Checkpoint Inhibitors Ipilimumab Research Articles

MO363CHECKPOINT-INHIBITOR-ASSOCIATED ACUTE KIDNEY INJURY AND MORTALITY: AN OBSERVATIONAL STUDY

Abstract Background and Aims Immune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of autoimmune-related side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors. Method Patients receiving checkpoint inhibitors between January 2013 and May 2020 were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in creatinine of ≥1.5 times the baseline value. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent kidney injury was diagnosed in AKI patients with a final creatinine measurement of >1.3 times the baseline value. Results Out of 676 patients receiving checkpoint inhibitors, AKI occurred in 96 (14.2%) patients. Chart review showed that AKI was checkpoint inhibitor-associated in 32 (4.7%) patients. Baseline variables associated with AKI were a primary gynecological malignancy (HR 3.91, 95% CI 1.55 to 9.85), treatment with checkpoint inhibitor ipilimumab (HR 2.31, 95% CI 1.03 to 5.20), and pre-existent use of a diuretic (HR 2.61, 95% CI 1.21 to 5.60), an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker (HR 2.49, 95% CI 1.10 to 5.60), and a proton pump inhibitor (HR 1.69, 95% CI 1.04 to 2.75). In 35.4% of the patients who had developed AKI, persistent kidney dysfunction was observed at the end of follow-up. Patients who developed AKI had a 2.13-fold (95% CI 1.58 to 2.87) increased mortality risk compared to patients who did not develop AKI. Mortality risk was not increased by checkpoint inhibitor-associated AKI (HR 1.11, 95% CI 0.64 to 1.92), but only by AKI related to other causes (HR 2.87, 95% CI 2.04 to 4.04). Conclusion Patients receiving checkpoint inhibitors frequently develop AKI, however, checkpoint inhibitor-associated AKI does not seem to increase mortality.

A phase 2 study using ipilimumab, nivolumab, and trabectedin for previously untreated metastatic soft tissue sarcoma.

11562 Background: Sarcoma cells are most immunogenic earlier in the disease course and before treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given to previously untreated patients with metastatic soft tissue sarcoma. Methods: Eligible patients for this Phase 2 study are previously untreated patients ≥ 18 years of age with unresectable or metastatic soft tissue sarcoma, with measurable disease by RECIST v1.1. Immune checkpoint inhibitors Ipilimumab (I) and Nivolumab (N) were given with Trabectedin (T), a marine derived alkaloid with defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks), and T (1.2 mg/m2 i.v. q 3 weeks). Primary endpoints: (1) Objective response rate by RECIST v1.1 via CT scan or MRI, (2) Progression-free survival (PFS): from first day of treatment to disease progression or death due to any cause; otherwise, it is censored at the time of last follow-up, and (3) Overall survival: from first day of treatment to death due to any cause; otherwise, it is censored at the time of last follow-up. Results: There were eighty-two evaluable subjects, having completed the first cycle of I, N, and T and have had a CT or MRI scan at the 6-week follow-up period. Best Overall Response by RECIST v1.1 = 7 CR (2 surgical CR), 9 PR, 54 SD, and 12 PD. Disease control rate was 85.4%. The median PFS was >6.4 (range: 0-32) months; 6-month PFS rate: 57.3%. The median OS was >12.0 (0-38) months; 6-month OS rate: 78.8%. Safety analysis: The most common Grade 3 TRAEs include increased ALT (26), anemia (11), increased AST (9), and fatigue (8). Common Grade 4 TRAEs include thrombocytopenia (2), increased AST (2), increased ALT (2), and increased CPK (2). There was one Grade 5 TRAE of rhabdomyolysis (1). Conclusions: Taken together, these results suggest that first-line combinatorial therapy with I, N, and T are (1) synergistic, and (2) may be equal or superior to, and safer than, standard first line therapy for advanced/metastatic soft tissue sarcoma. Clinical trial information: NCT03138161.

Nivolumab plus ipilimumab for the first-line treatment of metastatic NSCLC

ABSTRACT Introduction In the last decade, immune checkpoint inhibitors have revolutionized the treatment of several malignancies including non-small cell lung cancer (NSCLC). The inhibition of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed death receptor 1 (PD-1) pathways leads to an activation of the immune response against tumor cells. Thanks to a synergistic effect, the combination of the checkpoint inhibitors nivolumab and ipilimumab has the potential to improve outcomes of NSCLC patients. Areas covered We provide an overview of clinical trials evaluating the combination of nivolumab and ipilimumab in the first-line treatment of advanced NSCLC patients. Expert opinion The combination of nivolumab and ipilimumab, alone or with a few cycles of chemotherapy, was demonstrated to be a valid option for first-line treatment of metastatic NSCLC patients without EGFR mutation and ALK rearrangement. However, a better understanding of patients who can benefit from this approach is required.

Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

Adjuvant immunotherapy for melanoma

Surgical resection is the treatment for early cutaneous melanoma and is often curative. Some patients, however, will subsequently relapse. High-risk features in the primary tumor and regional lymph node metastasis highlight patient subsets that are at increased risk for recurrent disease. Immunotherapy in the form of checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab have been shown to improve recurrence-free survival for node-positive melanoma in the adjuvant setting and will be the focus of this review.

Развитие деструктивного тиреоидита и сахарного диабета после трех введений пембролизумаба по поводу меланомы кожи

The exponential rise in the use of immune checkpoint inhibitors (Ipilimumab, Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, and Avelumab) as the new standard for cancer treatment increase the incidence the immune-related adverse events due to immune activation. Endocrine immune-related adverse events are the third most commonly reported. Thyroid gland is most susceptible to autoimmune dysfunctions from immune checkpoint inhibitors and associated with the use of anti-PD-1 monoclonal antibodies. Hypophysitis develops more often during therapy with anti-CTLA-4 monoclonal antibodies. But such immune-related adverse events as diabetes mellitus, hypoparathyroidism are rare (about 1% of cases). We present a clinical case of the patient with skin melanoma who was prescribed therapy with immune checkpoints inhibitors (Pembrolizumab). Immune-related adverse events developed with damage to the endocrine organs after 3 Pembrolizumab injections. Of greatest interest is the development of two endocrine immune-related adverse events at once: destructive thyroiditis (with a short phase of thyrotoxicosis and subsequent persistent hypothyroidism) and diabetes mellitus. We tried to reflect the chronology of diseases and their features as fully as possible for endocrinologists, oncologists, therapists, family doctors and other medical doctors of related specialties.

Abstract PO030: A Novel T-cell Population Expressing the Ectoenzymes CD38 and CD39 is Associated with Melanoma Patient Non-Response to Immunotherapy

Abstract Cancer immunotherapy has emerged as one of the most potent therapeutic tools in treating melanoma and a variety of other malignancies. Immunotherapy includes inhibition of the modulators of T cell antitumor function, the immune checkpoints, by using antibodies against them. In advanced melanoma patients, immune checkpoint inhibitors ipilimumab (IPI) and nivolumab (NIVO) have had unprecedented efficacy. Although many patients respond well to this therapy, many patients remain unresponsive. The mechanism underlying treatment failures remains poorly understood. Using a novel high-dimensional flow cytometry analysis methodology, CytoBrute, we found that in the cohort of advanced melanoma patients receiving sequential NIVO-IPI, high baseline levels of a novel immunophenotype, CD4+CD38+CD39+CD127-GARP- T-cells (median frequency 0.3%), was associated with poor outcomes (disease progression p=0.008, and decreased overall survival p<0.0001 HR = 6.8). Both CD38 and CD39 are ectoenzymes with CD38 hydrolyzing NAD+ to cyclic-ADP ribose and CD39 converting extracellular ATP to immunosuppressive adenosine nucleosides. Both of these proteins are being evaluated as targets to increase the efficacy of immunotherapies. The association of this novel phenotype, which we have termed T-cells expressing ectoenzymes (Tee), was validated in two independent cohorts of melanoma patients treated with NIVO monotherapy, with progressors showing a higher frequency of this immunophenotype at baseline (p=0.047). In IPI+NIVO adjuvant treated melanoma patients, an increase in this population of cells was observed during treatment in relapsing patients, leading to a higher frequency of these cells in relapsing patients relative to patients with no evidence of disease (p=002). Preliminary data obtained from single cell RNA sequencing from the ectoenzyme expressing peripheral blood T cell population, demonstrated predominant expression of IL-32 and CD99 (a membrane glycoprotein associated with lymphocyte diapedesis) in this population, along with several additional clusters distinguished by expression of specific TcR V beta genes. Collectively, we have identified a novel population of ectoenzyme expressing T-cells (CD3+CD4+CD38+CD39+CD127-GARP-) associated with poor melanoma patient outcomes in response to checkpoint immunotherapy. Further investigation of the mechanisms by which this novel T-cell phenotype is associated with poor patient outcomes is under way. Citation Format: Ankita Mitra, David M. Woods, Anjali Rao, Andressa S. Laino, Aidan Winters, Itai Yanai, Pratip K. Chattopadhyay, Jeffrey S. Weber. A Novel T-cell Population Expressing the Ectoenzymes CD38 and CD39 is Associated with Melanoma Patient Non-Response to Immunotherapy [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO030.

Immune-Related Oral, Otologic, and Ocular Adverse Events.

Emerging immunotherapeutic agents, including immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death protein ligand 1 (PD-L1), have revolutionized cancer treatment. The first immune checkpoint inhibitor (ICI) ipilimumab, an anti-CTLA-4, was approved in 2011. Since then, the US Food and Drug Administration (FDA) has approved more than half a dozen immune checkpoint inhibitors to treat various malignancies. These agents are part of a broader class of chemotherapy agents termed immunotherapy, which selectively target different steps in the immune response cascade to upregulate the body's normal response to cancer. While the effects of traditional chemotherapy are well known, the toxicity profile of emerging immune therapies is not fully elucidated. They have been associated with atypical side effects labeled collectively as immune-related adverse events (irAEs).

Prospects of application of inhibitors of PD-1/PD-L1 checkpoints in malignant tumors of the stomach and esophagogastric junction

Malignant tumors of the stomach and esophagogastric junction in advanced stages progress quite aggressively, and the prospects for treatment of these patients remain unpromising. The use of checkpoint-inhibitors has proven to be an advanced treatment method for various types of cancer around the world. In theRussian Federation, nivolumab has been successfully registered as a monotherapy for common or recurrent stomach or esophagogastric junction cancer after two or more lines of systemic antitumor drug therapy. This literature review focuses on the use of registered checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab) as mono- and/or combined therapy in tumors of the stomach and esophagogastric junction, including tumors with high microsat- ellite instability (MSI-high). This review includes a description of the main therapeutic approaches using checkpoint inhibitors: prescription in mono-mode, in combination with other checkpoint inhibitors (ipilimumab) and cytotoxic drugs, and in combination with tyrosine kinase inhibitors (regorafenib). Issues of efficiency and tolerability of these combinations in patients in different therapeutic lines are considered. The role of possible predictors of therapy response is analyzed: biomarkers such as PD-Ll, MSI, dMMR and TMB expression in tumor tissues as well as immunofenotyping in fresh biopsy samples are evaluated. This article reviews and evaluates the strengths and weaknesses of checkpoint inhibitors and their possible uses.

Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929).

A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti-CTL antigen-4 (anti-CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment. Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot. Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival. Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.

Stereotactic Radiosurgery With Concurrent Immunotherapy in Melanoma Brain Metastases Is Feasible and Effective.

Objective: Stereotactic radiosurgery (SRS) is an established treatment for brain metastases in the management of metastasized melanoma. The increasing use of checkpoint inhibitors in melanoma therapy leads to combined treatment schemes consisting of immunotherapy and SRS that need to be evaluated regarding safety and feasibility.Methods: We retrospectively analyzed 36 patients suffering from cerebral metastasized melanoma. Between November 2011 and May 2016, altogether 66 brain metastases were treated with single-fraction SRS (18–20 Gy prescribed to the 80% isodose) in combination with a checkpoint inhibitor (ipilimumab: 82%, pembrolizumab: 14% or nivolumab: 4%), administered within 3 months before or after SRS. Toxicity was evaluated with focus on the incidence of central nervous system (CNS) radiation necrosis (CRN). Overall survival (OS), freedom from local progression (FFLP), freedom from central nervous system radiation necrosis (FFCRN), and freedom from distant intracranial progression (FFDIP) were analyzed using the Kaplan-Meier method.Results: The median follow-up was 25 months (range: 2–115 months). Two patients (6%) presented with cerebral edema CTCAE °III and another two patients (6%) presented with one-sided muscle weakness CTCAE °III after SRS. One of these four symptomatic cases correlated with an observed CRN, the other three symptomatic cases were related to local tumor progression (n = 2) or related to the performance of additional whole brain radiotherapy (WBRT). No further CTCAE °III or °IV toxicity was seen. During follow-up, seven of the growing contrast-enhanced lesions were resected, revealing two cases of CRN and five cases of local tumor progression. Altogether, the observed CRN rate of the irradiated metastases was 6–17% at the time of analysis, ranging due to the radiologically challenging differentiation between CRN and local tumor progression. The observed ranges of the 1- and 2-years FFLP rates were 82–85% and 73–80%, respectively. The median FFDIP was 6.1 months, the median OS was 22.2 months.Conclusion: In the presented cohort, the combination of SRS and checkpoint inhibitors in the management of cerebral metastasized melanoma was safe and effective. Compared to historic data on SRS only, the observed CRN rate was acceptable. To gain resilient data on the incidence of CRN after combined treatment schemes, prospective trials are needed.

The current state of adjuvant therapy of melanoma.

Melanoma adjuvant therapy targets residual micrometastatic disease destined for future recurrence. In patients with resected stage III or IV melanoma, adjuvant therapy was shown to reduce the risk of recurrence, death, or both, leading to the regulatory approval of several agents since 1995: IFNα, pegylated-IFNα, checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab, and BRAF and MEK inhibitors dabrafenib and trametinib. 1 Kirkwood JM Manola J Ibrahim J et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004; 10: 1670-1677 Crossref PubMed Scopus (456) Google Scholar , 2 Kirkwood JM Ibrahim JG Sosman JA et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001; 19: 2370-2380 Crossref PubMed Scopus (783) Google Scholar , 3 Eggermont AM Suciu S Testori A et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012; 30: 3810-3818 Crossref PubMed Scopus (208) Google Scholar , 4 Eggermont AM Chiarion-Sileni V Grob JJ et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015; 16: 522-530 Summary Full Text Full Text PDF PubMed Scopus (856) Google Scholar , 5 Tarhini AA Lee SJ Hodi FS et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609. J Clin Oncol. 2020; 38: 567-575 Crossref PubMed Scopus (51) Google Scholar , 6 Eggermont AMM Blank CU Mandala M et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018; 378: 1789-1801 Crossref PubMed Scopus (929) Google Scholar , 7 Long GV Hauschild A Santinami M et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017; 377: 1813-1823 Crossref PubMed Scopus (799) Google Scholar Key adjuvant trials, their outcomes, and current standard of care status are summarised in the appendix. Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trialAt a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB–C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab. Full-Text PDF

Checkpoint inhibitors-indications and application in melanoma patients

Die gesamte Onkologie wurde durch die Einführung von Ipilimumab, einem Checkpoint-Inhibitor, im Jahr 2011 revolutioniert. Seitdem wurden weitere effektive Checkpoint-Inhibitoren, wie die PD-1-Antikörper Nivolumab und Pembrolizumab entwickelt. Die Ergebnisse sind bahnbrechend, insbesondere beim fortgeschrittenen malignen Melanom, welches bis vor Kurzem in den meisten Fällen nach wenigen Monaten zum Tode führte. Die Anwendung der Checkpoint-Inhibitoren wurde mit vielversprechenden Ergebnissen auf weitere Tumorentitäten ausgeweitet.

Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment

Simple SummaryColorectal cancer (CRC) causes a high number (more than 800,000) of deaths worldwide each year. Better methods for early diagnosis and the development of strategies to enhance the efficacy of the therapeutic approaches used to complement or substitute surgical removal of the tumor are urgently needed. Currently available pharmacological armamentarium provides very moderate benefits to patients due to the high resistance of tumor cells to respond to anticancer drugs. The present review summarizes and classifies into seven groups the cellular and molecular mechanisms of chemoresistance (MOC) accounting for the failure of CRC response to the pharmacological treatment.The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: (i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; (ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of (i) new agents to be co-administered with the active drug; (ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); (iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes).

Abstract 5631: Leukaemia and lymphoma patient-derived xenografts (PDX) engraft on humanized mice and respond to immune therapy with check point inhibitors

Abstract Background The preclinical evaluation of novel immune therapies for cancer remains a challenge, as models require both, engraftment of human tumor cells and a matching human immune cell population. In previous experiments, we have demonstrated, that we can use either peripheral blood mononuclear cells (PBMC) or hematopoietic stem cells (HSC) to establish a humanized immune system on highly immunodeficient mice. In this study, we transplanted patient-derived xenografts (PDX) from leukaemia and lymphoma on these humanized mice. Further, we validated the models by evaluating treatments with checkpoint inhibitors Nivolumab (Nivo) and Ipilimumab (Ipi) or standard of care therapies. Methods HSC were transplanted i.v. on immunodeficient mice. Engraftment of human immune cells was monitored by FACS analysis of blood samples. Three lymphoma PDX and one acute myeloid leukaemia (AML) model were s.c. transplanted on humanized mice. To model systemic leukaemia, three AML models were transplanted i.v. on humanized mice. Engraftment of the PDX was compared to growth on non-humanized mice. After successful engraftment, mice were treated with Nivo, Ipi or in combination with standard therapies and irradiation. Results We confirmed successful engraftment of HSC in the humanized mice. Within 14 weeks after HSC inoculation, FACS analysis revealed an established functional human immune system with up to 20% T-cells, characterized by a high PD-1 expression. The s.c. transplanted leukaemia and lymphoma PDX engrafted on the humanized mice and tumor growth was measured with calipers. Engraftment of i.v. transplanted AML models was confirmed by FACS measurement of human CD33+ AML cells in the blood of the humanized mice. Treatment with Ipi or Nivo alone or in combination led to a minor growth delay. FACS analysis confirmed an increased percentage of activated T-cells in the blood and in the s.c. tumors. Response to checkpoint inhibitors was in correlation to PD-L1 expression on the lymphoma and AML cells. Combination of check point inhibitors with radiotherapy provided additive effects in our models. Conclusions We developed a humanized immune-PDX model for different blood cancers enabling appropriate preclinical translational research on tumor immune biology and the evaluation of new therapies and combinations, as well as the identification and validation of biomarkers for immune therapy. These novel model are currently optimized for the preclinical evaluation of new bispecific immune cell engagers (BITE) and cell therapies (CART). Citation Format: Maria Stecklum, Annika Wulf-Goldenberg, Antje Siegert, Bernadette Brzezicha, Anja Sterner-Kock, Wolfgang Walther, Jens Hoffmann. Leukaemia and lymphoma patient-derived xenografts (PDX) engraft on humanized mice and respond to immune therapy with check point inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5631.

12. OUTCOMES AFTER SURGICAL RESECTION OF MELANOMA BRAIN METASTASES IN THE AGE OF CHECKPOINT INHIBITOR TREATMENT

BACKGROUNDMetastasis of melanoma to the brain is associated with poor outcomes. Recent trials demonstrate improved survival after treatment with immune checkpoint inhibitors.OBJECTIVETo examine the impact that checkpoint inhibitor treatment has on overall survival (OS) and central nervous system (CNS) progression in a cohort of patients undergoing surgical resection of melanoma brain metastases.METHODSThis retrospective, single-center study included patients undergoing first-time surgical resection of melanoma brain metastases. A multivariate Cox proportional model was used to estimate the association of patient and treatment factors with OS and CNS progression.RESULTS85 patients underwent first-time resection of 97 melanoma brain metastases with a median follow-up of 9.5 months. Checkpoint inhibitors (Pembrolizumab, Ipilimumab, and/or Nivolumab) were used in 55.1% of cases (19 pre-op; 47 post-op; median 9 cycles). Patients treated with checkpoint inhibitors had similar peri-op systemic disease status and KPS but had been treated with more systemic agents and had more instances of CNS progression prior to surgery. Median OS and time to CNS progression for the cohort were 1 year and 237 days, respectively. In a multivariate Cox regression model, age (HR 1.03 by decade; p=0.02), treatment with a checkpoint inhibitor (HR 0.27; p<0.0001), prior radiotherapy (HR 2.44; p=0.007), and number of brain metastases at the time of surgery (HR 1.05 per metastasis; p=0.04) were significant predictors of OS. Checkpoint inhibitor treatment was associated with longer OS from surgery (median 3 vs 0.5 yrs, log-rank p=0.004). However, patients who underwent craniotomy after prior checkpoint inhibitor treatment had poor OS (median 0.56 yrs). Prior radiotherapy was also associated with poor OS (median 0.53 yrs).CONCLUSIONSWhile checkpoint inhibitor treatment was associated with improved survival in this surgical cohort of melanoma brain metastases, patients who require surgical resection after checkpoint inhibitor treatment or radiotherapy are poor surgical candidates.

Ipilimumab and Nivolumab as First-Line Treatment of Patients with Renal Cell Carcinoma: The Evidence to Date.

Immunotherapy has revolutionized the management of metastatic renal cell carcinoma with four checkpoint inhibitors (nivolumab, ipilimumab, avelumab, and pembrolizumab) approved either as monotherapy or as combination therapy. The use of ipilimumab and nivolumab for treatment-naïve, intermediate to poor risk, metastatic renal cell carcinoma was the first checkpoint inhibitor-based combination therapy and remains the only dual checkpoint inhibitor combination approved in mRCC. In this article, we review the trials that led to the approval of ipilimumab and nivolumab in this setting. We also highlight the ongoing trials using this combination, its use in special populations, and clinically relevant unanswered questions.

A Rare Case of Autoimmune Encephalitis in a Patient After Treatment of Metastatic Melanoma with a Combination of Immune Checkpoint Inhibitors Nivolumab and Ipilimumab (447)

A Rare Case of Autoimmune Encephalitis in a Patient After Treatment of Metastatic Melanoma with a Combination of Immune Checkpoint Inhibitors Nivolumab and Ipilimumab (447)

P73 Inflammatory anti- Hu positive demyelinating neuropathy induced by Checkpoint inhibitors Nivolumab and Ipilimumab

P73 Inflammatory anti- Hu positive demyelinating neuropathy induced by Checkpoint inhibitors Nivolumab and Ipilimumab

A phase II open label, randomised study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: the Ipi-Glio trial protocol

BackgroundMedian survival for patients with glioblastoma is less than a year. Standard treatment consists of surgical debulking if feasible followed by temozolomide chemo-radiotherapy. The immune checkpoint inhibitor ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has shown clinical efficacy in preclinical models of glioblastoma. The aim of this study is to explore the addition of ipilimumab to standard therapy in patients with glioblastoma.Methods/designIpi-Glio is a phase II, open label, randomised study of ipilimumab with temozolomide (Arm A) versus temozolomide alone (Arm B) after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma. Planned accrual is 120 patients (Arm A: 80, Arm B: 40). Endpoints include overall survival, 18-month survival, 5-year survival, and adverse events. The trial is currently recruiting in seven centres in the United Kingdom.Trial registrationISRCTN84434175. Registered 12 November 2018.