Journal For ImmunoTherapy Of Cancer Research Articles

Sex reporting of cells used in cancer research: A systematic review.

Sex and gender disparities in biomedical research have been emphasized to improve scientific knowledge applied for the health of both men and women. Despite sex differences in cancer incidence, prognosis, and responses to therapeutic agents, mechanistic explanations at molecular levels are far from enough. Recent studies suggested that cell sex is an important biological variable due to differences in sex chromosome gene expression and differences in events associated with developmental biology. The objective of this study was to analyze the reporting of sex of cells used in cancer research using articles published in Cancer Cell, Molecular Cancer, Journal of Hematology & Oncology, Journal for ImmunoTherapy of Cancer, and Cancer Research in 2020, and to examine whether there exists any sex bias. We found that the percentage of cells with sex notation in the article was 36.5%. Primary cells exhibited higher sex notation compared to cell lines. A higher percentage of female cells were used in cell cultures with sex notation. Also, sex-common cells omitted sex description more often compared to sex-specific cells. None of the cells isolated from embryo and esophagus reported the cell sex in the article. Our results indicate cell sex report in cancer research is limited to a small proportion of cells used in the study. These results call for acknowledging the sex of cells to increase the applicability of biomedical research discoveries.

Worldwide research trends on tumor burden and immunotherapy: a bibliometric analysis.

Various immunotherapy has been greatly applied to comprehensive treatment of malignant cancer under different degrees of tumor burden. Scientific researchers have gained considerable progress in the relationship between immunotherapy and tumor burden in recent years. This review aimed to explore the prospect and developing trends in the field of tumor burden and immunotherapy from a bibliometric perspective. Articles about tumor burden and immunotherapy were collected from the Web of Science Core Collection (WoSCC) (retrieved on 3 January 2023). The R package 'Bibliometrix' analyzed the primary bibliometric features and created a three-filed plot to display the relationship between institutions, countries, and keywords. VOSviewer was used for co-authorship analysis, co-occurrence analysis, and their visualization. And CiteSpace calculated the citation burst references and keywords. A total of 1030 publications were retrieved from 35 years of scientific researches. The United States (US) and China published the most articles. The most productive journals were Cancer Immunology Immunotherapy and Journal for ImmunoTherapy of Cancer . The top one institution of the highest output was University of Texas MD Anderson Cancer Center. The hot keywords of strong citation burst strength in recent years were 'nivolumab', 'tumor microenvironment', and 'immune checkpoint inhibitor'. The most popular tumor type is melanoma. This bibliometric analysis mapped a basic knowledge structure. The field of tumor burden and immunotherapy is entering a rapid growing stage and keeping it value for future research.

Immune-related adverse events: A bibliometric analysis.

Despite providing clinical benefit, immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) in a number of patients. This study explored the development pattern in irAEs research from a bibliometric perspective. We obtained articles and reviews related to irAEs from the Web of Science Core Collection (WoSCC) (retrieved on September 13, 2022). Using the R package "Bibliometrix", the main bibliometric features were calculated, and a three-filed plot was generated to show the relationship between authors, institutions, and topics. VOSviewer was used for co-authorship and keyword co-occurrence analysis and visualization. CiteSpace was used to detect burst references and keywords. A total of 3995 publications on irAEs were included. The United States (US), Japan, and China had the highest publications. The Journal for ImmunoTherapy of Cancer had the highest number of publications. In addition to "immune-related adverse events", "immune checkpoint inhibitors", "immunotherapy", and "nivolumab" were the most frequently used keywords. A bibliometric analysis of 17 years of irAEs research was conducted to map a basic knowledge structure including countries, institutions, authors, journals, and publications. The findings provided a comprehensive perspective on the broad future of this research area.

Visual Analysis of Colorectal Cancer Immunotherapy: A Bibliometric Analysis From 2012 to 2021.

An increasing number of studies have shown that immunotherapy serves a significant role in treating colorectal cancer (CRC) and has become a hotspot. However, few studies used the bibliometric method to analyze this field comprehensively. This study collected 1,899 records of CRC immunotherapy from 2012 to October 31, 2021, and used CiteSpace to analyze regions, institutions, journals, authors, and keywords to predict the latest trends in CRC immunotherapy research. The United States and China, contributing more than 60% of publications, were the main drivers in this field. Sun Yat-sen University was the most active institution, while the National Cancer Institute had the highest frequency of citations. Most publications were published in the Journal for Immunotherapy of Cancer. Adam E Snook was the most prolific writer, while Dung T. Le was the most commonly co-cited author. “T cell”, “MMI” and “PD-1blocked” were the most widely studied aspects of CRC immunotherapy. “Immune checkpoint inhibitor”, “combination therapy”, “drug therapy” and “liver metastases” were current research hotspots. “Tumor microenvironment”, “neutrophils”, “tumor-associated macrophages”, and “suppressor cell” have emerged as research hotspots in recent years. “Gut microbiota”, “nanoparticle” and “tumor mutational burden” as recently emerged frontiers of research that should be closely monitored.

Abstract P2-14-07: Marrow-infiltrating lymphocytes as adoptive immunotherapy for breast cancer

Abstract Background: The bone marrow harbors tumor-antigen specific T cells in patients with breast cancer (1). Marrow-infiltrating lymphocytes (MILs®) are the product of activating and expanding bone-marrow T cells (2). In multiple myeloma, transfer of MILs as adoptive cell therapy has demonstrated anti-tumor activity (3). The use of adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) has been used successfully for hormone-receptor positive (HR+) metastatic breast cancer (4). Expansion of MILs was previously shown to be feasible in breast cancer, non-small cell lung cancer (NSCLC), prostate, head and neck, glioblastoma and multiple myeloma (5). Using an expanded cohort, we demonstrate that tumor-specific MILs can be expanded from bone marrow in patients with breast cancer. Methods: Bone marrow aspiration and blood samples were collected from 8 patients with metastatic and high-risk early-stage breast cancer, including 3 patients with HR+/HER2-, 2 patients with HER2+, and 3 patients with triple negative subtypes, at Providence Cancer Institute (Portland, OR). MILs and peripheral blood lymphocytes were activated and expanded from patient samples during a 10-day proprietary process. T cell lineage-specific markers CD3, CD4 and CD8 were characterized by flow cytometry pre- and post- expansion. Tumor-specific T cells were quantitated in expanded MILs and peripheral blood lymphocytes using a previously described cytokine-secretion assay (3). Briefly, they were defined as the IFNy-producing population by flow cytometry. Autologous antigen-presenting cells (APCs) were pulsed with lysates from allogeneic cancer cell lines and co-cultured with activated MILs or peripheral blood lymphocytes. APCs pulsed with irrelevant mis-matched cancer cell line lysates or media alone were used as negative controls. Results: In all harvested samples, MILs expansion successfully resulted in a selective increase in CD3+ T cells. Cytokine-producing CD4+ and CD8+ T cells were detected in all expanded MILs samples, but not in any of the matched activated and expanded peripheral blood lymphocytes. MILs were successfully expanded in HR+/HER2-, HER2+, and triple negative subtypes without apparent differences in activity as measured by cytokine production. Conclusion: MILs isolated from this expanded cohort of metastatic and high-risk early stage breast cancer patients demonstrated cytokine production in response to pulsed cancer cell line lysates, consistent with our experience with other solid (5) and hematological (3) malignancies. A phase II trial to evaluate MILs in combination with a checkpoint inhibitor is underway in patients with anti-PD1/PDL1-refractory NSCLC (NCT04069936). These preclinical data demonstrate that expanding MILs is feasible and could be evaluated therapeutically in breast cancer.

PI3K δ /γ Inhibition Enhances the Expansion and Anti-Tumor Cytotoxicity of CART Cells for CLL Patients

Background:While CD19-targeted chimeric antigen receptor (CAR) based T cell therapy has shown promise in the treatment of chronic lymphocytic leukemia (CLL), overall efficacy is limited due to impaired T-cell fitness. We have previously shown that dual inhibition of PI3Kδ and PI3Kγ enhanced mitochondrial mass and ex vivo expansion of central and stem cell memory T cells from CLL patients(Funk, 2019,Journal for Immunotherapy of Cancer). In this study, we hypothesized that pharmacological inhibition of these pathways during ex vivo culture would increase the expansion and in vivo anti-tumor cytotoxicity.Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from the blood of CLL patients by ficol hypaque centrifugation. T cells were negatively selected using MACS beads and transduced with CD19 CAR lentivirus (encoding CD28 or 41BB co-stimulatory domains) and stimulated with anti-CD3/CD28 beads in media containing 30 U/mL interleukin-2 with or without the PI3Kδ/γ inhibitor duvelisib (Duv) for 15 days. NOG mice were engrafted with the OSU-CLL cell line for 14 to 18 days with tumor burden measured by flow cytometry of blood samples from the mice, comprising a mean 0.15% of peripheral nucleated cell content. Control-CART or Duv-CART were injected by tail vein injection. Frequencies of CART, OSU-CLL cells and immune checkpoint molecule expression of CART or T cells in blood were measured by serial flow cytometry. Kaplan-Meier survival plots were represented as recipient survival on the indicated daysResults: Treatment with either CD28 or 4-1BB Duv-CART cells led to significantly prolonged survival relative to control-CART (Figure 1, P<0.05). Recipients of Duv-CART cleared circulating OSU-CLL faster than control CART (Figure 2. P<0.05 at day26 for CD28 CART) and exhibited greater peak expansion and persistence of total CART and CD8+ CART. Recipients of Duv-CART cells had significantly greater in vivo persistence and expansion of total CART and CD8+ CART (Figure 3, P<0.001, day14 after CART were infused). Consistent with improved survival, both CD28 Duv-CART and 4-BB Duv-CART show reduced expression of LAG3, TIM3 and PD1 in the CD4 (Figure 4) and CD8+ subsets at earlier time point in vivo. (* p<0.05, **p≤0.01, ***p≤0.001, ****p≤0.0001).Conclusions: Inhibition of PI3Kd/g during CART cell culture decreased the expression of immune checkpoint molecules and enhanced in vivo expansion leading to greater efficacy in eliminating CLL. [Display omitted] DisclosuresWaller: Verastem Oncology: Consultancy, Research Funding; Cambium Oncology: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

Combination of Camidanlumab Tesirine, a CD25-Targeted ADC, with Gemcitabine Elicits Synergistic Anti-Tumor Activity in Preclinical Tumor Models

Camidanlumab tesirine (ADCT-301) is an antibody-drug conjugate (ADC) comprised of HuMax®-TAC, a monoclonal antibody directed against human CD25, conjugated to the pyrrolobenzodiazepine dimer payload tesirine[1]. Currently, camidanlumab tesirine is being evaluated in a pivotal Phase 2 clinical trial in patients with relapsed or refractory Hodgkin lymphoma (HL) (NCT04052997) and in a Phase 1b clinical trial in patients with advanced solid tumors (NCT03621982). In pre-clinical studies, camidanlumab tesirine demonstrated strong and durable single agent activity in CD25-expressing lymphoma xenograft models[1] and in vitro it synergised with selected targeted agents[2]. Moreover, CD25-ADC, a mouse CD25 cross-reactive surrogate of camidanlumab tesirine, induced potent anti-tumor immunity against established syngeneic solid tumor models by depleting CD25-positive tumor-infiltrating T regulatory cells (Tregs) and it showed synergistic activity when combined with PD-1 blockade[3]. Here, we investigated the in vitro and in vivo anti-tumor activity of camidanlumab tesirine combined with gemcitabine, a common standard-of-care chemotherapeutic agent used both in a hematological and solid tumor clinical setting. In vitro, the combination of camidanlumab tesirine and gemcitabine was evaluated in three human-derived cancer cell lines (two HL and one anaplastic large cell lymphoma, ALCL) and resulted in synergistic activity as determined by the Chou-Talalay method. In vivo, camidanlumab tesirine was tested either alone (0.05 or 0.1 mg/kg, single dose) or in combination with gemcitabine (80 mg/kg, q3dx4) in the CD25-expressing ALCL Karpas299 xenograft model. At both ADC dose levels, combination with gemcitabine resulted in synergistic anti-tumor activity (coefficient of drug interaction (CDI) 0.51 and 0.17, respectively), better response rates and increased survival compared to monotherapy with camidanlumab tesirine. In order to extend the investigation to solid tumor models, CD25-ADC was tested in the CT26 syngeneic model, a colorectal cancer model with CD25-expressing tumor-infiltrating Tregs. CD25-ADC was administered either alone (0.1, 0.5 or 1 mg/kg, single dose) or in combination with gemcitabine (80 mg/kg, q3dx4). At the 0.1 mg/kg dose of CD25-ADC, combination with gemcitabine resulted in synergistic anti-tumor activity (CDI 0.68). Moreover, at 0.5 and 1 mg/kg, the combination of CD25-ADC and gemcitabine resulted in more durable anti-tumor activity and better response rates compared to both monotherapy treatments. In conclusion, the combination of camidanlumab tesirine and gemcitabine was synergistic both in vitro and in vivo in lymphoma preclinical models. Synergistic anti-tumor activity was also demonstrated in a colorectal cancer model using CD25-ADC, a mouse-cross-reactive version of camidanlumab tesirine, in combination with gemcitabine. Altogether, these novel pre-clinical data warrant translation of the combination between camidanlumab tesirine and gemcitabine into the clinic. 1.Flynn, M.J., et al., ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody-Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies. Mol Cancer Ther, 2016. 15(11): p. 2709-2721. 2.Spriano, F., et al., The anti-CD25 antibody-drug conjugate camidanlumab tesirine (ADCT-301) presents a strong preclinical activity both as single agent and in combination in lymphoma cell lines. Hematological Oncology, 2019. 37(S2): p. 323-324. 3.Zammarchi, F., et al., A CD25-targeted antibody-drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity. Journal for ImmunoTherapy of Cancer, 2020. In press. Disclosures Jabeen: ADC Therapeutics: Current Employment. Hartley:ADC Therapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding. Van Berkel:ADC-Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zammarchi:ADC-Therapeutics: Current Employment, Current equity holder in publicly-traded company.

A Phase II Pilot Study of Avelumab in Combination with Hypofractionated Radiotherapy in Patients with Relapsed Refractory Multiple Myeloma

Background: Multiple myeloma (MM) is the 2nd most common hematologic malignancy and remains incurable despite significant treatment advances over the last decade. Patients with relapsed/refractory multiple myeloma (RRMM), who have exhausted available therapies, have limited treatment options and a median survival as brief as 6 months (Richardson PG et al., Oncology 2010). Immune checkpoint inhibitors (CPI) have dramatically changed treatment paradigms in multiple cancers, with growing evidence that radiation therapy (XRT) may synergize with these agents via the abscopal effect. MM cells express high levels of PD-L1. Preclinical models have demonstrated rejection of murine myeloma when PD-L1 blockade was combined with XRT (Kearl TJ et al., Journal of Immunology 2013), as well as longer survival in myeloma-bearing mice compared to controls (Jing W et al., Journal for ImmunoTherapy of Cancer 2015). Early phase single arm clinical trials with combinations of immunomodulatory drugs (IMiDs) and CPI showed response rates between 33 and 76% (Pianko MJ et al., Stem Cell Investigation 2017)(San Miguel J et al., Blood 2015)(Badros A et al., Blood 2017). However, subsequent phase 3 studies revealed a potential safety signal of this combination (FDA 2017). Nonetheless, a subset of patients appear to attain durable responses (Badros A et al., Blood Advances 2019). CPI combined with other therapies such as XRT, that help to prime the immune system, hold great promise in the treatment of patients with RRMM. Herein, we describe our phase II study of avelumab, an anti-PD-L1 IgG1 antibody with potential antibody-dependent cellular cytotoxic properties, in combination with XRT in patients with RRMM. Methods: Trial Design: The primary endpoint of this trial is to assess the systemic response rate with the combination of avelumab and XRT in the treatment of extramedullary plasmacytomas or active lytic lesions in patients with RRMM using the 2016 IMWG response criteria. Secondary endpoints include determination of complete response rate, progression-free survival, and overall survival. Patients will undergo bone marrow biopsies and imaging (PET/CT and DW-MRI) at baseline, during disease response evaluations, and at the end of treatment. Treatment: Treatment consists of a 4-week lead-in with avelumab at a flat dose of 800mg IV every 2 weeks followed by concurrent XRT of 5Gy for 5 consecutive days directed toward the plasmacytoma/lytic lesion (Figure 1). Monotherapy avelumab, 800mg IV every 2 weeks, will continue indefinitely until disease progression or unacceptable toxicity. Analysis: This is a single arm trial with a Simon minimax two-stage phase II trial design that will enroll up to 27 patients. The first stage will enroll 13 evaluable patients, and if 0 of the 13 have a clinical response, then no further patients will be accrued due to futility. If 1 or more of the first 13 patients have a response, then accrual will continue until a total of 27 evaluable patients have been treated in the second stage. This will provide a two-sided alpha of 5% and a Power of 80% to rule out an ORR of 5% in favor of a response rate of 20%. Response fractions and time to event endpoints will be reported along with 90 and 95% two-sided confidence intervals with nominal p values. Eligibility: Patients must have previously treated relapsed MM or RRMM refractory to, ineligible for, or intolerant of, available myeloma therapies and have ≥ 1 extramedullary plasmacytoma and/or lytic lesion. Lesions must be amenable to, and clinically indicated for, treatment with localized XRT. Eligible patients must have documented evidence of progressive disease on, or after, their most recent regimen as defined by the IMWG criteria. They must have achieved at least a minimal response to one or more prior regimens. Exclusionary criteria include patients with: clinically unstable lesions where a delay in XRT may be detrimental; active autoimmune diseases or history of serious autoimmune-related disorders; uncontrolled intercurrent illnesses; concurrent use of immunosuppressant medications; and recent or current anti-cancer treatment prior to the first dose of avelumab. Current Enrollment: This study is actively enrolling patients to the first stage. At the time of this submission, 4 patients have been enrolled and have received at least one dose of trial therapy. Clinical trial registry number: NCT03910439. Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: avelumab not approved in myeloma

IMMUNE CHECKPOINT INHIBITOR-INDUCED MYASTHENIA GRAVIS: A RARE NEUROLOGIC COMPLICATION OF IMMUNOTHERAPY FOR UROTHELIAL CELL CANCER

SESSION TITLE: Fellows Critical Care Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Immune checkpoint inhibitors (ICIs) such as anti-programmed death 1 (anti-PD-1) antibodies are approved for the treatment of several malignancies. Anti-PD-1 agents function by blocking tumor cell and T-cell receptor-ligand binding, thereby permitting anti-tumor T-cell immune response. Unfortunately, ICIs have been associated with a variety of immune-related adverse events, including rare neurologic complications like myasthenia gravis (MG). CASE PRESENTATION: An 81-year-old Caucasian male with bladder cancer status post cystectomy presented with one week of progressive shortness of breath and weakness, transient right-sided facial droop, intermittent diplopia, and confusion 20 days after receiving adjuvant pembrolizumab. He was afebrile, hypertensive, tachycardic and hypoxic. Lungs were clear, and his neurologic exam was normal. CT angiogram showed bibasilar atelectasis. An arterial blood gas was consistent with acute hypercapnia. He was started on non-invasive ventilation (NIV) and empiric steroids (1.5 mg/kg), however, his respiratory failure progressed requiring intubation. MRI brain and cerebral spinal fluid studies were negative for acute pathology. An electromyogram was suggestive of MG prompting initiation of plasma exchange (PLEX) for presumed ICI-associated MG. Acetylcholine receptor antibodies returned positive days later. Despite treatment, he remained ventilator-dependent and opted to pursue palliative extubation. DISCUSSION: Myasthenia gravis (MG) is a disorder of the neuromuscular junction that can lead to fatigable ocular, bulbar, respiratory, and limb muscle weakness. Ptosis, dyspnea, and diplopia are common. A recent systematic review identified 63 cases of patients who developed MG symptoms after ICI initiation. Fifty-two of these patients had de novo disease; 11 experienced exacerbations of preexisting MG. The median time from first infusion to symptom onset was four weeks. Anti-acetylcholinesterase receptor or anti-striated muscle antibodies were positive in 66 percent of cases, and 60 percent of patients demonstrated electrodiagnostic evidence of MG or MG and myositis. This heterogeneity in presentation and diagnostic evaluation can lead to delays in diagnosis and treatment. ICI-associated MG can progress to respiratory failure in a median of seven days, and mortality ranges from 38 to 50 percent. Discontinuation of ICI and IVIG or PLEX are mainstays of therapy. CONCLUSIONS: ICI-associated MG is a rare complication of cancer immunotherapy. To our knowledge, this is only the second reported case of de novo ICI-associated MG in a patient with urothelial cell cancer. ICI-associated MG can occur early after ICI initiation and progress rapidly as highlighted by this case. MG should be considered in patients with new neurologic symptoms on ICI therapy. Reference #1: Safa H, Johnson DH, Rodgers TE, et al. Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature. Journal for ImmunoTherapy of Cancer. 2019;7:319. Reference #2: Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti–programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017;74(10):1216–1222. Reference #3: Becquart O, Lacotte J, Malissart P, et al. Myasthenia gravis induced by immune checkpoint inhibitors. J Immunother. 2019;42(8):309-312. DISCLOSURES: No relevant relationships by Christine Cook, source=Web Response No relevant relationships by Andrew Moore, source=Web Response No relevant relationships by Matthew Sharpe, source=Web Response

Abstract LB-392: Optimizing dual immuno-oncology combinations with a virtual tumor

Abstract The purpose of the study was to investigate the application of a ‘virtual tumor' (‘VT') technology to optimizing the dosing and scheduling of dual immuno-oncology combinations in order to maximize the immunopotentiation and anti-tumor efficacy.The tumor microenvironment and local immune response play a key role in cancer biology, and immune resistance is a feature of many cancers. Immune checkpoints suppress the ability of the immune system to destroy cancer cells, and are a clear therapeutic target. However, response rates for such therapies are generally low. While anti-tumor efficacy can be improved by combining agents that target immune checkpoints with selected conventional anti-cancer therapies[1], the potential of immune-checkpoint blockade could be further unlocked through combination instead with other immunotherapies[2]. However, dosing and scheduling of immunotherapy combinations need to be optimized to take full advantage of a limited window for immunopotentiation[1]. Modelling can be used to deliver insights to help optimize such combination immunotherapies. We have developed a preclinical and a clinical VT technology that can predict how a tumor will respond to drug exposure[3]. This integrated PK/PD simulation platform can be used to optimize drug dosing and scheduling, and to design new combination therapies. The VT technology integrates pharmacokinetic and pharmacodynamic effects and models the way individual cells behave within a tumor population. These agent-based methods are particularly suitable for modeling not only tumor cells, but also other cell populations - such as those involved in the immune response - and also interactions between cells. Here we describe our recent development and application of the VT technology for modeling preclinical efficacy of novel immuno-oncology combinations.Building upon previous work, in which the VT platform was extended by the addition of a module that captured the synergistic interaction of PD(L)-1 blockade with conventional anticancer therapies[4], we have further expanded the model to allow simulation of immuno-checkpoint block with other immunotherapies. This module captures the mechanisms by which immunotherapies activate the innate antitumor immune response, either through immune-checkpoint block or by targeting immunosuppression by MDSC within the tumor microenvironment. Through a preclinical case study derived from the literature[5] and additional data available in the public domain, we demonstrate that the extended VT can be applied to simulate the efficacy of PD-1 blockade combined with an anti-C5a agent, and show that the combination treatment delays tumor progression. Furthermore, we demonstrate that the model can be applied to optimize the timing of the two therapies in order to maximize overall efficacy. Our enhanced VT capability represents a key step towards a strategic tool for optimizing dosing and scheduling of immuno-oncology combinations. [1] Ott, PA et al., Journal for ImmunoTherapy of Cancer 5, 16 (2017). [2]. Galon, J. &amp; Bruni, D. Nature Reviews Drug Discovery (2019) [3]. Orrell, D. &amp; Fernandez, E. Innovations in Pharmaceutical Technology 60-62 (2011). [4]. Brightman, FA et al., Abstract 4866. Cancer Res 75, 4866-4866 (2015). [5] Ajona, D. et al. Cancer Discov 7, 694-703 (2017). Citation Format: Fernando Ortega, Frances A. Brightman, Christophe Chassagnole. Optimizing dual immuno-oncology combinations with a virtual tumor [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 LB-392.

SAT-492 Impending Thyroid Storm Induced by Checkpoint Inhibitors

Introduction:Thyroid storm is a rare but life threatening condition due to thyroid hormone excess and is usually caused by Graves disease, toxic nodular goiter or rarely due to thyroiditis. Immune checkpoint inhibitors (ICI) are a novel choice for treating cancers, and carry a risk for development of endocrinopathies. We report a case of impending thyroid storm 5 weeks after initiation of ICI.Case Presentation:81-year-old Caucasian male with metastatic renal cell carcinoma presented with generalized weakness and fatigue 5 weeks after ipilimumab and nivolumab were started. He had no prior history of thyroid disease and had normal thyroid functions before the treatment. He complained of palpitations, heat intolerance and loose stools on admission. On examination he was disoriented, tachycardic (128bpm) with new onset atrial fibrillation, had moist skin and brisk reflexes. He had non-tender thyroid, no thyromegaly, and no nodules palpated. Burch-Wartofsky score was 35, suggesting impending thyroid storm. Laboratory investigation showed elevated free T4 (>7.77), elevated free T3 (8.6) with a suppressed TSH (< 0.02). He had positive anti-TPO but Thyrotropin receptor antibody was negative. He was treated with propranolol 40 mg three times daily, prednisone 40 daily, methimazole 30mg three times a day with significant improvement in free T4 (5.67) within first 48 hours.Discussion:Imipimumab and nivolumab are monoclonal antibodies against cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death receptor-1 (PD-1) respectively. The reported incidence of thyroid dysfunction after combined imipimumab and nivolumab therapy can be as high as 22%1. Thyroiditis could present as early as 2-6 weeks 2 after treatment, and hypothyroidism tends to present between 5 months and 3 years3. According to a current consensus4, baseline TSH and FT4 should be drawn prior to initiating ICI. Thyroid storm is a clinical diagnosis and Burch-Wartofsky score can help in diagnosis. A high degree of suspicion and prompt diagnosis of thyroid storm and treatment is of utmost importance especially in this patient population. Rapid improvements in thyroid hormone levels suggest thyroiditis as a potential cause for thyrotoxicosis.Conclusion:ICI induced thyroid disease is not an uncommon condition. It could present as either thyrotoxicosis or hypothyroidism. Both patient and clinician should be aware of potential signs and symptoms of thyroid storm for early recognition and timely treatment of this life-threatening condition.[1] Byun DJ et al.Nat Rev Endocrinol. 2017 Apr;13(4):195-207 [2] Iyer PC et al. Thyroid. 2018 Oct;28(10):1243-1251 [3] Endocr Relat Cancer. 2014 Mar 7;21(2):371-81 [4] Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95

Investigating the role of chromosomal instability in immune cell activation

Abstract Background Patients with high numbers of neoepitopes responds better to immunotherapy, but the correlation to response is imperfect, indicating that multiple layers of modulation and/or suppression plays a role in triggering an ongoing immune response. The STING/cGAS pathway senses cytosolic DNA and interact with P53 to trigger the innate immune system. Cytosolic DNA may be generated through chromosomal instability (CIN), a hallmark of cancer associated with poor prognosis. Here we investigate the interplay between tumour infiltrating lymphocytes (TILs) and CIN in a bladder cancer cohort from the The Cancer Genome Atlas. Methods Measures of CIN (Marquard AM, 2015, Biomark Res, Burrell RA, Nature 2013) were determined based on ASCAT segmented SNP6 data. TILs were estimated from RNAseq data as described (Danaher P, Journal for ImmunoTherapy of Cancer, 2017). CIN and TIL scores were subjected to hierarchical clustering to determine groups of high and low CIN and TIL. Results We performed hierarchical clustering separately on measures of CIN and measures of TILs, revealing for each analysis a low, intermediate and high group. To improve signal, we discarded samples in the intermediate group. This resulted in samples classified into four groups, as high/low CIN and high/low TILs. Biological characterization revealed the high CIN-low TIL group as an outlier, with fewer mutations overall, relatively higher expression of STING, and low proliferation. Kaplan-Meier analysis shows how overall survival associates with both CIN and TILs, with high-CIN associating with poor survival in high-TIL samples, but with improved survival in low-TIL samples. Conclusions Mobilization of the immune system to fight cancer is currently revolutionizing patient treatment. The adaptive immune system recognizes cancer neoepitopes and may drive an anti-cancer response. Stratifying tumours into high and low levels of CIN and TILs shows subgroup-specific biological variation potentially indicating how a dysfunctional STING/cGAS pathway may result in a reduced activation of the innate immune response with an association to overall survival. These observations need further confirmation in larger cohorts, and the implications of CIN must be explored in the context of immuno-oncology agents. Legal entity responsible for the study The authors. Funding Aarhus University Research Foundation. Disclosure All authors have declared no conflicts of interest.

A first-in-human, multicenter, open label, phase I study in patients with advanced and/or refractory solid malignancies to evaluate the safety of intravenously administered ATOR-1015.

TPS2653 Background: ATOR-1015 is a human bispecific IgG1 antibody targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and the tumor necrosis factor receptor superfamily member 4, OX40 (also known as CD134). Both in vitro and in vivo, ATOR-1015 induces activation of cytotoxic T cells and depletion of regulatory T cells (1). In syngeneic tumor models, using human OX40 transgenic mice cross-reacting with both targets, ATOR-1015 is demonstrated to localize to the tumor. Further, the effects of ATOR-1015 are shown to occur in the tumor area and not in the spleen (1). Treatment with ATOR-1015 also reduces tumor growth and improves survival in several tumor models in mice, including bladder, colon and pancreatic cancer (1). The non-clinical safety profile and the pharmacokinetics were established in cynomolgus monkeys and the data were used for the dosing schedule. Methods: This is a multicenter, open-label, dose escalation study enrolling patients with advanced and/or refractory solid malignancies (NCT03782467). The primary objective of the study is to determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) and to establish the safety profile of ATOR-1015. ATOR-1015 is administered intravenously biweekly as a single agent until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The study will start with single patient cohorts until grade 2 toxicities are observed, thereafter the study follows a modified 3+3 design. At the MTD/RP2D, or a lower dose, up to 20 patients are planned for additional safety and efficacy evaluation. Study enrollment was initiated in January 2019. A total of up to 53 patients are estimated to be enrolled in the study. (1) Månsson Kvarnhammar et al. Journal for ImmunoTherapy of Cancer 2018; 6(Suppl 1):115. Abstract P683. Clinical trial information: NCT03782467.

SUN-173 Nivolumab-Induced Fulminant Autoimmune Diabetes Presenting as Diabetic Ketoacidosis in a Patient with Melanoma

Background: Anti PD-1 antibody immunotherapies like nivolumab and pembrolizumab are newer agents used in the treatment of melanoma and multiple other types of advanced cancers. Immune-mediated endocrinopathies triggered by these drugs are increasingly reported in literature and encountered by endocrinologists in their daily practice. Fulminant diabetes characterized by rapid autoimmune destruction of the pancreatic beta cells, is a relatively rare (less than 1% reported incidence with nivolumab) but potentially lethal complication associated with anti PD-1 therapies. Case Presentation: A 44-year-old African American man with metastatic melanoma was treated with nivolumab for 3 months as second line therapy after disease progression on standard therapy. After receiving his third dose of nivolumab (doses q4 weeks), patient started complaining of gradually worsening polyuria, polydipsia, dehydration and blurry vision prompting hospitalization. The patient had no personal or family history of prior diabetes. His outpatient glucose values on office visits 1 month prior to hospitalization were normal, 80 and 82 mg/dL. Admission labs showed significant hyperglycemia with serum glucose of 938 mg/dL (nl 70-100mg/dL), elevated anion gap of 24 mEq/L (nl 7-17 mEq/L), mild acidemia with pH 7.35 (nl 7.32-7.45), elevated serum osmolality at 335 mOsm/kg (nl 281-304mOsm/kg), ketonuria and glucosuria. HbA1c at the time was 9.1% (nl 3.1-6.5%). A diagnosis of diabetic ketoacidosis was made, and the patient was admitted to the medical ICU for intravenous fluids and insulin therapy. Additional work up showed undetectable levels of C-peptide when blood glucose was 215 mg/dL. Patient tested positive for islet cell antibodies and had undetectable titers of anti-GAD antibodies. The patient was medically stabilized and eventually discharged home on a basal-bolus insulin regimen. Conclusion: Our patient is a rare case of nivolumab-induced autoimmune diabetes, clinically significant for the rapid onset and profound nature of DKA on presentation. The use of anti PD-1 immunotherapies like nivolumab is likely to become ubiquitous soon given their efficacy in treating advanced cancers. Clinicians should be aware and educated about monitoring for the potential endocrinopathies including fulminant autoimmune diabetes caused by these drugs. Refrences: Godwin, James Luke, et al. “Nivolumab-Induced Autoimmune Diabetes Mellitus Presenting as Diabetic Ketoacidosis in a Patient with Metastatic Lung Cancer.” Journal for ImmunoTherapy of Cancer, vol. 5, no. 1, 2017, doi:10.1186/s40425-017-0245-2.

Introducing the clinical trials monitor: a new section of the journal for immunotherapy of cancer

Since its inception, the Journal for Immunotherapy of Cancer (JITC) has focused on all aspects of tumor immunology and cancer immunotherapy from bench to bedside. Clinical advances in immuno-oncology are accelerating, with an increasing number of approved drugs that specifically target the immune

JITC launches a new section: commentary and editorials.

### Background We are pleased to announce the launch of a new section in the Journal for ImmunoTherapy of Cancer (JITC), the Commentary/Editorials section edited by Christian Capitini, MD of the University of Wisconsin. With all of the changes occurring in the field of immunotherapy, we felt having

JTM’s Tumor immunology goes broad: announcing the Immunobiology and Immunotherapy section

For the last four years the Journal of Translational Medicine (JTM) has hosted the Section of Tumor Immunology and Biological Cancer Therapy. Under the editorial leadership of Dr. Pedro Romero and with the direct support of the Society for Immunotherapy of Cancer (SITC), this section enriched the communication between basic immunological sciences and the clinical investigation arena in oncology. We are re-launching this Section of JTM, now entitled Immunobiology and Immunotherapy, succeeding Tumor Immunology and Biological Cancer Therapy. While aiming to build on the editorial success and focus of its predecessor, this novel Section will have a broader scope, hosting translational immunology topics pertaining to immunotherapy beyond oncology, including disciplines such as inflammation, autoimmunity, transplantation, metabolic disorders and others. As the vision of this re-launched Section of JTM broadens up to serve a communication need for translational immunologists involved with immunotherapy irrespectively of the therapeutic area, a novel and focused journal entitled Journal for Immunotherapy of Cancer (JITC) has just been initiated, sponsored by the SITC.