resulting in near CR, and she delivered a healthy full-term male at 38.2 weeks. A 30-day post-partum PET confirmed CR. In addition, maternal NIVO pharmacokinetic (PK) analyses showed levels were within normal ranges based on PK simulations (Figure 1). Cord blood concentration was 64% of the maternal exposure blood level, while there was no quantifiable NIVO detected in the placental tissue.Overall, 9 (39%) pts underwent transplantation post-partum (Table). With a median follow-up of 37 months for all pts, 3-year progression-free survival (PFS) and overall survival (OS) were 33% and 90%, respectively (Figure 2). Detailed maternal and fetal outcomes were available on 22 pts (Table). Of these, there were 18 lives births with the majority having vaginal delivery. The majority of pts had clinician-initiated late preterm deliveries with a median gestational age at delivery of 36 weeks (26-39). The median birthweight was 2777 grams (740-3900), and there were no reported malformations. For maternal complications, 1 pt each had preeclampsia, endometritis, and chorioamnionitis (all pts who deferred antenatal therapy).Conclusions: To the best of our knowledge, this is the largest cohort of pts diagnosed with relapsed LYM during pregnancy to date, including the first report of a LYM pt receiving antenatal checkpoint inhibitor immunotherapy. Treatment was deferred in the majority of pts, though it was well tolerated by those who received antenatal therapy. Furthermore, there were relatively few obstetrical or fetal complications. And despite modest PFS, OS was robust. Finally, use of antenatal NIVO in one relapsed HL pt was safe, effective, and associated with expectant maternal PKs. [Display omitted] DisclosuresAhmed: Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seagen: Research Funding; Merck: Research Funding; Xencor: Research Funding. Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Farooq: Kite, a Gilead Company: Honoraria. Vose: Kite, a Gilead Company: Honoraria, Research Funding. OffLabel Disclosure:nivolumab used in 2nd-3rd trimester of pregnancy for a woman w/ Hodgkins lymphoma

319 The tumor-intrinsic NLRP3 inflammasome establishes a pulmonary metastatic niche via type II epithelial HSP70/TLR4 signaling and facilitates disease hyperprogression in response to immunotherapy

BackgroundOur understanding of those underlying mechanisms that contribute to metastatic progression in melanoma remains limited. While uncommon, melanoma hyperprogression in response to immunotherapy is likely to be an extreme form of acquired resistance. Therefore, studies that define the underlying mechanisms of these processes are expected to provide insight into the discovery of novel therapeutic targets and predictive biomarkers. We previously demonstrated that tumor-intrinsic NLRP3 drives adaptive resistance to anti-PD-1 immunotherapy (anti-PD-1) by inducing the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via the upregulation of CXCL5. Gain-of-function polymorphisms in the TLR4 gene have been associated with pulmonary metastases in melanoma patients. We have shown HSP70 to promote PMN-MDSC chemotaxis via the stimulation of TLR4 signaling. As a result, we hypothesized that the tumor NLRP3 inflammasome may also contribute to distant metastatic progression and disease hyperprogression during immunotherapy by establishing a long-distance signaling axis mediated by HSP70-TLR4 signaling in the lung.MethodsWe pharmacologically and genetically inhibited the NLRP3 inflammasome and HSP70 in a transgenic BRAFV600E mouse model to examine their role in distant metastatic progression before and during anti-PD-1. An inducible type II pulmonary epithelial cell-specific TLR4 knock-out mouse model was engineered to examine the role of distant HSP70-TLR4 signaling in the recruitment of PMN-MDSCs and subsequent metastatic progression to the lung. Plasma HSP70 levels were monitored in melanoma patients undergoing anti-PD-1ResultsAnti-PD-1 significantly increases CXCL2/CXCL5 expression and PMN-MDSC accumulation in the lungs of the transgenic BRAFV600E model. This effect is reversed by 1) tumor-targeted ablation and pharmacologic inhibition of NLRP3 but not systemic host knock-out of NLRP3, 2) Pharmacologic Wnt5a ligand inhibition, 3) tumor-specific ablation and inhibition of HSP70. Inducible knock-out of TLR4 in type II epithelial cells suppressed Wnt5a and CXCL5 expression and inhibited the recruitment of PMN-MDSCs to the lung in response to anti-PD-1. Tumor-specific inhibition of NLRP3/HSP70 and lung-specific ablation of TLR4 suppressed metastatic progression following anti-PD-1 in the BRAFV600E melanoma model. Combination anti-PD-1 and NLRP3 inhibition suppressed primary melanoma progression and distant melanoma metastases versus anti-PD-1 monotherapy. Elevated plasma levels of HSP70 were associated with disease hyperprogression in metastatic melanoma patients undergoing anti-PD-1Abstract 319 Figure 1Tumor-intrinsic NLRP3 inflammasome and metastasisConclusionsTogether, these results describe a novel cross-talk mechanism between the primary tumor and the lung that mediates distant metastatic progression that is accentuated following anti-PD-1 (figure 1). Future clinical studies are needed to evaluate the pharmacologic inhibition of this tumor-lung NLRP3/HSP70/TLR4/Wnt5a/CXCL5 axis on melanoma metastasis and disease hyperprogression during checkpoint inhibitor immunotherapy

Chemorefractory extranodal nasal-type natural-killer/T-cell lymphoma with great response to pembrolizumab in a young patient: a case report

IntroductionExtranodal, natural-killer/T-cell lymphoma of nasal type is a rare but aggressive disease usually presenting as progressive necrotic lesions in the nasal cavity that responds poorly to chemotherapy. In this paper, we report a relapsing, chemorefractory case of extranodal natural-killer/T-cell lymphoma responding to checkpoint inhibitor immunotherapy with pembrolizumab.Case presentationA 32-year-old Hispanic woman with a history of recurrent sinusitis and preseptal abscess presented with a hoarse voice, swelling around the right eye, and diplopia. Laryngoscopy showed infiltrating tissue extending to bilateral laryngeal ventricles and false vocal cords. On immunohistochemical examination of laryngeal biopsy, the neoplastic cells showed positivity for CD3 (cytoplasmic), CD7, CD56, granzyme B, CD30, and Epstein–Barr virus-encoded ribonucleic acid (RNA). Extranodal natural-killer/T-cell lymphoma, nasal type, was confirmed. In the absence of distant organ involvement, the decision was to perform chemotherapy with etoposide, ifosfamide, mesna, cisplatin, and dexamethasone (VIPD protocol) followed by concurrent chemoradiation with weekly doses of cisplatin and two cycles of VIPD as adjuvant treatment. However, 1 month after completion of the treatment; disease recurrence was demonstrated. The patient was scheduled to receive salvage chemotherapy with steroid, methotrexate, ifosfamide, L- asparaginase, and etoposide (SMILE) protocol and CD30-targeting monoclonal antibodies. However, the mass was chemorefractory without response to either l-asparaginase-based salvage chemotherapy in combination with high-dose methotrexate or brentuximab vedotin. However, this case of chemorefractory extranodal natural-killer/T-cell lymphoma, nasal type, responded well to the novel drug pembrolizumab, which was able to control the disease.ConclusionCheckpoint inhibitors are potential treatment option in selected chemorefractory extranodal natural-killer/T-cell lymphoma, nasal type, cases.

Short-Course Palliative Radiotherapy Combined With Immunotherapy for Recurrent/Advanced/Metastatic Head and Neck Cancer

To evaluate tumor response rates in patients treated with a combination of palliative short-course radiotherapy (SCRT) and immune checkpoint inhibitor immunotherapy (IO) in patients with recurrent, advanced or metastatic (R/A/M) head and neck cancer (HNC).We reviewed the medical records of patients treated with short-course palliative intent radiation therapy (RT) (hypofractionated RT in 4-5 fractions) for R/A/M HNC between 2014-2020. Patient, disease, and treatment factors were abstracted from the medical record. Patients were categorized as having been treated with combined immunotherapy and radiotherapy (IO+RT) if the RT was given after at least 1 cycle of IO with at least 1 cycle of IO afterward. Treated gross tumor volume (GTV) was measured prior to and after RT and percent change in GTV volume from baseline to best overall response (BOR) was calculated. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.In total, 19 patients were treated with SCRT, 7 of whom were treated with combined IO+RT. Primary site included oral cavity (n = 6), larynx/hypopharynx (5), oropharynx (3), sinonasal (2), cutaneous (2), and thyroid (1). Squamous cell histology was most frequent (16/19) with the other 3 comprised of sinonasal intestinal-type adenocarcinoma, mucosal melanoma, and Hürthle cell carcinoma. Disease status included 6 patients with a recurrence, 6 were metastatic, 3 locally advanced/incurable, and 3 recurrent/metastatic. Prior treatments included RT (n = 9) and chemotherapy (6); ECOG performance status was 1-2 in 13 patients and 3-4 in 6 patients. Seventeen patients were treated with "quad-shot" radiotherapy (14.4-14.8 Gy in 4 fractions delivered twice daily) and 2 were treated with 20 Gy in 5 fractions. Median (range) number of IO cycles given pre- and post-RT were 7 (1-11) and 2 (1-21), respectively. Of the 17 evaluable patients for treatment response, 13 patients responded or were stable while 4 had progression. Median pre-RT target volume in the RT cohort was 37.2 (6.14-486.21) cc and 145.28 (24.21-219.51) cc in the IO+RT cohort. Median post-RT target volume in the RT cohort was 28.00 (17.23, 57.630 cc and 58.44 (0.00, 246.56) cc in the IO+RT cohort. Median change in target volume in RT cohort was -42% (range: -100, 259) cc and -54% (-100, 12) cc in the IO+RT cohort. 1-year PFS and OS were 5% and 21%, respectively. 1-year OS was numerically higher for IO+RT patients (43% v. 8%, P = 0.13).In this select cohort of patients with R/A/M HNC, combined IO+SCRT was feasible and showed an improved tumor response as evidenced by greater decrement in post-treatment tumor volume. An ongoing clinical trial (NCT04454489) aims to prospectively evaluate the potential benefit of combined quad-shot radiotherapy with Pembrolizumab to improve response rates to IO alone.

Barriers to patient-centered oncology care: Pilot study of home infusion of anticancer immunotherapy.

36 Background: ASCO published a position statement regarding home infusion of anticancer therapy in June 2020. This statement recommends independent research to evaluate the safety and effectiveness of home infusions. Intermountain Healthcare (IM) incorporated this statement into its oncology care with an IRB-approved, prospective single-arm pilot study to determine the safety and feasibility of home administration of checkpoint inhibitor (CPI) immunotherapy with synchronous telemedicine visits. Methods: Patients with cancer receiving treatment at Intermountain Medical Center and Intermountain Cancer Center St. George were screened for enrollment into an IRB-approved, non-randomized pilot study of 20 patients. Eligibility criteria required patients to receive a CPI for an FDA-approved indication, live in Washington County or Salt Lake County, Utah, and have commercial payer coverage of CPI home infusion. Eligible patients were required to receive 2 doses of CPI at an infusion center, and patients who experienced an infusion reaction were excluded from receiving home infusion. Home infusion nurses are trained in oncology, CPIs, and home infusion reaction protocol. During synchronous video visits, infusion nurses are trained to perform the hands-on portions of the physical exam. A financial analysis estimated cost to IM and commercial payers for routine and home CPI infusions. Results: 622 patients were screened, of which 104 were receiving a CPI. 64 patients lived in an eligible county and 19 patients had commercial payer coverage. Of patients on CPIs, 8.7% (9/104) met all eligibility criteria accounting for 1.4% (9/622) of all patients with cancer screened (Table). Financial analysis estimated $829 cost (excluding drug cost) to IM for standard infusion reimbursement compared to $599 for in-home CPI infusions, accounting for savings of $230 per infusion. Majority of cost savings are from elimination of infusion center facilities fee ($495). Analysis includes $269 for home infusion nurse wages. Subsequent analysis for commercial payer SelectHealth estimates $270 reimbursement savings for the payer. Conclusions: Home immunotherapy infusions are estimated to be cost effective for both IM and commercial payers. However, lack of drug coverage and the rural demographics of Utahns with cancer are barriers to home CPI infusions. The pilot study was discontinued per infeasibility stopping criteria.[Table: see text]

RNA Sequencing Data for FFPE Tumor Blocks Can Be Used for Robust Estimation of Tumor Mutation Burden in Individual Biosamples.

Tumor mutation burden (TMB) is a well-known efficacy predictor for checkpoint inhibitor immunotherapies. Currently, TMB assessment relies on DNA sequencing data. Gene expression profiling by RNA sequencing (RNAseq) is another type of analysis that can inform clinical decision-making and including TMB estimation may strongly benefit this approach, especially for the formalin-fixed, paraffin-embedded (FFPE) tissue samples. Here, we for the first time compared TMB levels deduced from whole exome sequencing (WES) and RNAseq profiles of the same FFPE biosamples in single-sample mode. We took TCGA project data with mean sequencing depth 23 million gene-mapped reads (MGMRs) and found 0.46 (Pearson)–0.59 (Spearman) correlation with standard mutation calling pipelines. This was converted into low (<10) and high (>10) TMB per megabase classifier with area under the curve (AUC) 0.757, and application of machine learning increased AUC till 0.854. We then compared 73 experimental pairs of WES and RNAseq profiles with lower (mean 11 MGMRs) and higher (mean 68 MGMRs) RNA sequencing depths. For higher depth, we observed ~1 AUC for the high/low TMB classifier and 0.85 (Pearson)–0.95 (Spearman) correlation with standard mutation calling pipelines. For the lower depth, the AUC was below the high-quality threshold of 0.7. Thus, we conclude that using RNA sequencing of tumor materials from FFPE blocks with enough coverage can afford for high-quality discrimination of tumors with high and low TMB levels in a single-sample mode.

Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis.

Simple SummaryThe tumor-intrinsic NLRP3 inflammasome is a newly recognized player in the regulation of tumor-directed immune responses and promises to provide fresh insight into how tumors respond to immunotherapy. This brief review discusses recent data describing how activation of the tumor-intrinsic NLRP3 inflammasome contributes to immune evasion and what this pathway may provide to the field of immuno-oncology both in terms of pharmacologic targets capable of boosting responses to checkpoint inhibitor therapies and predictive biomarkers indicating which tumors may be most susceptible to these new therapeutic strategies.The tumor-intrinsic NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) inflammasome, plays an important role in regulating immunosuppressive myeloid cell populations in the tumor microenvironment (TME). While prior studies have described the activation of this inflammasome in driving pro-tumorigenic mechanisms, emerging data is now revealing the tumor NLRP3 inflammasome and the downstream release of heat shock protein-70 (HSP70) to regulate anti-tumor immunity and contribute to the development of adaptive resistance to anti-PD-1 immunotherapy. Genetic alterations that influence the activity of the NLRP3 signaling axis are likely to impact T cell-mediated tumor cell killing and may indicate which tumors rely on this pathway for immune escape. These studies suggest that the NLRP3 inflammasome and its secreted product, HSP70, represent promising pharmacologic targets for manipulating innate immune cell populations in the TME while enhancing responses to anti-PD-1 immunotherapy. Additional studies are needed to better understand tumor-specific regulatory mechanisms of NLRP3 to enable the development of tumor-selective pharmacologic strategies capable of augmenting responses to checkpoint inhibitor immunotherapy while minimizing unwanted off-target effects. The execution of upcoming clinical trials investigating this strategy to overcome anti-PD-1 resistance promises to provide novel insight into the role of this pathway in immuno-oncology.

Intra- and inter-reader agreement of iRECIST and RECIST 1.1 criteria for the assessment of tumor response in patients receiving checkpoint inhibitor immunotherapy for lung cancer

ObjectivesTo investigate the inter- and intra-reader agreement of immune Response Evaluation Criteria in Solid Tumors (iRECIST) and Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in patients with lung cancer treated with immunotherapy. Materials and MethodsThis retrospective study included 85 patients with lung cancer treated with PD-1 blockade. Four radiologists evaluated computed topography (CT) scans before and after initiation of immunotherapy using iRECIST and RECIST 1.1. Weighted kappa (k) with equal weights was used to assess the intra-reader agreement between 2 repeated reads on overall response at all time points, best overall response, and the response at the time point of progression, as well as the intra-reader agreement between iRECIST and RECIST. The inter-reader agreement was calculated using Light’s kappa. ResultsIntra-reader agreement for overall response at all time points, best overall response, and time point of progression was substantial to almost perfect for both iRECIST and RECIST 1.1 (k = 0.651–0.983). Inter-reader agreement was substantial for iRECIST (κ = 0.657–0.742) while RECIST 1.1 was moderate to substantial (κ = 0.587–0.686). The level of inter-reader agreement was not higher on repeat read for iRECIST (κ = 0.677–0.709 and κ = 0.657–0.742 for first and second read, respectively) as well as for RECIST 1.1 (κ = 0.587–0.659 and κ = 0.633–0.686 for first and second read, respectively). Almost perfect agreement was observed between RECIST 1.1 and iRECIST at first (κ = 0.813–0.923) and second read (κ = 0.841–0.912). ConclusionThe inter- and intra-reader agreement of iRECIST is high and similar to RECIST 1.1 in patients with lung cancer treated with immunotherapy.

Systemic inhibition of PTPN22 augments anticancer immunity.

Both epidemiologic and cellular studies in the context of autoimmune diseases have established that protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a key regulator of T cell receptor (TCR) signaling. However, its mechanism of action in tumors and its translatability as a target for cancer immunotherapy have not been established. Here we show that a germline variant of PTPN22, rs2476601, portended a lower likelihood of cancer in patients. PTPN22 expression was also associated with markers of immune regulation in multiple cancer types. In mice, lack of PTPN22 augmented antitumor activity with greater infiltration and activation of macrophages, natural killer (NK) cells, and T cells. Notably, we generated a novel small molecule inhibitor of PTPN22, named L-1, that phenocopied the antitumor effects seen in genotypic PTPN22 knockout. PTPN22 inhibition promoted activation of CD8+ T cells and macrophage subpopulations toward MHC-II expressing M1-like phenotypes, both of which were necessary for successful antitumor efficacy. Increased PD1-PDL1 axis in the setting of PTPN22 inhibition could be further leveraged with PD1 inhibition to augment antitumor effects. Similarly, cancer patients with the rs2476601 variant responded significantly better to checkpoint inhibitor immunotherapy. Our findings suggest that PTPN22 is a druggable systemic target for cancer immunotherapy.

MP42-05 THE EXPRESSION LEVEL OF PD-L1 IS CORRELATED WITH CLINICOPATHOLOGICAL CHARACTERISTICS OF PATIENTS WITH VHL-RELATED RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Localized: Surgical Therapy III (MP42)1 Sep 2021MP42-05 THE EXPRESSION LEVEL OF PD-L1 IS CORRELATED WITH CLINICOPATHOLOGICAL CHARACTERISTICS OF PATIENTS WITH VHL-RELATED RENAL CELL CARCINOMA Kaifang Ma, Kenan Zhang, Lin Cai, and Kan Gong Kaifang MaKaifang Ma More articles by this author , Kenan ZhangKenan Zhang More articles by this author , Lin CaiLin Cai More articles by this author , and Kan GongKan Gong More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002063.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Von Hippel-Lindau (VHL) disease is an autosomal-dominant hereditary cancer syndrome, which characterized by renal cell carcinoma and central nervous system hemangioblastoma. Currently, the expression level and clinical significance of PD-1/PD-L1 in VHL-associated renal cell carcinoma (RCC) remain unclear. This study aimed to explore the correlation of PD-L1 expression with clinicopathological features in patients with VHL-related RCC. METHODS: Patients diagnosed with VHL disease and received nephrectomy were recruited. The clinicopathological features and prognosis of the patients were evaluated. The expression of RCC-associated molecular markers was detected by immunohistochemistry. RESULTS: From Dec. 2009 to Dec. 2020, 57 patients with VHL disease were eligible and included in this study. The median age of these patients were 43 years (IQR 31.5-51), the median follow-up period were 36 months (IQR 13-68.5) and the mean size of the renal tumors were 4.19±1.96 cm (range 1.3-10.5). The study about 112 renal tumors showed that 98.2% pathological type was clear-cell RCC, 89.3% pathological stage was pT1 and 69.6% Fuhrman nuclear grade was G1 in VHL-related RCC. The positive PD-L1, TFE-3, CA-9 and CD10 expression were 24.6%, 28%, 70.6% and 43.2%, respectively. The study revealed that positive PD-L1 expression was associated with higher pathological T stage (p <0.037) and advanced Fuhrman nuclear grade (p <0.007). CONCLUSIONS: PD-L1 expression was associated with aggressive clinicopathological features in patients with VHL-related RCC. Larger prospective studies are warranted to further evaluate whether PD-L1 expression level in CCRCC is related to the effectiveness of PD-1/PD-L1 checkpoint inhibitor immunotherapy. Source of Funding: This study was funded by the National Natural Science Foundation of China (No. 81572506 and 81872081) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e772-e773 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kaifang Ma More articles by this author Kenan Zhang More articles by this author Lin Cai More articles by this author Kan Gong More articles by this author Expand All Advertisement Loading ...

Plasmonic gold nanostars for synergistic photoimmunotherapy to treat cancer

Cancer is the second leading cause of death and there is an urgent need to improve cancer management. We have developed an innovative cancer therapy named Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) by combining gold nanostars (GNS)-mediated photothermal ablation with checkpoint inhibitor immunotherapy. Our previous studies have demonstrated that SYMPHONY photoimmunotherapy not only treats the primary tumor but also dramatically amplifies anticancer immune responses in synergy with checkpoint blockade immunotherapy to treat remote and unresectable cancer metastasis. The SYMPHONY treatment also induces a 'cancer vaccine' effect leading to immunologic memory and prevents cancer recurrence in murine animal models. This manuscript provides an overview of our research activities on the SYMPHONY therapy with plasmonic GNS for cancer treatment.

Current Status of Immune Checkpoint Inhibitor Immunotherapy for Lung Cancer.

Immunotherapy is a major breakthrough in the treatment of cancer in recent years. Immune checkpoint inhibitors (ICIs) including programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have been used for different histologic types of cancer including primary lung cancer that represents the most common and fatal cancer globally. Among ICI immunotherapy agents, atezolizumab, durvalumab, ipilimumab, nivolumab, and pembrolizumab are currently used as standard-of-care (SOC) treatment for metastatic or earlier stages of lung cancer. Major issues of ICI immunotherapy in lung cancer comprise the use of immune biomarkers prior to ICI therapy, selection of ICI agents, combination of ICIs/chemotherapy, combination of ICIs/radiotherapy, sequence of tyrosine kinase inhibitor (TKI) targeted therapy and ICI immunotherapy, sequence of chemotherapy and ICI immunotherapy, treatment duration of ICI regimen and ICI therapy for different histopathology, stage, PD-L1, and performance status. Based on the contemporary major clinical trials and authoritative guidelines, the objective of this review is to present an overview of the current status of ICI immunotherapy in lung cancer.

Response to Immune Checkpoint Inhibitor Treatment in Advanced Cervical Cancer and Biomarker Study.

Background: Checkpoint inhibitor immunotherapy or immuno-oncology (IO) treatment in refractory cervical cancer yielded an objective response rate (ORR) of 12% in tumors expressing the programmed cell death ligand-1 (PD-L1) in the KEYNOTE-158 phase II study. We hypothesized that the positive response might be associated with the level of PD-L1 expression and/or the tumor mutation burden (TMB). We also aimed to analyze if responses could be associated with platinum sensitivity.Methods: This is a retrospective study of all consecutive patients with cervical cancer who received pembrolizumab or nivolumab.Results: Ten patients were identified. Median age was 64.5 years old (range 48–80). The response rate was 70% and the median duration of response was 21.0 months (range 1.8–26.7) after 20.7 months of follow-up (range 2.0–31.0). The response rate was 80% in patients with PD-L1 combined positive score (CPS) ≥ 10, and 75% in patients with tumor mutation burden (TMB) ≥ 10 mut/Mb. The mean progression-free survival (PFS) for the entire cohort was 20.2 months (95% CI 12.0–28.5). Seven patients had treatment for >12 months (range 14.6–31.0). Five patients were platinum-sensitive and 5 patients were platinum-resistant at the time of immunotherapy, and the response rate was similar regardless of platinum sensitivity.Conclusions: The positive response to IO treatment in advanced cervical cancer in this study was higher than published, and a possible association with the level of PD-L1 expression and the TMB level was suggested. A PD-L1 CPS score ≥ 10 or TMB ≥ 10 may be biomarkers to correlate with response, which should be explored in large studies.

SURG-11. Surgery for control of brain metastases after prior checkpoint inhibitor immunotherapy: a single-center series

BackgroundDespite the promising results for treating metastatic cancer with checkpoint inhibitor immunotherapies, there are limited data on surgical outcomes for brain metastases (BMs) that have progressed after prior checkpoint inhibitor treatment. The objective of this study was to identify factors associated with local progression, leptomeningeal disease, and survival for patients undergoing surgical resection of a BM in patients previously treated with checkpoint inhibitor immunotherapy.MethodsA retrospective, single-center cohort study was conducted with inclusion of adult patients undergoing surgical resection of a BM in the setting of progression after prior checkpoint inhibitor treatment. Univariate and multivariate analyses were performed to identify factors associated with outcomes of interest.ResultsOver an 8-year period, 26 patients who underwent resection of 30 BMs met inclusion criteria. Median patient age at surgery was 63.9 years, and median clinical follow-up was 6.9 months (range 0.1 – 52.9). Extracranial disease was present at the time of surgery in 73.3% of cases. There were 6 postoperative complication events (20% of cases) by 30-days. By last follow-up, 65.4% of the cohort had died with a median censored survival of 7.6 months from surgery. Eight patients (30.8%) died within 3 months of surgery. On multivariate analysis, postoperative complications were associated with worse survival (HR 5.33, 95%CI 1.15–24.77, p=0.03). Four BMs had local progression (13.3%), and 60% of procedures were associated with distant progression within a median time of 3.6 months. Leptomeningeal disease developed in 32% of cases. On multivariate analysis, increased time from BM diagnosis to surgery was associated with a greater risk of leptomeningeal disease (OR 1.2, 95%CI 1.00–1.43, p=0.021).ConclusionPatients who require BM resection after prior checkpoint inhibitor treatment have an overall poor prognosis. Although local control rates are acceptable, these patients are at high risk for developing leptomeningeal disease postoperatively.

Survival Outcomes of Salvage Metastasectomy After Failure of Modern-Era Systemic Therapy for Melanoma.

Metastasectomy for selected patients with melanoma was associated with improved survival in the era before effective systemic therapy. Emerging evidence shows that these benefits persist even in this era of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. This study aimed to evaluate the outcomes of salvage metastasectomy after failure of systemic therapy. Stage 3 or 4 melanoma patients with extracranial disease progression after at least 4 weeks of systemic treatment between 2009 and 2020 were identified and categorized as resected to no evidence of disease (NED), non-progressive residual disease (NPRD), or progressive residual disease (PRD). Systemic therapy was stratified into BRAF-targeted therapy, immune checkpoint inhibitor immunotherapy, or both. The end points of overall survival (OS), progression-free survival (PFS), and locoregional disease control (LRC) were assessed using Kaplan-Meier curves. Uni- and multivariable Cox regression procedures were used to examine factors associated with OS, PFS and LRC. The study enrolled 190 patients. Among all the patients, the 5-year OS from metastatectomy was 52%, the 3-year PFS was 21%, and the 5-year LRC was 61%. After resection to NED, NPRD, and PRD, the 5-year OS values were 69%, 62% and 8%, respectively. Fewer lines of preoperative therapy, use of preoperative immunotherapy, and resection to NED were predictors of improved OS. After resection to NED, NPRD, and PRD, the 3-year PFS values were 23%, 24% and 10%, and the 5-year LRC values were 61%, 72% and 34%, respectively. Salvage metastasectomy was associated with durable survival and disease control, particularly after resection to NED, preoperative immunotherapy, and fewer lines of preoperative systemic therapy.

Dedifferentiated endometrial carcinoma: molecular characteristics and clinical outcomes

<h3>Objectives:</h3> We sought to describe the molecular characteristics of each histological component of undifferentiated and dedifferentiated endometrial carcinomas, as well as the clinical outcomes of cases from a large single institution cohort. <h3>Methods:</h3> Endometrial carcinoma cases with diagnosis of undifferentiated or dedifferentiated carcinoma from 2014-2017 were included. Demographic and clinical data were abstracted from the medical record. Central pathologic review was performed by expert gynecologic pathologist, and cases were excluded if final diagnoses was not dedifferentiated or undifferentiated endometrial carcinoma. Slides from hysterectomy specimen were evaluated via IHC for MMR (mismatch repair)proteins (MLH1, PMS2, MSH2, MSH6), p53, and PD-L1. Sanger sequencing for TP53 and POLE and MSI genotyping were performed on tumor DNA for each case. <h3>Results:</h3> A total of 12 of 772 cases (1.6%) with a clinical diagnosis of dedifferentiated or undifferentiated endometrial carcinoma were evaluated. A total of 2 were excluded after central pathologic review (carcinosarcoma, FIGO grade 3 endometrioid). All remaining cases were classified as dedifferentiated carcinoma. Seventy percent of patients presented with advanced stage disease. The majority of patients were treated with multimodal adjuvant therapy, however 30% progressed rapidly prior to completing treatment. Of those who completed primary treatment, no recurrences were noted. Ninety percent of cases showed MMR protein loss and 8/9 had concordant MMR IHC findings in the histologic subtypes. No <i>TP53</i> or <i>POLE</i> mutations were identified on tumor sequencing. <h3>Conclusions:</h3> Concordant MMR protein loss between histologic subtypes of dedifferentiated endometrial carcinoma lends credence to the theory that the undifferentiated component arises from the low-grade endometriod component. The high rate of MMR protein observed in dedifferentiated tumors points to immunotherapy checkpoint inhibitors an attractive treatment option. The current study does not offer molecular characteristics that can adequately explain the dichotomies in outcomes seen in our patients. Further research to identify prognostic and predictive biomarkers will greatly aid in expanding our ability to make informed decisions regarding optimal management strategies.

A Spatial Quantitative Systems Pharmacology Platform spQSP-IO for Simulations of Tumor-Immune Interactions and Effects of Checkpoint Inhibitor Immunotherapy.

Simple SummaryMathematical and computational models, such as quantitative systems pharmacology (QSP) models, are becoming a popular tool in drug discovery. The advancement of imaging techniques creates a unique opportunity to further expand these models and enhance their predictive power by incorporating characteristics of individual patients embedded in the image data obtained from tissue samples. The aim of this study is to develop a platform which combines the strength of QSP models and spatially resolved agent-based models (ABM), and create a model of cancer development in the context of anti-cancer immunity and immune checkpoint inhibition therapy. The model can be applied in virtual clinical trials and biomarker discovery to help refine trial design.Quantitative systems pharmacology (QSP) models have become increasingly common in fundamental mechanistic studies and drug discovery in both academic and industrial environments. With imaging techniques widely adopted and other spatial quantification of tumor such as spatial transcriptomics gaining traction, it is crucial that these data reflecting tumor spatial heterogeneity be utilized to inform the QSP models to enhance their predictive power. We developed a hybrid computational model platform, spQSP-IO, to extend QSP models of immuno-oncology with spatially resolved agent-based models (ABM), combining their powers to track whole patient-scale dynamics and recapitulate the emergent spatial heterogeneity in the tumor. Using a model of non-small-cell lung cancer developed based on this platform, we studied the role of the tumor microenvironment and cancer–immune cell interactions in tumor development and applied anti-PD-1 treatment to virtual patients and studied how the spatial distribution of cells changes during tumor growth in response to the immune checkpoint inhibition treatment. Using parameter sensitivity analysis and biomarker analysis, we are able to identify mechanisms and pretreatment measurements correlated with treatment efficacy. By incorporating spatial data that highlight both heterogeneity in tumors and variability among individual patients, spQSP-IO models can extend the QSP framework and further advance virtual clinical trials.

Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure

IntroductionAcquired resistance to TKI is an important unmet need in the management of EGFR mutated lung cancer. Recent clinical trial IMPower150 suggested that combination approach with VEGF inhibitor, check point inhibitor immunotherapy and platinum-based chemotherapy was effective in oncogene driven lung cancer. The current trial examined the efficacy of a modified regimen in an EGFR mutated cohort. MethodsAn open-labelled, single arm, phase II study was conducted in patients with EGFR mutated NSCLC who had progressed on at least one EGFR TKI. For those with T790M mutation, radiological progression on osimertinib was required for enrolment. Patients were treated with combination atezolizumab (1200 mg), bevacizumab (7.5 mg/kg), pemetrexed (500 mg/m2) and carboplatin (AUC 5) given once every 3 weeks until progression. ResultsForty patients were enrolled. Median age was 62 (range 45–76) years. More than one half (23/40, 57.5%) had progressed on osimertinib. PD-L1 expression was < 1% in 52.5%. Median follow-up time was 17.8 months. ORR was 62.5%. Median PFS was 9.4 months (95% CI: 7.6 – 12.1). One year OS was 72.5% (95% CI: 0.56–0.83). Treatment related grade 3 or above adverse events (AE) occurred in 37.5% (15/40). Immune-related AE occurred in 32.5% (13/40) patients. Quality of life measures of function and symptoms did not change significantly throughout the course of treatments. Post-trial rechallenge with EGFR TKI containing regimen resulted in PFS of 5.8 months (95% CI 3.9–10.0 months). ConclusionCombination approach of atezolizumab, bevacizumab, pemetrexed and carboplatin achieved promising efficacy in metastatic EGFR mutated NSCLC after TKI failure. The results were comparable with taxane based regimen of IMPower150 while toxicity profile was improved.

WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape

BackgroundDespite PD-L1 (Programmed death receptor ligand-1) expression on tumor cells and cytotoxic T lymphocytes tumor infiltration in the tumor microenvironment, human pancreatic cancer stands out as one of the human...