bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement of immune response after radiofrequency ablation in colorectal cancer.
Authors: Lemdani Katia , Mignet Nathalie , Seguin Johanne , Peschaud Frederique , Emile Jean-François , Boudy Vincent , Capron Claude , Malafosse Robert
Published: February 2018

102

Background: Radiofrequency ablation (RFA) efficiency of liver tumors is compromised by high rates of relapse. Death of cancer cells by hyperthermia induced tumor antigen releasing, expression of danger signals that activate a specific T-cell response. This effect is ineffective to avoid recurrence. We propose to combine RFA with priming of a strong immune antitumor response as curative treatment of an aggressive colorectal cancer (CRC) in immunocompetent mouse. Methods: RFA was used to treat a CT26- luc tumor as primary lesion. In two distinct clinical situations, macroscopic or microscopic distant tumors were established as secondary lesions. The immune response was modulated by the injection, in the treated area, of a thermo-reversible hydrogel loaded by GM-CSF and BCG, targeting recruitment and maturation of dendritic cells. In mice with far large lesions, this strategy was combined with PD1checkpoint inhibition. The efficiency was assessed on survival, evolution of distant lesions, characterization of tumoral lymphocyte infiltration TNF-α and IFN-y expression in peripheral T lymphocytes. Results: The in situ immunogel injection after RFA resulted in prolonged survival of mice. Regression of distant lesions was related to the induction of a strong systemic antitumor immune response and a great improvement of tumor infiltration by CD3+ T lymphocytes. In adjuvant situation, the use of immunogel induced a complete cure of microscopic secondary lesions without another treatment. Immune escape of large secondary lesions was reversed by association of the RFA-immunogel vaccination with a systemic immune checkpoint inhibition, separately ineffective. Conclusions: Validation of this strategy, combining RFA of macroscopic lesions and activation of a strong immune response controlling the residual disease, could result in the design of a clinical assay including this approach within a standard treatment of colorectal liver metastases. The synergy between in situ immunomodulation as priming process and checkpoint blockade, ineffective alone in metastatic microsatellite stable CRC or after single RFA, allows reconsidering the use of checkpoint inhibitors in CRC.
CD4, CD8 and PD1 immunoexpression in oral premalignant lesions (PML) and oral squamous cell carcinoma (OSCC) and its association with malignant transformation.
Authors: Chaves Aline Lauda Freitas , Silva Ana Gabriela , Maia Flavia M , Lopes Gabriele F , Muniz Luciana V. , Soares Joao Marcos A. , Santos Helio B. , Barbosa Leandro A , Andrade Alexandre , Paula Luiz Fernando B , Loyola Adriano M , Murta Eddie F.C , Michellin Marcia A , Ribeiro Rosy I.M.A.
Published: February 2018

113

Background: OSCC is a public health problem worldwide, mainly due to its advanced stage diagnosis. The late diagnosis is a nonsense problem in view of this neoplasia often begins as PML. Clinical, molecular and immunological factors have been associated with the cancerization process. Objective: evaluate clinical differences and immunohistochemistry expression of PD1, CD4 and CD8 in PML that transformed in OSCC (PML-OSCC) and PML that didn´t transformed in OSCC (PML-NOSSC). Methods: CD4, CD8 and PD1 immunohistochemistry studies were carried out on PML and OSCC samples of 11 patients with PML – OSCC and PML samples of 14 patients with PML-NOSCC. Statistical differences were analyzed between the two groups: PML-OSCC and PML-NOSCC. Results: Non-homogenous leukoplakia, tongue and lack of exposure to tobacco were associated with cancerization. PD1 strong immunoexpression were observed in 63.6% of PML and 90.9% of OSCC. There was no statistical difference CD4+ cells level in PML-OSCC and PML-NOSCC. A significant increase in CD8+ cells was noted in OSCC comparing with PML–OSCC (p = 0.05). CD8+ cells levels is higher in PML-NOSCC compared with PML-OSCC (p = 0.027). Conclusions: CD8+ cells infiltrate more PML-NOSCC than PML-OSCC. Carcinoma is more infiltrated by CD8+ cells than its associated premalignant lesion. The evolution of immune response from an immunosurveillance phase to editing, equilibrium, suppression and immuno-escape can be present in oral carcinogenesis process. Research Funding: FAPEMIG (Minas Gerais State Research Foundation).
Comparison of HPV E6,E7 mRNA/PD-L1 assay using flow cytometry and p16 IHC expression in oral cancer samples.
Authors: Carrasco Yvette , Chargin Amanda , Mirghani Haitham , Patterson Bruce Kendrick
Published: February 2018

114

Background: Research into causality of head and neck squamous cell carcinoma (HNSCC) has found a link to HPV infections affiliated with better survival than tobacco associated HNSCC. Currently, p16 immunohistochemistry is used as a predictive biomarker for HPV infection in HNSCC. We were interested in looking at an additional biomarker, HPV E6,E7 mRNA overexpression by flow cytometry, to see if it correlated with p16 status. Each test looks at a different marker of HPV infection, p16 as a surrogate of E7 activity, and E6,E7 mRNA overexpression as a marker of transcriptionally active and integrated virus. Currently p16 positive samples are confirmed with an ISH assay. Additionally, we looked at the PD-L1 expression in these tumors to see if it correlated with HPV mRNA overexpression. Advances in immuno-oncology have brought immunotherapy to the forefront of cancer treatment including HNSCC. Methods: Swabs were collected from Institut Gustave Roussy patients with lesions of the oral pharynx. Swabs were placed into a vial with a proprietary fixation solution and shipped overnight for processing. Upon receipt, samples were passed through a 35 uM filter to remove aggregates. Cells underwent in situ hybridization with E6, E7 mRNA probes (HPV OncoTect), were labeled with PD-L1 Ab, and then stained with a cell cycle dye identify single nucleated cells prior to analysis on the flow cytometer. FFPE biopsy tissue of the lesion was tested with p16 IHC. Positive samples were confirmed by ISH. Results: We analyzed samples from 27 patients with oral cancer with the combined E6, E7 mRNA/PD-L1 assay by flow cytometry and p16/ISH. Concordance between HPV E6,E7 mRNA positive results and p16 positive confirmed by ISH was 74%. Interestingly, PD-L1 expression was seen only in samples without HPV infection (according to HPV E6,E7 mRNA flow result). Samples are still being accrued and updated data will be presented at the meeting. Conclusions: Here we report a novel assay to quantify both HPV E6, E7 mRNA and PD-L1 simultaneously in single cells from head and neck squamous cell carcinoma. In addition, the ability to characterize both E6,E7 mRNA expression and PD-L1 in one test can provide clinicians with insight into treatment options.
Effect of therapeutic vaccine on CTLA4 and tumor debulking response in recurrent and metastatic HNSCC.
Authors: Chindavijak Somjin , Har-Noy Michael , Lausoontornsiri Wirote
Published: February 2018

115

Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is associated with multiple immune suppression and avoidance mechanisms . Blocking the PD-1 signal axis in second line provides a significant survival advantage compared to chemotherapy. However, checkpoint blockade efficacy is limited to the subset of patients that present with tumors highly infiltrated with effector immune cells. We investigated a novel vaccine designed to increase the infiltration of tumor-specific effector cells and counter-regulate the suppressive tumor microenvironment. Methods: Pre-treated r/m HNSCC patients with externally visible tumors were accrued. Tumor biopsy samples were processed at baseline to purify endogenous chaperones with calreticulin, hsp70, hsp90 and gr94/gp96 (CRCL) as a source of tumor neoantigen. Ex-vivo differentiated, allogeneic Th1 memory cells with CD3/CD28-coated microbeads attached (aTh1) expressing CD40L and IFN-gamma served as adjuvant. Subjects were primed with 4 weekly aTh1 ID injections to increase allo-specific Th1 memory titer. Primed subjects were provided 3 weekly ID injections of CRCL + aTh1 to increase tumor-specific Th1 memory titer followed by intravenous aTh1 in the 4th week to activate circulating memory cells through CD40-CD40L, causing their extravasation and trafficking to tumor lesions. Allo-rejection response produces a sustained Type 1 cytokine release which dys-regulates suppressor circuits. The ID/IV cycle was then repeated. Results: 10 subjects with recurrent or metastatic disease were accrued. All with prior radiochemotherapy. 50% (5/10) had clinical response with visible reduction in tumor burden. Vaccine was well tolerated. Debulking response correlated with increased CD3+ immune cell infiltration and decreased CTLA-4 expression. Conclusions: This individualized vaccine caused increased immune cell infiltration in tumors, down-regulation of CTLA4 and visible tumor debulking in a heavily pre-treated, chemotherapy-refractory population. These results provide rationale for further evaluation of this vaccine in a first-line setting with and without PD1/L1 blockade. Clinical trial information: NCT01998542.
Targeting CD19-negative relapsed B-acute lymphoblastic leukemia using trivalent CAR T cells.
Authors: Fousek Kristen , Watanabe Junji , George Ann , An Xingyue , Samaha Heba Samir , Navai Shoba Alaska , Byrd Tiara T , Jang Albert , Kim Hye Na , Joseph Sujith , Baker Matthew , Varadarajan Navin , Hegde Meenakshi G. , Kim Yong-Mi , Heisterkamp Nora , Abdel-Azim Hisham M. , Ahmed Nabil M.
Published: February 2018

121

Background: Chimeric antigen receptor (CAR) T cells targeting CD19 have shown remarkable efficacy in treating relapsed B cell acute lymphoblastic leukemia (B-ALL). However, recent reports show that up to 40% of patients who relapse after CD19 CAR T cell therapy have CD19-negative disease, justifying a need to expand CAR T cell therapy for B-ALL to include additional tumor-associated antigens. We hypothesize that targeting CD19, CD20, and CD22 will improve B-ALL therapy outcomes and control disease progression during CD19-negative relapse. Methods: We designed two trivalent CAR T cell products with exodomains derived from single chain variable fragments (ScFv) targeting CD19, CD20, and CD22. Each CAR contains the 4-1BB and T-cell receptor zeta chains. Donor T cells were engineered to express the CARs using a retroviral system. We used primary CD19-negative relapsed bone marrow samples and CRISPR CD19 knockouts of primary ALL to model CD19 escape and standard cytotoxicity and immune assays to evaluate anti-tumor efficacy. Results: Due to the use of viral 2A sequences we detected near equal expression of each CAR by flow cytometry. The first T cell product expresses three CARs individually (TriCAR), and the second expresses a single CAR targeting CD19 and a second bi-specific CAR targeting CD20 and CD22 via a tandem arrangement (SideCAR). Using primary B-ALL cells, we observed that TriCAR and SideCAR T cells killed ALL cells more robustly than CD19 CAR T cells at low E:T ratios. Further, in ImageStream analysis of single cell interactions between CAR T cells and primary B-ALL cells, TriCAR T cells exhibited increased actin polymerization compared to CD19 CAR T cells, suggesting remodeling and increased cell activation. Finally, in multiple models of CD19 escape in primary ALL, we showed that trivalent CAR T cells mitigated CD19 negative relapse, producing IFN-γ/TNF-α and killing CD19-negative primary ALL, while CD19 CAR T cells remained ineffective. Conclusions: Trivalent CAR T cells effectively target primary ALL cells with varying antigen profiles and mitigate CD19-negative relapse. This strategy has the potential for use as an initial CAR therapy in relapsed ALL or a salvage therapy for patients with CD19-negative disease.
Immune-related adverse events (IrAE) of elderly patients (pts) receiving PD-1 or PDL-1 inhibitors (PDIs) in a community-oncology setting: The experience at Kaiser Permanente California.
Authors: Truong Thach-Giao , Yamamoto Christopher , Chiu Timothy , Niu Fang , Spence Michele M. , Chan Jim , Cooper Robert Michael , Moon Helen , Hui Rita L.
Published: February 2018

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Background: Checkpoint inhibitors (CI) are rapidly changing the treatment (Tx) landscape across multiple cancers. They have brought with them a new set of immune-related toxicities and complications . Currently, our knowledge of irAEs has been largely informed by clinical trials enrolling younger and fitter pts. In this study, we report the experience of our large community practice, where many elderly pts of diverse backgrounds received PDIs. Methods: We conducted a retrospective cohort study, including pts who were ≥65 years old (yo) and had received PDIs between FDA approval in 2014 and September 2016, with follow-up through December 2016. Through data-mining of our electronic medical record, we evaluated the incidence of irAE and Tx outcomes, stratified by age, ethnicity, gender, co-morbidity index, and tumor subtype. Results: There were 776 pts included in the analysis. 58% were male and 29% were non-Caucasian. 83% were ages 65 to 79 yo and 17% were ≥80 yo (range 80-94 yo). 28 % of pts had a CCI > 5. Over 55% received PDIs for non-small cell lung cancer (NSCLC), followed by 12% for melanoma. 65-79 yo pts experienced similar incidence of irAE compared to pts ≥80 yo (14% vs 18%, p = 0.26). Notably, incidence was similar for gastrointestinal, pulmonary, and endocrine toxicity, though pts ≥80 yo experienced higher incidence of dermatologic toxicity (p = 0.01). Pts 65-79 yo received PDIs for median 3.3 months (mos), while pts ≥80 yo were on Tx for median 2.8 mos.The rate of irAE that resulted in health care utilization were noted in 15% of pts. Time to onset of irAE was similar between the 2 age groups (p = 0.40). Unadjusted hazard ratio (HR) for survival at the end of study was similar for pts 65-79 yo and ≥80 yo who had melanoma (HR = 0.99, p = 0.97) or NSCLC (HR = 1.32, p = 0.12). Conclusions: This is the first report of Tx outcomes with PDI use in elderly pts in a real-world setting. We found irAE rates and Tx outcomes to be similar for pts age 65-79 yo and those ≥ 80 yo. With rising cancer incidence among an ageing population, it is important for the oncology community to understand how CI therapy affects older pt groups to improve their cancer outcomes.
Inpatient admissions related to immune-related adverse effects (irAE) among patients treated with immune checkpoint inhibitors for advanced malignancy: A tsunami is coming, but are we ready?
Authors: Reynolds Kerry Lynn , Cohen Justine Vanessa , Durbin Sienna , Thomas Molly , Dougan Michael , Martinson Holly S , Faje Alex , Guidon Amanda , Channick Colleen , Chen Steven T , Lo Jennifer , Schoenfeld Sara , Sise Meghan , Leaf Rebecca , Neilan Tomas G , Awadalla Magid , Long Aidan , Sullivan Ryan J. , Bardia Aditya
Published: February 2018

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Background: Disruption of the immune system with immune checkpoint inhibitors can result in a multitude of immune-related adverse effects (irAE). While irAEs have been well-reported in clinical trials, the impact and magnitude of irAE’s in the real-world, particularly inpatient is unclear. Methods: Data was collected on patients with advanced malignancy who experienced a suspected irAE needing admission to an academic hospital (Feb 2011 to June 2017). Each case was reviewed comprehensively by minimum of two reviewers, including one sub-specialist. In addition, oncologists at our institution were surveyed regarding their confidence about managing patients with irAEs. Results: Over a span of 6 years, there were 343 hospitalizations for suspected irAEs and the majority (65%; N = 223) were confirmed irAEs that required treatment with immunosuppression or therapy stopped as result. The mean length of stay was 6.3 days (range 1 to 31 days), readmission rate for another irAE event 25%, total readmission rate 61.7%, and inpatient mortality 8%. The most common irAEs were enterocolitis (43.9%), pulmonary (16%), hepatic (15%), neurological (8.9%), endocrinopathies (7.1%), rheumatological (4%), dermatological (3%), cardiovascular (3%), renal (1.8%), and allergy (1.3%). Over the past 5 years, there was a significant increase in admissions due to irAEs (admissions in 2016 vs 2011, odds ratio = 3.07; p < 0.01). The Cancer Center survey (N = 26) revealed majority of oncologists do not feel very comfortable managing irAEs, and 48% felt that irAE complications should be managed on a different service. Conclusions: irAEs from immune checkpoint inhibitors can result in prolonged hospitalizations, high rate of readmissions, and mortality. The number of patients admitted due to irAEs has significantly increased by more than three-fold in the recent years, but majority of oncologists do not feel very comfortable managing irAEs. Consequently, there is a critical need for coordinated multidisciplinary approach, comprehensive provider education, and translational research program for early detection and intervention.
Survey analysis: Assessing the needs of immunotherapy patients, caregivers, and health care providers.
Authors: Aspiras Anabella , Power Nicholas James , Gonzalo Maria Belen
Published: February 2018

135

Background: As the use of cancer immunotherapy increases, unique challenges emerge for both patients undergoing immunotherapy and the clinical staff who care for them. To better understand these challenges, the Cancer Support Community (CSC) conducted surveys of patients, caregivers, and healthcare staff (e.g. oncologists, nurses, social workers) at nine oncology centers across the country. Methods: Needs assessments were conducted through paper and online surveys between August and September, 2017. The analysis is based upon a cross-sectional survey of adult (18 years old and older) cancer patients, caregivers, and healthcare providers. 93 healthcare providers, 65 patients, and 21 caregivers completed the survey. Descriptive statistics and statistical analyses were performed using SPSS Version 24; analyses of association used a significance level of .05. Results: Findings from this analysis yielded important provider perspectives and illustrated targeted areas of patient and caregiver concern. Of note, while only about one-third of patients and caregivers (31% and 38%, respectively) indicated that it was important to understand the science of immunotherapy, nearly half of healthcare providers (46%) reported that educational resources should go “quite a bit” in-depth into immunotherapy science. Also, although caregivers reported greater difficulty finding information about immunotherapy, the majority of both patients (55%) and caregivers (85%) identified managing treatment-related side effects as their foremost education need. Conclusions: CSC’s analysis revealed valuable insights in both clinical care and patient education. Needs assessment results will inform the development and implementation of Immunotherapy & Me, a CSC pilot program to determine whether layering in patient education and care-management tools leads to improved patient and clinical outcomes. CSC’s needs assessments conclude that for both patients and providers, treatment-related side effects are top-of-mind. This underscores the importance of developing turnkey resources to help patients and healthcare providers manage immunotherapy-related side effects – an express goal of the Immunotherapy & Me pilot.
Association of the T-cell receptor landscape with survival in non-small cell lung cancer.
Authors: Reuben Alexandre , Gittelman Rachel , Zhang Jiexin , Quek Kelly , Vence Luis M , Behrens Carmen , Chen Runzhe , Fujimoto Junya , Chow Chi-Wan , Wu Xifeng , Allison James Patrick , Sharma Padmanee , Zhang Jianhua , Lee J. Jack , Sepesi Boris , Gibbons Don Lynn , Heymach John , Futreal Andrew , Wistuba Ignacio Ivan , Zhang Jianjun ,   ICON-PROSPECT Team
Published: February 2018

140

Background: Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types which respond best to immune checkpoint blockade, likely through its ability to enhance the anti-tumor T cell response. However, the lung is constantly exposed to the outside environment, which may result in a continuous state of inflammation targeting pathogens rather than tumor cells. Therefore, a greater understanding of the T cell receptor (TCR) landscape and phenotypes across normal lung and tumor is warranted. Methods: Here, we performed sequencing of the CDR3 variable region of the beta chain of the TCR as well as whole exome sequencing on peripheral blood, normal lung and tumor in 235 NSCLC patients. We further analyzed the immune microenvironment by Cytometry by Time-of-Flight (CyTOF) in 10 NSCLC patients with paired normal lung and tumor. Results: Comparison of the TCR repertoire showed 9% (up to 15%) of T cells were shared between normal lung and tumor, though the most dominant were generally shared (up to 95%). Interestingly, T cell clonality was higher in the normal lung than tumor in almost all patients (89%, p < 0.0001) suggesting potential differences in the ongoing immune response in different regions of the lung. A substantial number of non-synonymous exonic mutations (NSEM) were detected in tumors (average = 566 NSEM) but also in the normal lung (average = 156 NSEM), with many shared (up to 45.6%). CyTOF confirmed marked differences in the immune microenvironment, including higher frequency of VISTA+ antigen-presenting cells in the tumor (p = 0.04). Finally, analysis of clinicopathological attributes revealed a greater T cell diversity in the periphery in patients with increased overall survival (OS, p = 0.001), while patients with a more similar normal lung/tumor T cell repertoire showed decreased OS (p = 0.028). Conclusions: These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be lung-resident T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes, which highlights differences in the ongoing antigenic response within the lung.
Response and adverse events to chemotherapy after prior checkpoint inhibition in lung cancer.
Authors: Judd Julia , Ramamurthy Chethan , Handorf Elizabeth , Borghaei Hossein , Zibelman Matthew R. , Geynisman Daniel M. , Bauman Jessica Ruth
Published: February 2018

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Background: Historically, responses to chemotherapy beyond the first line for lung cancer range from 5-10%. The effect of antecedent immunotherapy on the response and reaction to chemotherapy is not well-established, but the immunomodulatory effects of many chemotherapy agents may lead to synergistic effects including both improved responses and unique toxicities. Methods: We reviewed the charts of patients at our institution who received at least one dose of an anti-PD-1 agent (aPD-1) as monotherapy prior to June 1, 2017. Patients with a diagnosis of non-small cell lung cancer or small cell lung cancer who received subsequent chemotherapy were included for analysis. Charts were assessed for response to aPD-1, occurrence of immune-related adverse event (irAE) on aPD1, type of post-aPD-1 (PaPD-1) chemotherapy, PaPD-1 best response to chemotherapy, and occurrence of irAE during PaPD-1 chemotherapy. irAEs were assessed based on treating physician diagnoses. We tested the association between response and treatment characteristics using Fisher’s exact and Wilcoxon rank-sum tests. Results: A total of 40 patients met criteria for inclusion. Histology was NSCLC in 38 (95%) and SCLC in 2 (5%). Median age was 68 and mean number of lines of therapy prior to aPD-1 was 2.00 (95% CI, 1.72-2.28). PaPD-1 chemotherapies included paclitaxel (15%), docetaxel (28%), gemcitabine (23%), docetaxel-ramucirumab (7.5%), pemetrexed (2.5%) and platinum doublet (15%). The disease control rate to PaPD-1 chemotherapy was 35% and the ORR was 15% (0 complete responses, 6 partial responses). The response to PaPD-1 was not higher in taxane-containing regimens than in non-taxane-containing regimens (16% v. 13%, p = 0.99). Four (10%) patients were diagnosed with an irAE during their receipt of PaPD-1 chemotherapy. These PaPD-1 irAEs included dermatitis, colitis, and pneumonitis that responded to steroid therapy and occurred on various chemotherapy agents (gemcitabine, paclitaxel, docetaxel). Conclusions: In lung cancer, the response to chemotherapy beyond first line may be modestly higher when administered after aPD-1 therapy. Immune-related adverse events can occur during chemotherapy administered after aPD-1 therapy has been stopped.
Treatment with PD-1 inhibitors in NSCLC beyond disease progression: Impact on symptoms and cost.
Authors: Moskovitz Mor Tal , Matthews Priscilla M , Pavel Alexandra M , Xu Wei , Bradbury Penelope Ann , Liu Geoffrey , Shepherd Frances A. , Leighl Natasha B.
Published: February 2018

174

Background: Immunotherapy with PD-1 axis inhibitors has become standard of care in the treatment of patients with advanced non-small cell lung cancer (NSCLC), with improved survival and less toxicity than chemotherapy. Response patterns to PD-1 axis inhibitors can be unconventional, including pseudoprogression. Identifying disease progression using RECIST has been challenging. We explored treatment past progression (TPP) with PD-1 inhibitors and its impact on patient symptoms and costs. Methods: Retrospective analysis of consecutive patients with advanced NSCLC that received single agent PD-1 inhibitors at the Princess Margaret Cancer Centre (PMH) between 2013 and 2017. Patient symptom burden was assessed by Edmonton Symptom Assessment Scale (ESAS) at outpatient clinic visits. Drug acquisition costs were calculated using hospital-based costs for the agents used and both actual and fixed dosing recommendations. Results: The study cohort included 89 patients with advanced NSCLC. Median age was 62, half were female and 75% had adenocarcinoma. Most, 70%, developed disease progression during treatment, 19% stopped due to toxicity. Twenty-one patients received TPP (23% of entire cohort, 34% of those with progression). Demographic characteristics except age and baseline symptom scores were similar between groups. Younger patients (p = 0.046), those with lower symptom burden upon RECIST progression (mean ESAS 14.7 vs. 27.2 non-TPP, p = 0.013) and greater symptom improvement from baseline (mean ESAS change -11.7 vs. -2.3 non-TPP, p = 0.11) were more likely to receive TPP. During TPP, only 1 patient achieved tumor response. TPP represented 29% of total treatment costs. This did not vary significantly between weight- based and fixed dosing. However, the costs of treatment of the entire cohort was 23% higher using fixed dosing compared to weight-based. Conclusions: : Treatment with immunotherapy beyond RECIST progression is common in advanced lung cancer, although patient benefit is rare. This can lead to substantial expenditure without clear value for most patients. Better methods for detecting early failure of immunotherapy in advanced NSCLC are needed, to allow patients to switch to more active treatment.
Effect of STING agonist on tumor immune microenvironment of non-inflamed lung cancer and efficacy of immune checkpoint blockade.
Authors: Chon Hongjae
Published: February 2018

178

Background: Cancer immunotherapy targeting immune checkpoints are now emerging as a promising therapeutic strategy in various tumors. However, the treatment of T cell non-inflamed tumor which lacks intratumoral T cell infiltrates are still major clinical hurdle. Therefore, drugs that target signaling pathways to increase T cell infiltration in non-inflamed tumor microenvironment (TME) should be investigated. In this study, we aimed to explore the therapeutic potential of STING agonist in murine model of non-small cell lung cancer to overcome immunotherapy resistance. Methods: C57BL/6 mice, which are 6 to 8 weeks of age, were used for the experiment. Mice were injected with Lewis lung carcinoma cells on the right flank. STING agonist (cGAMP) was injected intratumorally. CD8+ and CD31+ cells were detected using immunofluorescence (IF) staining. Gene expressions of tumor microenvironment were analyzed by NanoString RNA sequencing. Flow cytometry (FACS) was performed to detect CD8+, CD4+, Treg and myeloid cell population. Tumor growths were evaluated in combination with anti-PD1 and STING agonist treatment. Results: Local injection of STING agonist effectively delayed tumor growth of LLC. STING agonist increased intratumoral CD8+ T cells and vascular disruption. Expressions of inhibitory checkpoint molecules (PD-1, PD-L1), cytokines (IFN), CD8+ and CD4+ T cells were increased, which showed that anti-cancer immune responses were augmented. Combination treatment of anti-PD-1 antibody and STING agonist synergistically decreased tumor growth. Conclusions: In this study, STING agonist was shown to delay tumor growth and remodel tumor microenvironment in non-inflamed lung carcinoma model. Combination therapy of STING agonist and immune checkpoint inhibitors (ICI) targeting PD-1 synergistically suppressed the growth of lung cancer which is resistant to ICI monotherapy. Collectively, our findings demonstrated that localized STING therapy effectively sensitizes non-inflamed lung cancer to systemic ICI treatment and induces a maximal anti-cancer immune response.
MHC-II expression to drive a unique pattern of adaptive resistance to antitumor immunity through receptor checkpoint engagement.
Authors: Balko Justin M. , Johnson Douglas Buckner , Wang Daniel Ying , Ericsson-Gonzalez Paula , Nixon Mellissa , Salgado Roberto , Sanchez Violeta , Schreeder Daniel , Kim Ju Young , Bordeaux Jennifer , Sanders Melinda , Davis Randall S.
Published: February 2018

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Background: Anti-PD-1 therapy is effective in many cancers, but tumor-intrinsic factors governing response and resistance are largely unknown. MHC-II (HLA-DR) expression on tumor cells can predict response to anti-PD-1. Thus, we sought to determine the molecular features of MHC-II+ tumors in the evolution of anti-PD-1 response. Methods: We performed RNA-seq on 58 anti-PD-1 treated melanoma and lung tumors, including a subset of matched specimens prior to treatment and at acquired resistance. We performed immunohistochemistry (IHC) for immunologic markers, including HLA-DR on tumor cells. In triple-negative breast cancers (TNBC; n = 103), we performed IHC and/or quantitative immunofluorescence (QIF) for LAG3, PD-L1, CD4, CD8, Fc-receptor-like 6 (FCRL6), and granzyme B (GZMB). QIF images were assessed by Automated Quantitative Analysis (AQUA). To determine the functional effect of MHC-II on tumor cells, we generated isogenic MHC-II+ mouse tumors and assessed immune responsiveness and efficacy of checkpoint inhibition. Results: We identified unique inflammatory signatures in HLA-DR+ tumors, correlating with enhanced pre-treatment CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) and response to anti-PD-1. LAG3+ and FCRL6+ TILs were enriched in HLA-DR+ tumors. LAG3 and FCRL6, known inhibitory receptors which bind MHC-II, were elevated at anti-PD-1 resistance. Similarly, in > 100 TNBCs, HLA-DR+ tumor cells associated with increased CD4+ and CD8+ TILs and enhanced LAG3+ and FCRL6+ TILs. Further, presence of MHC-II-suppressing (LAG3+/FCRL6+) TILs associated with decreased GZMB+ CD8+ T cells, suggesting suppressed cytotoxicity. In mice, enforced expression of MHC-II on tumor cells enhanced CD4-enhanced anti-tumor immunity but was thwarted by LAG3+ TIL recruitment. Combined anti-LAG3 and anti-PD-1 therapy was selectively effective in MHC-II+ tumors. Conclusions: MHC-II+ tumors are immunologically active and may circumvent anti-tumor immunity by targeting MHC-II antigen presentation via recruitment of MHC-II-suppressing TILs. MHC-II expression may be useful to stratify patients to anti-PD-1/anti-LAG3 and eventually, anti-PD-1/anti-FCRL6 combinations.
Outcomes of immunotherapy in advanced melanoma in relation to age.
Authors: Joshi Krishna Prasad , Atwal Dinesh , Ravilla Rahul , Tao Jun , Su Joseph , Makhoul Issam , Hutchins Laura Fulper , Mahmoud Fade A.
Published: February 2018

187

Background: Older age is a risk feature in melanoma. Elderly are more likely to have immunosenescence, which could help melanoma cells escape immune surveillance. Hence, there is a belief that elderly people cannot mount a potent immune response to checkpoint inhibitors (CPI) to fully eliminate melanoma. The objective of the study was to investigate age-related differences in the time to progression (TTP), overall survival (OS), and immunotherapy related adverse events (irAEs) among patients with metastatic melanoma who received CPI. Methods: We retrospectively identified patients with stage IV melanoma who received at least 1 dose of ipilimumab, pembrolizumab, nivolumab, or combined ipilimumab and nivolumab. Demographics, pathologic, and clinical characteristics were obtained. Immune-related response criteria were utilized to define responses. Results: Sixty patients were included; 29 were less than 65 years old and 31 were 65 years or older. No significant differences, when adjusted for gender, type of melanoma and presence of brain metastasis, in TTP [HR 0.79; 95% CI (0.371.70); p = 0.46] and OS [Hazard ratio (HR) 0.75; 95% CI (0.31-1.82); P = 0.491] was observed between the < 65 and ≥65 year-old groups who received CPI for metastatic melanoma. Overall irAEs in two groups was comparable with 62% in the younger patients and 45% in the older patients (P = 0.19). Thirty responders had a median age of 66.9 (54.3-73.3 years old) and 30 non-responders had a median age of 62.7 (54-69.1 years old). Non-responders, regardless of age, were more likely to have BRAF mutated melanomas (53.3% vs. 27.6%; P = 0.04) and less likely to have irAEs (40% vs. 66.7%; P = 0.04) than responders. Conclusions: No difference in TTP, OS or irAEs was observed between the elderly and the young patients who received CPI for metastatic melanoma. In general, responders had higher irAEs and less BRAF mutated melanomas than non-responders.
Preliminary findings from part 1 of COMBI-i: A phase III study of anti–PD-1 antibody PDR001 combined with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma.
Authors: Dummer Reinhard , Arance Fernández Ana María , Hansson Johan , Larkin James M. G. , Long Georgina V. , Gasal Eduard , Kaper Mathilde , Upalawanna Allison , Mookerjee Bijoyesh , Atkinson Victoria
Published: February 2018

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Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with advanced BRAF V600–mutant melanoma; however, many still progress and die from this disease. Thus, new treatment strategies are needed. BRAF and MEK inhibitor combinations (eg, D+T) may reverse immunosuppressive phenotypes induced by oncogenic BRAF and improve sensitivity to checkpoint inhibitors by enhancing HLA and melanocytic antigen expression and tumor antigen–specific T-lymphocyte recognition. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating the anti–PD-1 antibody PDR001 in combination with D+T in treatment-naive pts with BRAF V600–mutant unresectable or metastatic melanoma in 3 parts: 1, safety run-in; 2, biomarker cohort; and 3, randomized, double-blind, placebo-controlled part. Here we report preliminary findings for 9 pts in part 1 dosed with PDR001 400 mg Q4W + D 150 mg BID + T 2 mg QD. Response was assessed at wk 12 and Q8W thereafter. Results: At data cutoff (16 Jul 2017; median follow-up, 2.7 mo), all 9 pts completed the 8-wk dose-limiting toxicity (DLT) period, during which 1 DLT (transaminitis [AST and ALT > 8 × ULN]; n = 1) occurred. Adverse events (AEs) of any grade occurring in > 3 pts included pyrexia (n = 9), headache (n = 6), chills (n = 4), and vomiting (n = 4). Grade 3/4 AEs reported in > 1 pt included hepatitis (n = 3), increased lipase (n = 2), and increased transaminases (n = 2). AEs leading to discontinuation occurred in 2 pts (22%; transaminitis, n = 1; grade 3 hepatitis, n = 1) who permanently discontinued PDR001 but were still receiving D+T at the data cutoff. All 9 pts responded: 3 (33%) achieved a complete response (confirmed, n = 1), and 6 (67%) had partial responses (confirmed, n = 1). Additional safety and efficacy results for these 9 pts, all ongoing at the data cutoff, will be presented. Conclusions: These preliminary results indicate that PDR001 can be combined with D+T with a manageable safety profile and demonstrate promising activity in pts with BRAF V600–mutant melanoma. Clinical trial information: NCT02967692.
Effect of CTLA-4 overexpression on response to ipilimumab in melanoma.
Authors: Nesline Mary , Puzanov Igor , Ernstoff Marc S. , Pabla Sarabjot , Conroy Jeffrey M. , Glenn Sean T. , Papanicolau-Sengos Antonios , Burgher Blake , Giamo Vincent , Andreas Jonathan , Qin Maochun , Lenzo Felicia L. , Gardner Mark , Morrison Carl
Published: February 2018

190

Background: CD8 positive tumor infiltrating lymphocytes (TILS) are highly associated with immune response and prognosis, and are also under investigation as a marker of response to checkpoint inhibitors. Given lack of predictive biomarkers for ipilimumab, growing number of trials for new indications for combination ipilimumab + nivolumab, and evidence to support therapeutic target overexpression as markers of response, we examined the role of CTLA-4 expression and TILS in response to ipilimumab and combination ipilimumab + nivolumab in melanoma. Methods: Formalin-fixed paraffin embedded melanoma samples taken prior to treatment by ipilimumab (n = 36) or combination ipilimumab + nivolumab (n = 10) were evaluated by a comprehensive immune gene expression profile to establish the relationship between CTLA-4 and CD8 and therapeutic response (RECIST v1.1). Results: Increased CTLA-4 expression was moderately associated with increased TILS (r2= .41, p = .004). This was observed in the monotherapy group (r2= .38, p = .02), and was higher in the smaller combination therapy group, though not statistically significant (r2= .59, p = .06). Higher levels of TILS were observed in responders who achieved clinical benefit from either regimen within 6 months (n = 20). No significant difference was observed between responders (M = 57.1, SD = 30.2) and nonresponders (M = 48.6, SD = 32.9); t(44) = -.895, p = .376. Lower levels of CTLA-4 were observed in responders who achieved clinical benefit from either regimen within 6 months. No significant difference was observed between responders (M = 54, SD = 35) and nonresponders (M = 38.7, SD = 26.8); t(44) = 1.70, p = .09. The ratio of TILS to CTLA-4 expression was higher in responders who achieved clinical benefit within 6 months (n = 20).No significant difference was observed between responders (M = 5.2, SD = 14.0) and nonresponders (M = 1.4, SD = 2.7); t(41) = -1.2, p = .212. Conclusions: While not statistically significant, CTLA-4 expression in melanoma patients treated with either ipilimumab or combination ipilimumab + nivolumab was lower in responders compared to nonresponders. This analysis does not support the concept that over-expression of CTLA-4 is a biomarker of response to anti-CTLA-4 therapy.
Development of gene expression signatures characterizing the tumor-immune interaction.
Authors: Danaher Patrick , Warren Sarah , Cesano Alessandra
Published: February 2018

205

Background: The efficacy of anti-tumor immunity depends on diverse factors, including not just abundance of immune cell populations but also activities of those populations and of tumor cells. Many of these processes are onerous to assay, but all are reflected in a tumor’s gene expression profile. Using a novel method, we develop gene expression signatures measuring a variety of biological processes underlying the tumor-immune interaction. These signatures fall into categories including antigen availability, structural barriers to immune infiltration, inhibitory signaling by both immune and tumor cells, inhibitory metabolism, pro-immune signaling, killing of tumor cells, tumor receptiveness to immune signaling, and tumor proliferation and death. Methods: We develop a method to train signatures of biological processed by synthesizing biological knowledge and large gene expression datasets. For a given process, we use literature searches and expert knowledge to derive lists of candidate genes. We then evaluate the co-expression of these candidate genes in data from The Cancer Genome Atlas (TCGA), discarding genes whose co-expression patterns are incompatible with their measuring their putative biological process. This approach safeguards the interpretability of our signatures: we only report signatures whose genes show evidence for measuring the desired biology. Finally, we further exploit co-expression patterns to obtain optimal weights for each signature gene. Results: We attempted to train signatures of over 30 biological processes involved in immune oncology. Of these, 17 candidate gene sets displayed sufficient evidence for measuring their putative biology. We show these signatures provide granular but intelligible descriptions of both immunotherapy datasets and single samples. We find they improve power in differential expression analyses and in training of predictors of drug response. Conclusions: The signatures we derive convert gene expression data into measurements of biological processes central to immune oncology, and they improve statistical power and interpretation of results in immunotherapy studies. Our training procedure ensures these signatures measure their intended biology.
A phase 1 study of p53MVA vaccine in combination with pembrolizumab.
Authors: Chung Vincent M. , Kos Ferdynand , Hardwick Nicola , Yuan Yuan , Chao Joseph , Li Mengsha , Zurcher Kathryn , Frankel Paul Henry , Li Daneng , Waisman James Ross , Diamond Don J.
Published: February 2018

206

Background: Mutations in the p53 gene are present in a majority of solid tumors, resulting in the accumulation of oncogenic and potentially immunogenic p53 protein within tumor cells. We have developed a genetically engineered Modified Vaccinia Ankara (MVA) virus to express wild type p53 transgene (p53MVA) as an immunotherapeutic strategy. We observed robust p53-specific CD8+ T cell responses which were further enhanced by anti-PD-1 treatment. This phase 1 study evaluates the safety and tolerability of the p53MVA vaccine in combination with pembrolizumab. Methods: Patients with non-small cell lung, head and neck squamous cell (HNSCC), hepatocellular (HCC), renal cell, melanoma, bladder, soft tissue sarcoma, triple-negative breast (TNBC), pancreatic (PDAC) and MSI high colorectal cancer failing or intolerant to standard treatment were eligible. Confirmation of p53 involvement by immunohistochemistry or mutational analysis was required for eligibility. A 3-at-risk rolling design was employed and patients received 5.6 x 108 pfu p53MVA for 3 doses in combination with 200 mg pembrolizumab for 7 doses every 3 weeks. Blood draws for immunological monitoring were obtained pre-treatment and up to week 19. Results: Two patients (TNBC and HNSCC) showed clinical benefit associated with durable p53-specific CD8+ T cell responses with gene expression pathway scores of T cell function and associated immune response categories elevated for more than 6 months. The TNBC patient had complete regression of cutaneous metastases and stable disease for > 6 months. Two patients (TNBC and PDAC) were on study for 35 and 9 weeks respectively; however, p53-specific T cells were not generated. Four patients (HCC, PDAC and 2 with TNBC) had rapidly progressive disease. Conclusions: Targeting p53 antigen associated with cancer using a viral vaccine p53MVA in combination with PD-1 blockade represents a novel immunotherapeutic approach capable of stimulating systemic immune responses and associated clinical benefit. Clinical trial information: NCT02432963.
Radiation therapy and immune-related side effects in patients treated with PD-1 inhibitors.
Authors: Abdallah Nadine , Patel Suketu Nagin , Nagasaka Misako , Kim Seongho , Kim Harold E. , Sukari Ammar
Published: February 2018

207

Background: Checkpoint inhibitors exert their antitumor effects by producing a heightened immune state, and inadvertently give rise to immune-mediated toxicities, including pneumonitis and hypothyroidism. We investigated whether these side effects were more common in patients who were treated with both PD-1 inhibitors and radiation. Methods: Our institution’s pharmacy database was used to collect data on patients who received ≥ 1 dose of PD-1 inhibitors, with or without radiation before August 31, 2016. Adverse effects of hypothyroidism, and pneumonitis were recorded and graded based on CTCAEv4. A logistic regression analysis was performed between radiation and hypothyroidism among patients with Hodgkin’s lymphoma (HL) and head and neck squamous cell carcinoma (HNSCC) and between radiation therapy (RT) and pneumonitis in lung cancer patients. Results: 231 patients received at least one dose of PD-1 inhibitors prior to data cut-off. Median age was 65 (24-92). There were 125 patients (54%) with lung cancer, 18 (8%) with HL and 9 (4%) with HNSCC. 115 patients received radiation. HL and HNSCC patients had higher odds to experience hypothyroidism (adjusted p = 0.023) but this did not seem to be due to RT exposure [HR:0.156, 95% CI 0.008-1.122, p = 0.110]. Lung cancer patients with thoracic radiation had higher odds to experience pneumonitis [HR:2.206, 95% CI 0.451-15.931] although this was not statistically significant (p = 0.358). Conclusions: There was no association between RT and hypothyroidism. Our results suggested a possible increased risk of pneumonitis with thoracic radiation among lung cancer patients treated with PD-1 inhibitors, although statistically insignificant. Larger prospective studies are needed to further delineate this effect.
Cancer immunotherapy using trabectedin and nivolumab in advanced soft tissue sarcoma: A retrospective analysis.
Authors: Gordon Erlinda Maria , Sankhala Kamalesh Kumar , Stumpf Nathan , Ravicz Joshua , Arasheben Suzan , Leong Bryan , Kang Grace , Kim Seth , Tseng William W. , Chawla Sant P
Published: February 2018

40

Background: To restore innate tumor surveillance that is lost in cancer patients, a tumoricidal agent may have synergistic activity with an immune checkpoint inhibitor. Herein, we report on a retrospective analysis of our clinical experience using trabectedin, an alkylating agent, and nivolumab, a PD-1 inhibitor in advanced soft tissue sarcoma. Methods: Twenty previously treated STS patients received trabectedin (1.5 mg/m2 continuous intravenous infusion, CIV, for 24 hours) every 3 weeks, and nivolumab (3 mg/kg IV over 30 minutes) every 2 weeks. Safety/toxicity was analyzed using the NIH/NCI CTCAE v.4.03. Tumor responses were assessed by RECIST v1.1 and immune-related response criteria (irRECIST). Results: Histologic subtypes in 20 patients include undifferentiated pleomorphic sarcoma (UPS; n = 7), leiomyosarcoma (n = 5), synovial sarcoma (n = 2), myxoid liposarcoma (n = 4) and chondrosarcoma (n = 2). All patients had metastatic disease and a median of 4 lines of prior chemotherapy. Safety analysis (n = 20): Grade 3 treatment emergent adverse events include anemia (n = 2), fatigue (n = 1), decreased platelet count (n = 1), decreased granulocyte count (n = 1) and increased creatine kinase (n = 1). Efficacy analysis (n = 17): Seventeen patients were followed for at least 6 months and their results are reported here. There were 4 partial responses (UPS = 1, myxoid liposarcoma = 1, chondrosarcoma = 1, leiomyosarcoma = 1), 7 stable disease, and 6 progressive disease, with best overall response rate of 23.5%, median progression free survival (PFS) of > 11.6 months (range: 2.3- > 16.9 months), median overall survival (OS) of > 14.2 months (4.5- > 24.0 months), 6 month PFS rate of 64.7%, and 6 month OS rate of 94.1%. In a Phase 3 study, the median PFS was 4.2 months using trabectedin alone (Demetri et al., 2015). Conclusions: Taken together, the data suggest that paired administration of trabectedin and nivolumab is safe, and that this chemo-/immuno-therapy approach has synergistic activity.