bluuebunny/crossref_metadata_2025 huggingface dataset:
A quantum biochemistry investigation of cancer immunotherapy.
Authors: Albuquerque E.L. , Tavares Ana Beatriz M.L.A. , da Silva L.R. , Lima-Neto J.X. , Fulco U.L.
Published: September 2018

e14558

Background: Immunotherapy is a procedure to boost the patient's own immune system to fight diseases such as cancer. In some types of cancer, it has been found that the programmed cell death receptor PD-1 impedes the body's immune defenses from functioning at full strength. Therefore drugs, like pembrolizumab, which prevent the interaction between this protein and the T-cells, may be a key tool to avoid the onset of cancer tumors. Methods: The aim of this work is to describe the interaction energies between the protein PD-1 and its drug inhibitor pembrolizumab by using a quantum biochemistry calculations, taking advantage of the X-ray crystal structure of the protein PD-1 in complex with its inhibitor. The protonation state of the drug was obtained using the Marvin Sketch code (Marvin Beans Suite). The optimization procedure was performed using the parametrization tool for organic molecules CHARMM (Chemistry at Harvard Macromolecular Mechanics). Afterwards, simulations within the density functional theory (DFT) framework were carried out by using the Gaussian code to provide a detailed energy profile of the interactions between the inhibitor and the receptor. Results: The interaction energy between each PD-1 molecule and the drug was calculated considering any significant attractive and repulsive drug’s amino acid residues. A searchfor an optimal binding pocket radius was done, looking for no significantvariation in the total binding energy. The converged binding pocket radius was found to be 1.5 nm, comprising a total of 145 amino acids residues displayed in a BIRD (Binding site, Interaction energy and Residues Domain) graphic panel. Although it was observed few repulsive interactions, the attractive ones were predominant, pointing out to a strong inhibition of the programmed cell death receptor. Conclusions: Immunotherapy is ranked nowadays as an important alternative to treat cancer. Among the drugs been tested, those blocking the protein PD-1 and its ligands have been considered an efficient way to trigger the T-cells. In this context, the computational method used in this work is a low cost efficient first step to unveil the drug’s amino-acids residues that play the most important role on the binding affinity of the receptor-ligand complex.
Some patients who achieved CR due to accelerator+brake therapy that was performed in the form of activated autologous lymphocytes with the concomitant use of low-dose immune checkpoint inhibitors.
Authors: Abe Yoshinobu , Aikawa Yoshiyuki
Published: September 2018

e14561

Background: Otsuka et al. from Kyoto University reported in Oncoimmunology (October 24, 2016) that a group responding to Opdivo showed an increase in the number of “Type-9 helper T (Th9) cells”, which are a type of lymphocyte. On the basis of this clinical study, in September 2015, our clinic introduced immunotherapy that is performed in the form of activated autologous lymphocytes with the concomitant use of low-dose Opdivo and Yervoy. This therapy was named Accelerator+Brake therapy, and obtained a registered trademark in Japan. Methods: Accelerator+Brake therapy was performed for 359 patients between September 2015 and September 2016. These patients had lung cancer (n = 84), breast cancer (n = 45), colorectal cancer (n = 32), etc. The therapy was also performed for patients with sarcoma, which is a rare type of cancer. The patients underwent 5 courses of Accelerator+Brake therapy with 2-week intervals (overall treatment period: two and a half months), and the numbers of NK and T cells increased to approximately two billion through culture activation. In every course, Opdivo and Yervoy were administered at doses of 20 and 10-25 mg, respectively. Although not all patients have been followed up on a long-term basis, we encountered some patients who achieved CR after one or two courses. Results: I present 6 cases of CR. First case is 65 y.o. male, renal pelvis cancer has spread to his mediastinal lymph nodes. Second case is 57 y.o. male, intrahepatic cholangiocarcinoma has spread to his bilateral lungs. Third case is 64 y.o. female, breast cancer has spread to her lumbar vertebra. 4th case is 53 y.o. male, renal cancer has spread to his lung. 5th case is 55 y.o. female, breast cancer has spread to her lung. Last case is 39 y.o. male, renal cancer has spread to his pleural lesion. All 6 cases result in CR. I also present several cases of PR. Conclusions: Activated autologous lymphocytes with the concomitant use of low-dose Opdivo and Yervoy named Accelerator+Brake therapy is may become a breakthrough treatment to solid cancer.
Inflammatory arthritis: An under-recognized immune-relate adverse effect.
Authors: Mooradian Meghan , Cohen Justine Vanessa , Giobbie-Hurder Anita , Fadden Riley , Rubin Krista M. , Flaherty Keith , Lawrence Don P. , Sullivan Ryan J.
Published: September 2018

e14565

Background: Checkpoint inhibition (CPI) has significant and durable effectiveness against a broadening range of cancers and currently is FDA approved for more than 10 different malignancies. With increasing use of CPI, there is a need to understand the range and extent of immune-related adverse effects (irAE). Though certain irAEs, such as colitis and pneumonitis have been well studied, CPI- induced arthritis (CA) has not been widely recognized nor well characterized with data on the subject largely comprised of case reports and small case series. Methods: We retrospectively reviewed 125 patients (pts) with advanced melanoma treated with CPI to define the incidence and clinical features of CA. We identified 20 pts who developed CA during the course of CPI treatment. Cases were included only if active rheumatic signs or symptoms developed after receiving therapy. Demographic data (gender, age), type of CPI, number of CPI cycles, treatment of CA and other irAE manifestations were extracted from the medical chart. Results: 16% of patients treated with CPI developed CA. Among the 20 pts, the average age at CA onset was 70.3 (43, 84) with 75% of pts male. 80% had received anti-PD-1 monotherapy, 15% combination anti-PD-1 + anti-CTLA-4 and 5% monotherapy with CTLA-4 inhibition. The average number of infusions prior to symptom onset was 13.5 (1-48) after a median time point of 6.6mths on therapy. Basic rheumatologic testing (RF, CCP, ANA) was only positive in 10% of cases. 20% of pts were treated with non-steroidal anti-inflammatory drugs alone, whereas 40% required corticosteroids (systemic or injection). The remaining 40% necessitated treatment with disease modifying anti-rheumatic drugs. Conclusions: CA is a debilitating irAE with a higher incidence (16%) than most other irAEs and a negative impact on the quality of life of pts affected. Based on our retrospective review, this irAE tends to delayed in onset and often requires systemic immune suppressants for effective treatment. We posit that this is an under recognized and undertreated irAE. Further work is needed to better define the clinical factors that may affect or predict its development.
Isolation and expansion of OCT4/Sox2 specific cytotoxic T lymphocytes in vitro.
Authors: Zhang Xueyan , Lou Yuqing , Zheng Xiaoxuan , Zhang Yanwei , Xu Jianlin , Gu Ping , Wang Huiming , Han Baohui
Published: September 2018

e14578

Background: The main reason for tumor MDR (multidrug resistance ,MDR) is the presence of CSC(cancer stem cells,CSC). In the CSC of lung cancer, OCT4 and Sox2 are closely related to the tumor MDR. Therefore, in the current study, we introduced a method for the generation of OCT4+/Sox2+ CSC specific CTL(cytotoxic T lymphocytes,CTL) through co-culture with CD154+ feeder layer cells. Methods: Lenti/CD154 was constructed. The NIH3T3 cells were incubated with Lenti/CD154 (103 vp per cell) for 24 h at 37 °C and 5% CO2. Then the NIH3T3 cells were subsequently maintained in fresh complete DMEM medium. Lenti/GFP was used as a control. On the 6th day post infection, the infection rate was determined by flow cytometry after incubation with CD154-PE antibody. The feeder layer cells were co-cultured with CD40B cells and the biomarkers of CD40B cells were determined by flow cytometry. The CTL were treated with OCT4 plus Sox2 antigen and then the biomarkers of CTL were examined by flow cytometry and IL-2 and IFNγ were determined by ELISA. Results: The rate of CD154+ NIH3T3 cells was 99.7%, which was higher than that of uninfected-cells (14.8%). After co-culture with CD154+ NIH3T3 cells, the rates of CD40B expressing CD80, CD86 and HLA-A were significantly increased. OCT4 plus Sox2 treatment further increased the CD3, CD4 and CD8 expression and elevated the secretion of IL-2 and IFNγ. After co-culture of CTL with MDR PC9-drived cancer stem cells (CSC) and parental PC9 cells at different ratio, CTL significantly killed the tumor cells compared with control. Conclusions: The generation and expansion of OCT/Sox2 specific CTL is a feasible method for the treatment of lung cancer.
Identification of DNA repair/replication genes mutations in determining response to immune checkpoint inhibitors in non-small cell lung cancer patients.
Authors: Li Meng-Xia , Wang Guan , Yang Xiao , Lu Xianfeng , Zhang Shiheng , Xu Jiayue , Wang Dong , Xu Qiang
Published: September 2018

e14582

Background: Tumor mutational burden (TMB) is considered a promising predictive biomarker for immune checkpoint blockade (ICB) therapy response . However, the measurement of TMB relies on the whole-exome sequencing (WES), which is technically limited by sample volume and freshness, thus restricts its use in clinical practice. Since TMB is controlled by the balance between DNA damage and the repair, it is a rational approach to identify a subset of DNA repair/replication gene mutations associated with increased TMB as a surrogate, which could be monitored in clinic to predict ICB efficacy even busing limited archived tissues. Methods: The mutation status of 471 genes associated with DNA repair and replication were analyzed for the correlation with TMB and/or ICB therapeutic responses in three cohorts of NSCLC patients, which are: Cohort A, WES data of 100 Chinese NSCLC patients; Cohort B, WES data of NSCLC patients from TCGA database; Cohort C, WES data and therapeutic response to PD-1 mAb from a Science paper (Rizvi et al. 2015, Science). Results: We identified somatic mutations in 32 DNA repair/replication genes associated with high TMB in both Cohort A and Cohort B. In Cohort C, mutations were found in 20 out of these 32 genes, and the mutation status of 17/20 genes were associated with the clinical benefit of ICB therapy. Noteworthy, mutations of TP53, POLQ, MMS22L, HERC2, CEP164, BRCA1/2, FANCM and MSH4 were mostly common mutations associated with TMB in all 3 cohorts, and ERCC2 and ERCC6 were uniquely high mutated and associated with high TMB in Chinese Han people from Cohort A. Interestingly, EGFR activating mutations were inversely correlated with both high TMB and good ICB response. Conclusions: This retrospective study identified 17 DNA repair/replication-related genes, whose mutation status was associated with high TMB and/or ICB response. Mutational patterns of DNA repair genes are likely different between western and Chinese NSCLC patient population. The data also suggested that NSCLC patients carrying EGFR activating mutations are not preferential population for ICB therapy. Further data is needed to verify the validity of these observations.
Adoption of immunotherapy into real-world practice: Insights from the use of checkpoint inhibitors.
Authors: O'Connor Jeremy , Seidl-Rathkopf Kathi , You Paul , Nussbaum Nathan C. , Torres Aracelis Z. , Fessele Kristen L. , Darius Katie , Adelson Kerin B. , Yin Emily , Presley Carolyn Jean , Chiang Anne C. , Ross Joseph S. , Abernethy Amy Pickar , Gross Cary Philip
Published: September 2018

e14583

Background: Cancer research has been criticized regarding the generalizability of trials to older persons, as well as the timeliness of the impact of new trials on real-world practice. Despite growing enthusiasm about programmed death 1 checkpoint inhibitors (anti-PD1s), little is known about the speed with which these drugs are adopted into real-world practice, or whether anti-PD1 treated patients in real-world practice are older than patients treated in trials. Methods: We used retrospective data from Flatiron Health’s electronic health record database, which includes 250 cancer clinics and 1.5 million patients with cancer. We identified patients diagnosed after January 1, 2011 who underwent systemic therapy for: advanced melanoma (n=1,670), advanced non-small cell lung cancer (aNSCLC; n=19,536), or metastatic renal cell carcinoma (mRCC; n=2,018). Then, we determined the proportion treated with anti-PD1s in the 2nd line or later following US Food and Drug Administration (FDA) approval. Therapy lines containing study drugs were excluded. Chi-square tests were used to compare age distributions of patients treated in real-world practice to patients treated in trials that support FDA approval. Results: At 6 months following FDA approval, 71.9% of patients with melanoma undergoing treatment were receiving anti-PD1s, versus 33.0% of patients with aNSCLC and 46.0% of patients with mRCC. Within 1 year, more than half of all treated patients with these 3 cancers were receiving anti-PD1s (71.0% in melanoma; 51.4% in aNSCLC; and 51.8% in mRCC). The median ages at first receipt of anti-PD1s were ≥65 years (65.1 years in melanoma; 67.9 years in aNSCLC; 66.0 years in mRCC). Anti-PD1 treated patients were significantly older in real-world practice than patients treated in trials (Table: all p<0.001). Conclusions: In a large national sample of patients with cancer, anti-PD1s were adopted rapidly into real-world practice. Compared to patients treated in real-world practice, older patients were underrepresented in clinical trials. [Table: see text]
Digital image analysis as an aid in the assessment of the combined positive score in ovarian carcinoma.
Authors: Kulangara Karina , Calcagno David , Boyer Scott , Hanks Debra Ann , Yamada Holly
Published: September 2018

e14584

Background: Developing scoring methods for PD-L1 to identify patients who will respond effectively to anti-PD1 therapy is key in the development of companion and complementary diagnostic assays. The Combined Positive Score (CPS) is an elegant method for the evaluation of PD-L1 expression in solid tumors. CPS includes the number of PD-L1 positive cells (tumor, lymphocytes and macrophages) in relation to total tumor cells. The accurate manual capturing of total number of tumor cells can be a challenge to pathologists. Methods: Image analysis was used to evaluate possibledifferences in tumor density for well, moderately, and poorly differentiated ovarian epithelial serious carcinomas. Multiple regions of interest of 158 hematoxylin-stained specimens were analyzed. Algorithm parameters were systematically adjusted to minimize mean differences in tumor count relative to manually counted scores in small, user-selected regions of 33 representative specimens. Results: The average nuclei count ranged between 2000 and 7000 with ~50% falling between 4.0-5.5 x 103. Conclusions: Digital image analysis of nuclear quantification has been shown to be a useful tool to aid the pathologist with the correct assessment of the CPS score.
Clinical outcomes of patients on check point inhibitor therapy who receive routine vaccinations.
Authors: Schenk Erin Lynn
Published: September 2018

e14597

Background: Routine vaccination reduces preventable illness and infection in cancer patients even while undergoing therapy. Increasingly, patients with advanced malignancies receive check point inhibitors (CPI) and, with tumor response, can remain on therapy for extended periods of time. These agents promote tumor clearance by impeding a normal route of immune regulation which can result in autoimmunity. To the best of our knowledge, clinical outcomes for patients on CPI therapy who receive routine vaccinations have not been studied. Methods: The medical records of patients who received CPI therapy at Mayo Clinic in Rochester, Minnesota from March 25, 2011 to August 25, 2015 were reviewed for type and date of immunizations, CPI duration, adverse events (AE) at least possibly related to therapy, and survival from start of CPI. Patients who received > 1 dose of pembrolizumab or nivolumab were included in analysis. Patients were excluded if no follow up was done at our institution. Results: One hundred and eight patients were included in the analysis. Most patients received CPI therapy for metastatic melanoma (n = 71) or non-small cell lung cancer (n = 23). A total of 53 routine vaccinations were administered to 30 patients while on CPI therapy. Eighteen patients received a single vaccination. Annual influenza vaccination was most frequently administered (n = 38) followed by pneumococcal vaccines (n = 9). AEs were reported in 17/30 vaccinated patients and in 22/78 non-vaccinated patients (p = 0.004). In the vaccinated cohort, 11 patients experienced AEs after immunization and was not significantly different from the non-vaccinated patients (p = 0.265). For both cohorts, thyroid, rash, and pneumonitis were the most common AEs. Grade 3 AEs occurred with similar frequency between the 2 groups. Patients in the vaccinated cohort received more cycles of therapy (median 20.5 vs 6 cycles, p < 0.001). Median survival of patients who were not vaccinated was 503 days and median survival was not reached in the vaccinated group (p = 0.005). Conclusions: Routine vaccination of patients receiving CPI therapy did not significantly increase number or severity of adverse events. Routine vaccination did not reduce patient benefit from CPIs.
Potential therapeutic target for PD1/PDL1 blockade in microsatellite medullary carcinomas based on PDL1 expression by tumor cells and infiltration by numerous PD1+ T lymphocytes.
Authors: Bossard Celine , Ott Eva , Dansette Delphine , Ouary Adrien , Jarry Anne , Bezieau Stephane , Toquet Claire , Mosnier Jean-François
Published: September 2018

e14599

Background: PD1/PDL1 blockade showed therapeutic efficacy in only microsatellite (MSI) colorectal carcinomas (CRC), however, the profile of PDL1 and PD1 expression in CRC is only partially described. Methods: We thus analyzed on FFPE whole-tissue sections of 80 CRC, the expression profile of PDL1 by tumor and/or immune cells by immunohistochemistry (clone E1L3N) depending on the MSI status and the histological subtype, and correlated to the density of PD1+ and Tbet+ (able to secrete IFNg known to induce PDL1) tumor-infiltrating lymphocytes (TIL). Results: 78% of MSI CRC (32/41) overexpressed PDL1 either by tumor or immune cells versus 46% of MSS CRC (18/39) (p 0.005). This overexpression was heterogeneous within the same tumor in most of cases. Among MSI CRC, PDL1 was preferentially overexpressed in medullary carcinomas (MC, 19/21, 90%) compared with 65% (13/20) in non medullary adenocarcinomas (p 0.06). PDL1 expression by tumor cells was only observed in MSI CRC (19/41, 46% with PDL1 expression in more than 5% of tumor cells – score 1), and preferentially in MC (57% vs 5% in no medullary adenocarcinomas, with PDL1 expression in more than 50% of tumor cells – score 3, p 0.0005). Conversely, PDL1 expression by immune cells was observed in MSI CRC (23/41, 56% with PDL1 expression by more than 5 sheets of 50 positive cells) but also in MSS CRC (18/39, 43%) (p 0.5). The density of PD1+ cells was significantly correlated to the PDL1 expression, as well as the density of Tbet+ TIL. Conclusions: PDL1 expression is 1) heterogeneous in CRC, among CRC but also within the same tumor, 2) preferentially observed in MSI CRC (78%), especially in MC (90%), where PDL1 is expressed by tumor cells, 3) correlated with the density of PD1+ or Tbet+ TIL, and 4) observed in a significant proportion of MSS CRC (46%) by immune cells only. From a clinical point of view, PDL1 expression has to be determined at best in full tissue section and besides its preferential expression in MSI CRC, its significant frequency and expression profil (only by immune cells) in MSS CRC should be taken into account in the future clinical trials testing the efficacy of anti-PD1/PDL1 antibodies.
Analysis of a large patient cohort with nivolumab: Predictive clinical factors for continued benefit after an immune-related adverse event.
Authors: Osman Diaa , Win Khine Zar , Wong Morgan , Phan Alexandria T.
Published: September 2018

e14600

Background: Nivolumab (NIVO), a PD-1 inhibitor, is used in various advanced malignancies with meaningful and durable outcomes. However, its use can be limited by severe immune-related adverse events (irAEs). We analyzed our large single institution patient cohort who have been treated with NIVO to risk stratify and identify clinical factors associated with continued benefit after irAEs. Methods: 125 patients with advanced malignancies, treated with NIVO during 2011-2016 at the University of New Mexico Comprehensive Cancer Center, were evaluated. Inclusion criteria included a minimum of 1 completed treatment of NIVO (1 or 3mg/kg). Stratifying factors including age, gender, BMI, ethnicity, co-morbidities, pretreatment WBC and albumin, number of treatments received, type of malignancy, number of metastatic sites, overall tumor response rate (ORR), irAEs, and tumor response rates after irAE were identified. Results: Primary sites of cancer for the 125 patients who received NIVO were lung (44, 35%), melanoma (43, 34%), head-neck (8, 6%), renal (14, 11%), Hodgkin’s (16, 13%), 2 patients with more than one malignancy (1 with lung and head-neck, and 1 with lung and melanoma), and other non-approved indications (16, 13%). The overall tumor response rate was 34.4%. Total All CTCAE v4 grades irAEs experienced were 32% (40/125), and 33% (13/40) were severe (grade > 3). Eighteen (18/40, 45%) patients continued to have tumor response after experiencing any grade irAE. The mean age of those experiencing an irAE with subsequent tumor control (CR, PR, or SD) was 72.3 years, mean BMI 28.2 kg/m2, 38.9% were female, 11.1% were non-Caucasian, 61.1% had > 2 co-morbidities, 72.2% with > 2 metastatic sites and the mean albumin was 3.4 g/dl. Conclusions: Patients who had a tumor response after being re-challenged with NIVO, despite experiencing an irAE, were found to be older, had a higher BMI, an increased number of co-morbidities, higher tumor burden, and mean albumin > 3.0g/dl. Risk stratifying these patients prior to starting treatment is possible and can be helpful in anticipating which patients should be re-challenged or will have continued benefit with NIVO after experiencing an irAE.
Immune checkpoint inhibitor treatment of advanced age metastatic melanoma (MM) patients.
Authors: Hegde Upendra P. , Kerr Phil , Masternak Sophie , Brenner Bruce Mark , grant-Kels Jane
Published: September 2018

e14603

Background: Immune checkpoint inhibitor (ICI) treatment has become effective method of treating mm including in those over 65 years of age. Increasing number of advanced age mm patients (pts.) are eligible for ICI treatment but not much is known about its efficacy and safety in relation to senescent immune system. We are reporting our updated experience of ICI treatment of advanced age mm pts. from a single Institute. Methods: Between 2011 and 2016, 32 eligible pts. diagnosed with mm were treated at the University of Connecticut with ICI including anti CTLA-4 antibody Ipilimumab, anti PD-1 antibody Pembrolizumab or combination of Ipilimumab and Nivolumab at their FDA approved doses on a standard protocol. Pts. were monitored for immune related adverse events (irAE) that were graded and managed with standard immune suppressive regimens Results: 12 out of 32 mm pts. were over 70 years of age (median 82.5 years, range 73-88 years). Nine pts. were treatment naïve, two had previously failed Ipilimumab treatment and one anti-BRAF and anti- MEK targeted therapy. Clinical benefit occurred in 5 out of 12 pts. (Complete response (CR) 3, partial response 1 and stable disease 1). Nine out of 12 pts. developed irAE that included three grade II (fatigue, diarrhea, hypopituitarism each) and 6 grade IV events (skin rash-1, colitis-1, encephalopathy-1, myasthenia gravis-1, and pneumonitis in 2 pts. each respectively). Of note, an 87-year-old male developed polymyalgia rheumatica after second dose of anti PD-1 treatment that responded to steroids, but developed autoimmune diabetes mellitus and pneumonitis following third dose. Two pts. died from irAE that included an 87-year-old woman from treatment refractory myasthenia gravis and 77-year-old male who suffered sudden death during steroid treatment of pneumonitis. Six pts. died of progressive disease including sudden death in a 77-year old woman and a 87-year-old male following five and two anti PD-1 treatments respectively. One pt. died from pulmonary embolism and four pts. are alive, 2 in CR and two with disease. Conclusions: Our experience indicate advanced age mm pts. respond to ICI treatment but have heightened risk of developing serious irAEs.
Effect of adenoviral p53 (Ad-p53) tumor suppressor immune gene therapy on checkpoint inhibitor resistance and abscopal therapeutic efficacy.
Authors: Sobol Robert E. , Chada Sunil , Wiederhold Dora Bocangel , Yun Chae-Ok , Ahn Hyomin , Oh Eonju , Murthy Ravi , Subbiah Vivek , Menander Kerstin B.
Published: September 2018

e14610

Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients do not respond or become resistant to this form of immune therapy. Methods: We evaluated the ability of Ad-p53 to reverse immune checkpoint inhibitor resistance and induce abscopal effects in the immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before initiating Ad-p53 intra-tumoral therapy. Results: Anti-PD-1 had minimal therapeutic efficacy compared to control treatment. A statistical analysis of variance (ANOVA) comparison of tumor volumes revealed that the combined effect of Ad-p53 and anti-PD-1 treatment was synergistic and superior to either therapy alone (p = 0.0001). Surprisingly, there was a statistically significant abscopal effect with decreased growth of contralateral tumors not injected with Ad -p53. The Ad- p53 alone (p = 0.046) and Ad- p53 + anti-PD-1 (p = 0.0243) treatment groups both demonstrated a statistically significant decreased abscopal tumor growth compared to treatment with anti-PD-1 alone. Combined Ad- p53 and anti-PD-1 therapy demonstrated a statistically significant increase in survival compared to Ad- p53 therapy alone (p = 0.0167) and anti-PD-1 therapy alone (p < 0.001) by the log rank test. We have initiated a Phase 1 clinical trial of Ad-p53 intra-hepatic arterial therapy in combination with capecitabine for patients with solid tumor liver metastases. In the first cohort of patients at a dose of 2 x 1012viral particles, treatment has been well tolerated with transient fever, chills and rigors. In one patient, decreased SUV uptake on PET scans of distant lymph node metastases suggested possible abscopal effects. Conclusions: These results suggest that Ad-p53 tumor suppressor immune gene therapy may reverse immune checkpoint inhibitor resistance and induce abscopal effects supporting the planned clinical evaluation of combined Ad-p53 and anti-PD-1 therapy in patients resistant to immune checkpoint inhibitor therapy. Clinical trial information: NCT02842125.
A novel phase I/IIa open-label study of IMM-101 in combination with selected standard of care regimens in patients with metastatic cancer or unresectable cancer at study entry.
Authors: Cunningham David , Blay Jean-Yves , Marabelle Aurelien , Stanbury David , Mudan Satvinder , Rosa Brunet Laura
Published: September 2018

e14627

Background: The MODULATE (IMM-101-011, EUDRACT 2016-001459-28) trial recruits patients with metastatic or unresectable cancer considered for a new line of recognised SOC (1st, 2nd or 3rd line and beyond). IMM-101 is a heat-killed whole cell Mycobacterium obuense (National Collection of Type Cultures [NCTC] 13365) for intradermal injection. Methods: The primary objective of the study is to provide safety data for IMM-101 in combination with several selected SOC regimens. The secondary objectives of the study are to provide safety and tolerability data for extended administration (beyond 28 weeks) of the immunomodulator IMM-101 in combination with a number of selected SOC regimens. A particular focus of the study is to evaluate safety data for the combination of IMM 101 with anti PD1 and with anti-CTLA 4. Pre-clinical data suggests that IMM-101 increases the response to PD1 in a syngeneic in vivo model of EMT6 breast cancer. Furthermore, in a syngeneic B16 melanoma tumour model the combination of IMM-101 with anti-PD1 antibodies increased T effector cells in the tumour and reduced the numbers of T-regulatory cells; significantly shifting the T-cell ratio towards anti-tumour efficacy. Results: The study aims through its translational programme to evaluate the best combination partner for IMM-101 due to the SOCs immunogenic cell death capabilities and supportive immunological activities. MODULATE will monitor selected markers of tumour burden and immunological status in patients taking IMM-101. Conclusions: The MODULATE study will initially recruit patients in the UK and France with US sites added in Q4 2017. Clinical trial information: NCT03009058. [Table: see text]
A clinical trial for the safety and immunogenicity of a DNA-based immunotherapy in men with biochemically (PSA) relapsed prostate cancer.
Authors: Shore Neal D. , Heath Elisabeth I. , Nordquist Luke T. , Cheng Heather H. , Bhatt Kamalnayan , McMullan Trevor , Kraynyak Kimberly , Lee Jessica , Sacchetta Brian , Tagawa Scott T. , Parikh Rahul Atul , Tutrone Ronald F. , Garcia Jorge A. , Whang Young E. , Lin Jianqing , Kelly William Kevin , Csiki Ildiko , Bagarazzi Mark L. ,   PCa-001
Published: September 2018

e14634

Background: Introducing amino acid sequence changes in highly expressed self-antigens for prostate cancer (PCa) patients (pts) might lead to avoidance of immune tolerance. We evaluated a DNA vaccine (INO-5150) including SynCon PSA and PSMA. Administration of INO-5150 to PCa pts along with plasmid encoded adjuvant IL-12 (INO-9012) via electroporation (EP) is postulated to break tolerance, resulting in antigen-specific immune responses which could lead to stabilization of disease progression. Methods: Phase I, open-label, multicenter study of PCa pts post-definitive therapy with a rising PSA ≥ 1.0 ng/ml after surgery, or ≥ 2.0 ng/ml above nadir after RT and PSADT > 3 months, testosterone > 150 ng/dL, no concomitant androgen deprivation therapy and no evidence of metastases within 12 months. We evaluated safety, tolerability and for efficacy signals. INO-5150 low (2 mg, arms A and C) or high (8.5 mg, arms B and D) dose with or without INO-9012 (1 mg) was administered IM followed by EP in total 4 dosing arms on Day 0 and at Wks 3, 12, and 24 in 60 planned pts (15/arm). Pts were followed for 72 Wks. Results: 62 pts, 16 each in arms A and D and 15 in B and C were enrolled. Median age: 69.5 yrs (range 55.4-87.7), Gleason score: 7 (5-10), time from initial diagnosis: 8.2 yrs (0.5-23.8) and ECOG PS: 0 (0-1). As of data cutoff of 23Jan17, 52 pts had EOT visit, 7 withdrawn from treatment and 6 (10%) reported disease progression, 3 biochemical and 3 radiographic. Median serum PSA at enrollment was 4.6 ng/mL (range 1.2, 113.7) and at EOT was 6.5 ng/mL (0.1, 73.6). Median PSADT at enrollment was 8.7 months (3.1, 218.1) and at EOT it was 3.1 months (-23.1, 100.0). Safety: no reports of Grade 4-5 SAEs. 6 Grade 3 SAEs in 5 pts: presyncope, cardiac disorder, fall, neoplasm, ALT and AST elevation. Grade 1-3 AEs reported in 51 (82%) pts: 12 (75%) in Arm A, 13 (87%) B, 13 (87%) C, and 13 (81%) in D. Common AEs were injection site pain (24/39%), swelling (14/23%), erythema (14/23%), all Grade 1-2. Conclusions: INO-5150 (+) and (-) INO-9012 was generally safe and well-tolerated at all 4 dose levels in this patient population. Preliminary data suggest PSA stabilization in some patients. Immune analyses are ongoing. (NCT02514213) Clinical trial information: NCT02514213.
Real world eligibility of treatment-refractory stage IV colorectal cancer patients for palliative intent regorafenib monotherapy.
Authors: Angeles Arkhjamil , Hung Wayne , Cheung Winson Y.
Published: September 2018

e15007

Background: The CORRECT trial demonstrated overall survival benefits of regorafenib monotherapy in patients with metastatic colorectal cancer (CRC) who were refractory to prior chemotherapy and biological therapy. However, stringent criteria used to determine treatment eligibility in the trial setting may limit its external validity in the real world. We aimed to examine treatment attrition rates and eligibility of regorafenib in routine clinical practice. Methods: All patients diagnosed with metastatic CRC between 2009 and 2014 who received 2 or more lines of systemic therapy at the British Columbia Cancer Agency were identified. During the study timeframe, cetuximab (cmab) and panitumumab (pmab) were only used in the chemo-refractory setting. Data on clinical factors, pathological variables and outcomes were ascertained and analyzed. Eligibility was defined based on criteria outlined in the CORRECT trial. Results: A total of 391 patients were included among whom only 39% were considered eligible for regorafenib. Median age was 61 (range 22-84) years. 247 (63%) were men, 305 (78%) were Caucasian, and 237 (60%) had a colonic primary. The disease burden at diagnosis was high: 267 (81%) had lymph node involvement, and 225 (59%) had distant metastases. In patients previously treated with cmab, main reasons for regorafenib ineligiblity were Eastern Cooperative Oncology Group performance status (ECOG PS) > 1 (26.9%), aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN) (6.5%), and arterio-venous thrombotic or embolic events in the preceding 6 months (6.5%). In the group treated with pmab previously, main reasons for ineligibility were ECOG PS > 1 (46.6%), total bilirubin > 1.5 x ULN (14.1%), and thrombotic or embolic events in the past 6 months (5.7%). Additional analyses showed that regorafenib-eligible patients had increased median overall survival compared to ineligible patients (44.0 vs 37.1 months, P= 0.028). Conclusions: The strict trial eligibility criteria disqualified the majority of real world patients with metastatic CRC for regorfenib. As ineligibility predicts poorer outcomes, trials aimed at serving protocol-ineligible patients are warranted.
Analysis of survival and prognostic factors in metastatic colorectal cancer patients treated with first line bevacizumab.
Authors: Demircan Nazim , Dane Faysal , Ozturk Mehmet Akif , Besiroglu Mehmet , Babacan Nalan , Kaya Serap , Ercelep Ozlem , Simsek Eda Tanrikulu , Halil Suleyman , Koca Sinan , Alan Ozkan , Hasanov Rahib , Yumuk Perran Fulden
Published: September 2018

e15009

Background: Colorectal cancer is a major cause of mortality worldwide. Survival has been improved by usage of bevacizumab. Our study aimed to analyze survival and prognostic factors in metastatic colorectal cancer patients treated with first-line bevacizumab. Methods: Files of patients were examined retrospectively and 360 patients treated with first-line bevacizumab were included. Data regarding age, gender, family history, location of the primary, histopathology, KRAS status, surgery and chemotherapy were acquired from the files. Overall response rates (ORR) to chemotherapy, progression and exitus dates or dates of last examination were recorded. Median progression-free and overall survival (PFS and OS) were calculated. Survival was analyzed with Kaplan-Meier method. Log-rank test and Cox regression model were used for univariate and multivariate analysis, respectively. Results: 201 (%55,8) of the patients were male and 159 (%44,2) were female. Median age at the time of the diagnosis was 59.5. 260 patients (%72,2) had initially stage IV disease. KRAS was mutant in 125 patients (%34,7). Median PFS was 8.5 months, median OS was 25.3 months and ORR was %51,4. Median PFS was 8.2 and 9.5 months, median OS was 30.4 and 28.1 months, ORR was %62,6 and %58.4 in KRAS wild type and mutant groups, respectively. In patients with left colon cancer median PFS and OS (9.6 and 27.1 months) were superior compared to patients with right colon cancer (7.3 and 19.4 months) (p = 0.005 and 0.016, respectively). Location of the primary, histopathologic grade, primary surgery, metastasectomy and KRAS status affected overall survival significantly (p < 0.05) in univariate analysis. In multivariate analysis, histopathologic grade (p = 0.034) and metastasectomy (p = 0.001) were independent prognostic factors. Conclusions: In our study, response rates and survival of metastatic colorectal cancer patients treated with first-line bevacizumab were similar to previous studies. Left colon cancer patients had superior median PFS and OS compared to right colon cancer patients as shown in recent studies. Histopathologic grade and metastasectomy were independent prognostic factors in correlation with literature.
Treatment patterns of metastatic colorectal cancer (mCRC) in commercially-insured populations in Washington state.
Authors: Snider Jeremy Williams , Fedorenko Catherine R. , Warnick Greg S , Steelquist Jordan , Wang Ed , Anderson Sibyl , Ramsey Scott David , Shankaran Veena
Published: September 2018

e15011

Background: Few studies have examined patterns of care relating to guideline-recommended therapies for metastatic colorectal cancer (mCRC) in real-world settings. The goal of this study was to investigate treatment patterns for initial and subsequent therapies for mCRC patients in two large commercial plans in Washington State, USA. Methods: We utilized the Hutchinson Institute for Cancer Outcomes Research linkage of Western Washington Cancer Surveillance System (CSS) SEER data with claims from Regence BlueShield and Premera BlueCross (representing 20% of the WA insured population) for patients diagnosed with mCRC between 2012 and 2016. We identified all patients with Stage IV CRC at diagnosis or stage I-III CRC with subsequent claims suggesting metastatic recurrence. We conducted descriptive analysis and multivariate modeling to evaluate the association between age, race, gender, and rurality with receipt of systemic therapy. We examined 1L (first line) regimens received in the first 15 days of treatment, and classified them as adherent or not to NCCN guidelines. In light of recent FDA approval for regorafenib (9/2012) and TAS-102 (9/2015), we examined use of these therapies for refractory mCRC. Results: Among 4,536 CRC cases identified in the database, 426 patients had evidence of metastatic disease and met all inclusion criteria. 87 (20.4%) received no systemic therapy. Of the 339 (79.5%) who received systemic therapy, FOLFOX was the most common 1L regimen (29.5%), followed by FOLFOX+bevacizumab (12.3%). There was evidence of 1L treatment outside of NCCN guidelines – 8.5% of patients received single-agent bevacizumab, and 8.0% received single-agent oxaliplatin. Patients who did not receive systemic therapy were more likely to be older and live in a large metropolitan area. For subsequent therapies, 24 (7.1%) patients received regorafenib, and 5 (1.5%) received TAS-102. Conclusions: In a commercially-insured mCRC cohort, a majority received 1L guideline-based therapy. Many patients did not receive systemic therapy despite current recommendations - further evaluation of factors contributing to these decisions are warranted. Use of regorafenib and TAS-102 was uncommon.
Parenchymal sparing surgery for colorectal liver metastases: The need for a common definition.
Authors: Desjardin Marie , Evrard Serge , Brouste Véronique , Desolneux Gregoire , Fonck Marianne , Bechade Dominique , Bonhomme Benjamin , Becouarn Yves
Published: September 2018

e15013

Background: Colorectal cancer metastases (CRLM) are major public health issue. Recently, surgeons have advocated the use of parenchymal sparing surgery (PSS) however, a common definition of the concept is lacking.To clarify and try to validate the concept of PSS to treat CRLM through the available retrospectives studies, including ours. Methods: Retrospective analysis of a cohort of patients treated by combined resections and intra-operative ablation (IOA) based on PSS, prospectively recorded in a database from 2003 to 2015 in a regional referral cancer center. All the patients benefited from the same strategy, constituting a homogenous series.PSS consists of using resection or IOA in order to spare the healthy parenchyma. One-stage is favored over two-stage surgery and use of portal vein embolization was restricted to the minimum.Post-operative complications were the primary endpoint with a special focus on post-operative liver failure. Liver toxicities and overall survival were also scrutinized. Results: Three hundred and eighty-seven patients underwent a PSS out of which 348 patients received a median of 9 pre-operative cycles of oxaliplatin or irinotecan with targeted therapies for half of them. Resection was major in 128 patients, combined with IOA in 137 patients and IOA alone in 50 cases. Thirty-eight patients had a PVO by strict necessity. The 5yr-overall survival was 50.3%. Seventy-eight patients had a complication > grade 3 out of which 10 patients died. Nine patients had a liver failure (LF) grade B and C and four died. There was no difference in post-operative complications comparing minor and major resections, validating our PSS definition. Chemotherapy and liver toxicity were not related to more post-operative complications. Only one patient died from a primitive LF. Conclusions: With PSS, healthy liver is no more a target. Routine use of chemotherapy does not impair the results and severe LFs are rare. PSS is the optimal strategy to treat CRLM. Definition of PSS cannot be based just on the retrived volume but on the ratio Tumor burden/Healthy liver. A major hepatectomy can be a PSS and a minor may not be one. That is why PSS defintion must be clarify especially for further prospective validations.
Effect of tumor location in metastatic colorectal cancer to response anti-EGFR and anti-VEGF treatment: One center study.
Authors: Ozkan Metin , Dogan Ender , Ucar Mahmut , Sakalar Teoman , Alghareeb Ahmet , Ozaslan Ersin , Inanc Mevlude
Published: September 2018

e15023

Background: Colorectal cancer is the one of the most common malignancy in western countries. In addition to standart treatment antiEGFR and antiVEGF agents have improved PFS and overall survival. Current studies showed that the colorectal cancers have heterogenous characteristics. The Colon is divided into two parts as a right and left colon according to embrological origin. Recent years supposed that right and left located colorectal tumors may not response samely to anti egfr and anti vegfr therapies. We performed a retrospective study in our clinic to answer this questions. Methods: Study Population and data collection: Between January 2005 and December 2016, all metastatic colorectal cancer patients (n = 285) who received anti-EGFR and anti- VEGF agent with chemotherapy on initial treatment at the Erciyes University Medical Oncology Department were retrospectively reviewed. We included patients with diagnosed metastatic colorectal cancer and who received at least 1 dose of antiEGFR-based or antiVEGFR-based triplet bio-chemotherapy as their first-line treatments. Study population was divided into two groups as right and left colon. Results: A total of 251 patients met the inclusion criteria: 55 patients classified as a right colon cancer (RCC) and 196 patients classified as a left colon cancer (LCC) . 16 patients in RCC group received anti-EGFR-based triplet and 39 patients in RCC group received antiVEGF-based triplet; 76 patients in LCC group received anti-EGFR-based triplet and 120 patients in LCC group received antiVEGF-based triplet as first-line bio-chemotherapy. There were no differences between the patients received antiEGFR and antiVEGF therapy in RCC group (PFS,antiEGFR vs anti VEGF, 7 vs 8 months,P = 0.378; OS, 21 vs 19 months, P = 0.876). There were no differences between the patients received antiEGFR and antiVEGF therapy in LCC group (PFS,antiEGFR vs anti VEGF, 10 vs 10 months,P = 0.202; OS, 27 vs 24 months, P = 0.656). Conclusions: Our study shows that there were no significiant difference between the metastatic colorectal cancer patients received antiEGFR and antiVEGF treatment in LCC and RCC.
Safety analysis of regorafenib prior to selective internal radiation therapy (SIRT) using 90Y resin microspheres for the treatment (tx) of patients (pts) with refractory metastatic colorectal cancer (mCRC) with liver metastases (mets).
Authors: Kennedy Andrew S. , Shipley Dianna , Blakely L. Johnetta , Hemphill Michael Brian , Shih Kent C. , Mainwaring Mark G. , Peyton James D. , Zubkus John D. , Wright David Donald , Bendell Johanna C. , Singh Jaswinder
Published: September 2018

e15040

Background: SIRT (or radioembolization) has been successfully used in the tx of mCRC patients with liver mets who are not surgical candidates. The addition of the multi-kinase inhibitor, regorafenib to SIRT is an attractive option as anti-tumor and maintenance tx for refractory CRC. Here we present the safety analysis of the 1st of 2 cohorts of our Phase II, open-label study comparing the safety of the combination of SIRT and regorafenib where chemotherapy occurs either before or after SIRT. Methods: mCRC pts with evidence of liver mets not treatable by surgical resection or local ablation were tx with 160 mg regorafenib QD PO on days 1-21 of a 28-day cycle followed by a 1 week (wk) washout then SIRT infusion (SIR-Spheres; Sirtex, North Sydney, Australia). Liver function was evaluated 2 wks and 4 wks after SIRT, and regorafenib was re-initiated if liver function was normal. Pts were evaluated for safety, and restaged on wk 6 and 12 following SIRT. The primary objective was to evaluate the safety of this tx schema. Results: 25 pts were enrolled from 7/15 to 8/16: median age 56 yrs, 48% male; 88% colon cancer, 12%, rectal cancer; 48% KRASmt, 4% BRAFmt. 68% of pts had prior systemic therapy for metastatic disease and 80% of pts had prior CRC surgeries. Pts received a median 11 wks regorafenib. 3 pts received regorafenib, but not SIRT due to disease progression. The median activity of SIRT delivered to the liver was 38 mCi and the median lung shunt fraction was 4%. The median tumor volume treated was 76 mL. The most common tx-related adverse events (AEs) were fatigue (60% all grades [G]; 8% G3/4), decreased appetite (32% all G; 0 G 3/4), and nausea (32%, all G; G 3/4). There were 4 tx-related serious AEs (bowel perforation, intractable abdominal pain, portal hypertension, and diarrhea) and no tx-related deaths. The overall response rate was 4%. The median PFS was 4 months and the median OS was 12 months. Conclusions: The treatment of mCRC pts with liver mets with regorafenib followed by SIRT infusion was found to be tolerable in this pt population. Further efficacy analysis of this treatment schema is merited. Clinical trial information: NCT02195011.