bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist G100 on a clinical response and CD4 T-cell response locally and systemically.
Authors: Seo Yongwoo David , Zhou Jing , Morse Kevin , Patino Jeremy , Mackay Sean , Kim Edward Y. , Conrad Ernest U. , O'Malley Ryan Blair , Cranmer Lee D. , Lu Hailing , Hsu Frank J. , Xu Yuexin , Loggers Elizabeth Trice , Hain Taylor , Pillarisetty Venu Gopal , Kane Gabrielle , Riddell Stanley , ter Meulen Jan H. , Jones Robin Lewis , Pollack Seth
Published: February 2018

71

Background: Soft tissue sarcomas (STS) are heterogeneous tumors which are morbid and lethal. G100 is under investigation in multiple clinical trials and contains a potent TLR4 agonist (oil-in-water emulsion of glucopyranosyl lipid A) that has been tested as vaccine adjuvant. We hypothesized IT G100 would induce robust local and potentially systemic anti-tumor immune response, leading to improved outcomes. Methods: 15 metastatic STS patients with superficial lesions were treated with weekly IT G100 for 8-12 wks; 12 patients received radiation (RT) for 2 wks to start, while 3 received IT G100 for 6 wks prior to RT. Biopsies and PBMC were collected pre and post treatment, and flow cytometry was performed on biopsies. TIL and PBMC were analyzed with TCR deep sequencing. PBMC were analyzed by single cell multiplex cytokine profiling. Results: No grade ≥ 3 toxicity was observed, and local tumor control was achieved in all evaluable tumors (14/14). Treated tumors tracked post-trial (mean 156 days) had persistent local control with 1 CR (7%), 1 PR (7%), and 11 SD (79%). In 3 patients with long term follow up, treated lesions remained controlled vs index lesions (-53% vs +31% at mean 235 days, p = 0.002). In all tumors after G100 alone, T cell infiltration increased. In P14, CD3 live cells in tumor rose from < 1% to 62%. PBMC clonality increased in 8/14 tested including P06, who had 4× increase in clonality and CR in the injected lesion; PBMC and TIL TCR overlap increased from 13.4% to 21.5%. P13 had a 2.3× rise in TIL clonality; the top clone (a CD4 T cell) expanded from 0.1% to 38% and expressed more TNFα than the rest (p < 0.0001). Single cell cytokine analysis of PBMC showed 7/13 (54%) increased in polyfunctionality (producing > 2 cytokines) in CD4 T cells; no consistent increase was seen in CD8 T cells. TNFα levels in pre-treatment monocytes correlated with PFS (R2= 0.5, p = 0.02). Conclusions: IT G100 is a viable agent for local control of metastatic STS lesions. With or without RT, G100 appears to cause CD4 T cell mediated local and systemic response. Combination of G100 with other immunomodulators could induce clinically significant systemic responses, as seen in follicular NHL treated with G100. Clinical trial information: NCT02180698.
CXCR4 antagonist (BL-8040) to enhance antitumor effects by increasing tumor infiltration of antigen-specific effector T-cells.
Authors: Gaur Pankaj , Verma Vivek , Gupta Seema , Sorani Ella , Vainstein Haras Abi , Oberkovitz Galia , Peled Amnon , Khleif Samir
Published: February 2018

73

Background: C-X-C chemokine receptor type 4 (CXCR4) helps to retain the hematopoietic stem cells (HSC) in the bone marrow (BM). CXCR4 binds to its ligand CXCL12/SDF1 which is constitutively expressed in the BM thereby inhibiting the mobilization of CXCR4 expressing immune progenitor cells. Moreover, increased numbers of effector cells in the tumor microenvironment (TME) are directly correlated to enhanced immunotherapeutic efficacy. Therefore, we hypothesized that CXCR4 antagonism will result in movement of immune progenitor cells from BM to periphery leading to increased availability of T-cells in the periphery and better infiltration of effector cells into the TME. Methods: In TC-1 mouse tumor-model, we tested the effects of CXCR4 antagonist (BL-8040; 4 doses; 24 h apart; 20 mg/kg) on the tumor growth and mice survival in the presence of tumor-specific antigen priming using E7 peptide vaccine (3 doses, one week apart). Anti-tumor immune responses were determined in the tumor tissues obtained 3-4 days after the second vaccination using flow cytometry. Results: We found that BL-8040 given with specific antigenic stimulation results in significantly enhanced anti-tumor immune response, leading to a decrease in tumor growth (p≤0.001 at day 21) and prolonged mice survival. At day 35 after tumor implantation, 80% of mice survived in the BL-8040 + vaccine treatment group compared to 0% survival following BL-8040 or vaccine treatments. Interestingly, we also found that BL-8040 leads to a significant increase in the numbers of antigen-specific CD8+ T-cells in the TME. We also found that starting BL-8040 prior to or together with the priming of the mice did not affect the outcome, suggesting that the scheduling of BL-8040 does not affect the therapeutic outcomes. Conclusions: These results suggest that BL-8040 treatment enhances anti-tumor immune response by potentially increasing the immune progenitor cells in the periphery leading to a better immune response. These results also suggest that BL-8040, a CXCR4 antagonist, is a promising immune-modulatory agent with potent anti-tumor effects.
Association of changes in vaginal microbiome with oligoclonal T-cell expansion and early response to chemoradiation for cervical cancer.
Authors: Colbert Lauren Elizabeth , Medrano Andrea Delgado , Previs Rebecca A. , Eifel Patricia J. , Jhingran Anuja , Ramondetta Lois M. , Futreal Phillip Andrew , Jazaeri Amir A. , Hillman Robert Tyler , Frumovitz Michael M. , Schmeler Kathleen M. , Mikkelson Megan , Mathew Geena , Ajami Nadim , Okhuysen Pablo , Petrosino Joseph , Hahn Stephen M. , Klopp Ann
Published: February 2018

8

Background: The composition of the vaginal microbiome has been shown to affect clearance of HPV virus and transformation to invasive cancer. Clinical studies correlating the vaginal microbiome with immune activation and response to cancer treatment are lacking. We profiled intratumoral T-cell clonality during radiation therapy and correlated it with the diversity of the vaginal flora. Methods: Thirty patients with newly diagnosed locally advanced cervical cancer were enrolled on a prospective study to characterize changes in the cervical microbiome during chemoradiation. Cervical samples were obtained before radiation therapy and during the 1st, 3rd, and 5th week of radiation therapy. The vaginal microbiome was characterized using 16 sRNA gene sequencing to produce operational taxonomic units (OTU’s) representing individual bacterial species. Disease response was categorized as early response (ER), late response (LR), or nonresponse (NR) on the basis of clinical examination at brachytherapy and 3-month PET/CT. Twenty patients had T-cell receptor β sequencing of DNA performed using the ImmunoSEQ platform. The maximum productive frequency of the top three clones (MP3) was used to assess T-cell clonality. Results: Early response was associated with clonal T-cell expansion with an increase of MP3 of 11.1% during treatment as compared to a decline of 6.1% in patients with LR/NR (p = 0.05). Early response was also associated with lower quantity of observed OTU’s of vaginal microbiota (25.0 [SD 12.68]) vs patients with LR/NR (41.15 [SD = 23.3]) (p = 0·03). Increased MP3 was associated with increased abundance of Corynebacteriales (R = 0.90; p < .0001) , Actinomycetales (R = 0.83; p < .0001) and Bifidobacteriales (R = 0.82; p < .0001) . Decreased MP3 was associated with increased abundance of lactobacillus (R = -0.61; p < .0001). Conclusions: Increased diversity of the vaginal microbiome is negatively associated with outcome, supporting previous clinical studies in non-cancer settings. Specific vaginal bacterial species are associated with increased or decreased T-cell clonality at completion of radiation.
Profile of programmed death ligand-1 (PD-L1) expression and PD-L1 gene amplification in Indonesian colorectal cancer patients.
Authors: Budiyati Akterono dwi , Putra Teguh Pribadi , Kusumo Gita Dewi , Rexana Fritzie , Kurniawan Antonius , Sudoyo Aru Wisaksono , Utomo Ahmad Rusdan , Utama Andi
Published: February 2018

82

Background: The presence of the programmed death ligand-1 (PD-L1) has been used as biomarker to select patients and analyze responses to anti-PD-1/L1 antibodies. PD-L1 positivity may be a result of genetic mechanism leading to constitutive PD-L1 expression or inducible mechanism by T-cell presence. Each mechanism may have different significance and response to such therapy. In colorectal cancer (CRC), targeting immune checkpoint inhibitor has been recommended for patients with microsatellite instable (MSI). This study aimed to investigate the mechanism of PD-L1 gene activation in colorectal cancer (CRC) patients, particularly in MSI population. Methods: We have investigated 61 archived formalin fixed paraffin embedded CRC specimens of patients from Medistra Hospital, Jakarta admitted in 2010 - 2016. Immunohistochemistry was performed to measure expression of PD-L1 in tumor cells as well as MSI status using antibodies against PD-L1 and MMR (MLH1, MSH2, PMS2 and MSH6), respectively. Subset of PD-L1 positive patients was then assessed for copy number variations (CNVs) using Single Tube TaqMan CNA Gene CD247PD-L1. We also observed KRAS mutation to profile possible genetic mechanism leading to the presence or absence of PD-L1 expression. Results: Analysis of 61 CRC patients revealed 15 patients (24%) expressed PD-L1 on their tumor cell membranes. The prevalence of surface membrane PD-L1 was significantly higher in patients with MSI (87%; 7/8) compared to patients with microsatellite stable (MSS) patients (15%; 8/53) (P = 0.001). Although amplification of PD-L1 gene was not found among PD-L1 positive patients, low level amplification of PD-L1 gene was commonly observed in MSS patients (75%; 6/8) than in MSI patients (43%; 3/7). We found 26% of CRC patients harbored KRAS mutations (16/61), so far the distribution of KRAS status did not correlated with PD-L1 expression. Conclusions: Our data suggest genetic mechanism through amplification of PD-L1 seems not to be the mechanism underlying upregulation of PD-L1 expression in CRC patients. However, further studies are warranted to confirm the results.
A novel Immunoscore signature to predict survival in patients with gastric cancer: Implications for immunotherapy.
Authors: Zeng Dongqiang , Yu Yunfang , Zhou Rui , Liao Wangjun
Published: February 2018

84

Background: Immunotherapies are transforming the treatment of gastric cancer (GC). Unfortunately, the majority of patients do not respond to immunotherapy. Thus, a novel risk score is needed to estimate tumor-infiltrating immune cells in predicting survival of GC and guide of more effective immunotherapy strategies. Methods: In total, 700 patients with GC from Gene Expression Ominus were sorted by training (490 patients) and validation (210 patients) cohorts.Immune risk score (IRS) signature based on the association between the expression of every immune cell and the duration of individual patients' survival was constructed using the LASSO Cox regression model. The relation between immunomodulatory genes, microsatellite instability and IRS value in GC was explored. Results: We established an IRS signature consisting of 11 types of immune cell fractions selected by the LASSO model, an IRS signature for GC was significantly different developed to classify patients into high- and low-risk groups in three cohorts. In the initial training cohort of patients, an IRS signature for GC was developed to classify patients into high- and low-risk groups in 8-year overall survival (hazard ratio [HR] = 2.93, P < 0.0001). The performance of IRS was validated in the validation cohort (HR = 1.77, P = 0.011) and in the entire cohort (HR = 2.54, P < 0.0001). In an ad-hoc analysis, we found the IRS value was substantially correlated with the expression of immunomodulatory genes including PD-1, PD-L1 and PD-L2, a prominent lower IRS was observed in microsatellite-instable (MSI) tumors compare with the microsatellite-stable (MSS) tumors. We developed nomograms for clinical use that integrated IRS signature and four clinicopathological risk factors was generated to predict which patients might have better survival with GC, and it performed well in the three cohorts (concordance index: 0.775, 0.682, and 0.752, respectively). Conclusions: These findings indicate that the assessment of the immune status via Immunoscore provides a potent predictor of survival in patients with GC and this resource may help facilitate the development of precision immunotherapy.
Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist.
Authors: Hidalgo Manuel M. , Epelbaum Ron , Semenisty Valeriya , Geva Ravit , Golan Talia , Borazanci Erkut Hasan , Stemmer Salomon M. , Borad Mitesh J. , Park Joon Oh , Pedersen Katrina , Wolpin Brian M. , Ramirez Robert A. , Becerra Carlos , Shaw Steven , Oberkovitz Galia , Vainstein Haras Abi , Sorani Ella , Lustig Tzipora M , Peled Amnon , Von Hoff Daniel D.
Published: February 2018

88

Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.
Association of DNA repair gene-mutation, mutation burden and, neoantigen load in breast cancer.
Authors: Lin Po-Han
Published: February 2018

9

Background: Anti-cancer therapy with immune checkpoint inhibitors demonstrated high efficacy in hypermutated tumors; Food and Drug Administration recently proved PD1/PDL-1 blockade therapy in solid tumors characterized with deficiency of mismatch repair (MMR). However, several malignancies contain less feature of MMR deficiency. Except MMR, it remains uncertain whether mutations of other DNA repair genes are associated with hypermutated status. We aim to analyze the relationship between DNA repair gene-mutation statuses, mutation burden and neoantigen load in breast cancer. Methods: Whole exome sequencing was performed on germline and tumor DNA in 82 patients with early-onset breast cancer (≤ 40 year-old). Calculation of mutation burden includes tumor-specific insertion/deletion (Indel) and single nucleotide variants. Missense mutations, frameshift mutations and uncorrected splicing were considered to generate new peptides (neopeptides). Binding affinity of neopeptide-major histocompatibility complex class I and their immunogenicity were predicted by NetMHC 4.0 and POPI 2.0. Results: A total of 18 pathogenic mutations were found, 4 in ATM (2 germline and 2 somatic), 3 in BRCA1 (germline), 4 in BRCA2 (germline), 1 in BRIP1 (germline), 1 in CHK2 (germline), 1 in ERCC8 (germline), 2 in MSH2 (1 germline and 1 somatic), 1 in RAD51C (somatic) and 1 in OGG1 (germline). The median number of exomic mutations (missense mutations and Indels) were 744 (min. 355; max. 3587) variants per sample. Tumors with mutations of homologous recombination (HR) and MMR genes contained a higher trend of exomic mutations than those without mutation. However, tumors with mutations of HR and MMR genes contained significantly higher numbers of neopeptides with high binding affinity and immunogenicity than those without mutation (p = 0.04). Conclusions: Tumors with mutations of HR and MMR genes contained higher numbers of neoantigens. This study showed that HR and MMR mutation may be a biomarker predicted clinical benefit of immune checkpoint blockade therapy in breast cancer.
Fever after anti-programmed cell death-1 treatment to predict the response in advanced hepatocellular carcinoma.
Authors: Chen San-Chi
Published: February 2018

90

Background: Anti-programmed cell death (PD)-1, an immune checkpoint inhibitor, has been recently approved for the treatment of patients with HCC following prior sorafenib. However, a reliable predictor of treatment response has not been established. Patients who experienced immune-related adverse events (irAEs) of any grade yielded a significantly higher response rate than did those did not experience irAEs. Methods: Three cases of advanced HCC with or without previous sorafenib treatment, underwent anti-PD-1 treatment (pembrolizumab, 2 mg/kg, at 3-week interval) with or without combination of sorafenib (400mg daily). Results: Case 1 Fever (38.3°C) developed 2 days after anti-PD-1 treatment. The fever persisted for 2 months and gradually subsided (Figure 2B). Follow-up computed tomography (CT) revealed persistent tumor shrinkage and complete response at the latest time of examination (Figure 1B); the treatment is ongoing. Case 2 Spiking fever developed after each time of anti-PD-1 treatment. Follow-up CT revealed a remarkable decrease in the tumor size (3 cm), resulting in a partial response (Figure 1D); the treatment is ongoing. Case 3 Twelve days after the treatment, the patient complained of fever and general weakness. Laboratory data revealed tumor lysis syndrome and disseminated intravascular coagulopathy (DIC). HBV, hepatitis B virus; HCV, hepatitis C virus; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha-fetoprotein; TACE, transarterial chemoembolization; CR, complete response; PR, partial response. Conclusions: Fever may be an early predictor of response to anti-PD-1 treatment. The degree of fever seemed to be correlated with tumor burden. High fever may suggest cytokine storm and possible tumor lysis syndrome. Early detection is necessary for the immediate prescription of steroids and management of tumor lysis.[Table: see text]
Comprehensive analysis of tumor mutational load, genomic alterations, and PD-L1 status in gastrointestinal cancers using a multiplatform molecular profiling tool.
Authors: Suero-Abreu Giselle Alexandra , Gonzalez Velez Miguel , McKenna Marshall , Duma Narjust , Kothadia Sejal , Krishnasamy Shalini R , Liu Janice , Dong Ning , Sharif Khawaja Umar , Pievsky Daniel , Proverbs-Singh Tracy Ann , Gutierrez Martin
Published: February 2018

93

Background: Tumor mutational load (TML) has been proposed as a biomarker of responsiveness to novel immune checkpoint inhibitors (ICIs) due its association with increased neoantigen formation and tumor immunogenicity. Gastrointestinal cancers (GICs) are generally insensitive to ICIs; therefore the aim of this study was to evaluate the TML, clinically relevant genomic alterations (CRGAs), and PDL-1 status of GIC patients (pts). Methods: We analyzed samples of pts with GICs using a multiplatform profiling tool (Caris Life Sciences, Phoenix, AZ). TML and CRGAs were calculated based on next generation sequencing and mutational load was stratified as high (≥17 mut/Mb), intermediate (8-16 mut/Mb), and low (≤ 7 mut/Mb). PD-L1 status was determined by IHC. Descriptive statistics and simple linear regression were used for analysis. Results: A total of 85 pts with GICs were analyzed. The median pt age was 65. 53% were males and 47% were females. Tumors were colorectal 51%, pancreatic 13%, esophageal 13%, gastric 9%, hepatobiliary 11%, anal canal 4%, and small intestine 1%. 80 cases (94%) had an adequate sample for profiling and TML was available in 59 cases (74%). Cases were 5% TML-high, 56% TML-intermediate, and 39% TML-low. The median TML was 9 mut/Mb and median CRGAs was 3. The most commonly detected CRGAs were TP53 (56%), APC (44%), KRAS (40%), ATM (18%) and PTEN (6%). A positive but very weak correlation was found between TML and number of CRGAs (R2 = 0.3). PD-L1 status was available in 74 cases (93%) with 86% being PD-L1 negative and 14% PD-L1 positive. PD-L1 expression was most commonly seen in esophageal (50%) and anal canal (30%) cancers. Among 57 tumors tested for both biomarkers, no correlation was found between a high TML and PD-L1 expression. Conclusions: TML varies among GICs, and higher TML scores were not associated with PD-L1 expression, but there was a weak correlation between TML and the number of CRGAs. Further analysis by stratification of GIC type and prognostic analysis to assess the correlation between TMB and response to ICIs is warranted.
Checkpoint inhibitors assessment in oropharynx carcinoma (CIAO).
Authors: Ferrarotto Renata , Glisson Bonnie S. , Bell Diana , Hutcheson Kate A. , Phan Jack , Tran Hai T. , Gibbs Dyanne L , Lee J. Jack , Gillison Maura L. , Sikora Andrew G. , Gross Neil D.
Published: February 2018

TPS118

Background: Oropharyngeal squamous cell carcinoma (OPSCC) is classified by HPV status. Patients with HPV negative OPSCC have worse prognosis when compared to HPV positive. The epidemic of HPV associated OPSCC emphasizes the need to improve outcomes and reduce treatment related toxicities in this patient population. Taken together, there is an unmet need for novel treatment approaches to improve survival and/or quality of life in patients with OPSCC. Checkpoint inhibitors, particularly anti-PD-1/PD-L1, have shown encouraging activity in metastatic head and neck SCC. Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity. Durvalumab and tremelimumab are immune checkpoint inhibitors that target, respectively, PD-L1 and CTLA-4. The optimal integration of novel therapeutics into clinical practice requires a thorough understanding of the molecular effects of treatment that is best evaluated by longitudinal tumor sampling. Minimally invasive transoral robotic surgery (TORS) provides opportunities to leverage standard-of-care surgery to interrogate the tumor microenvironment after neoadjuvant treatment. Methods: This is a randomized, window of opportunity trial evaluating durvalumab single agent or combined with tremelimumab in OPSCC patients amenable to curative intent surgery. The primary objective is to quantify differences in CD8+ TILs between pre- and post-treatment surgical specimens in patients treated with durvalumab vs. durvalumab plus tremelimumab. Secondary objectives include assessing the safety and toxicity of durvalumab plus or minus tremelimumab in the preoperative setting; objective response rate by RECIST at 8 weeks; percentage of patients undergoing surgery at 8 weeks; percentage of viable tumor cells in the surgical specimen; and patient-reported outcomes. Pre- and post- treatment tumor and blood based immune biomarkers will be evaluated and correlated with HPV status, outcomes, and toxicity. Eligible patients must be ≥ 18 years old, have surgically resectable stage II-IVA newly diagnosed OPSCC or loco-regional recurrence from an OPSCC primary ≥ 6 months after completion of curative intent treatment, and have a performance status ECOG 0-1. Enrollment is ongoing. Clinical trial information: NCT03144778.
Phase I/II trial of pembrolizumab in combination with binimetinib in unresectable locally advanced or metastatic triple negative breast cancer.
Authors: Chumsri Saranya , Polley Mei-Yin , Anderson Sarah L. , O'Sullivan Ciara Catherine Maria , Colon-Otero Gerardo , Knutson Keith L , Thompson E Aubrey , Moreno-Aspitia Alvaro
Published: February 2018

TPS17

Background: Emerging studies suggest that breast cancer, particularly triple negative breast cancer (TNBC), may be sensitive to immunotherapy. However, the response rate of single agent immune checkpoint blockade agent in TNBC is rather low. Previous genomic study in residual tumor after neoadjuvant chemotherapy showed inverse correlations between MEK activation signature and the amount of tumor infiltrating lymphocytes (TILs) in residual disease samples as well as poor outcome. Preclinical study also showed that the combination of MEK inhibitor and anti-PD-L1 antibody in mouse model can eradicate TNBC tumors. Methods: This is a single arm, Phase I/II trial of Pembrolizumab (P) in combination with Binimetinib (B) in patients with unresectable locally advanced or metastatic TNBC. This trial is currently opened for accrual at Mayo Clinic in Florida and Minnesota. Patients with TNBC defined as ER ≤ 10% and PR ≤ 10% who received ≤ 3 prior lines with measurable disease will be enrolled. The primary objective of the Phase I part is to determine the maximum tolerated dose of B in combination with P and for the Phase II part is objective response rate (ORR) by RECIST criteria. The secondary endpoints include ORR by irRECIST, progression free survival, and overall survival. The total sample size is 15-38 patients with 6-12 patients in Phase I with 2 dose levels and 9-26 patients in Phase II. Simon’s Two-Stage Optimal Design is used to test the null hypothesis that this two-drug combination has an ORR of at most 15% vs. the alternative hypothesis that it has an ORR of at least 35%. Patients will receive single agent B for 2 weeks prior to starting P. A mandatory biopsy will be performed before starting B and an optional biopsy will be performed after 2 weeks of B. Tumor tissue will be evaluated for the amount and phenotypes of TILs, PD-L1 expression, and gene expression analysis using PanCancer Immune Profiling Panel, and PDJ amplification. Peripheral blood will be evaluated for circulating immunoregulatory cells, cytokine profiling, circulating tumor cells (CTCs), as well as p-ERK and PD-L1 expression on CTCs. Clinical trial information: NCT03106415.
A prospective, randomized, blinded, placebo-controlled, phase IIb trial of an autologous tumor lysate + yeast cell wall particles (YCWP) + dendritic cells (DC) vaccine vs unloaded YCWP + DC and embedded phase I/IIa trial with tumor lysate particle only (TLPO) vaccine in stage III and stage IV (resected) melanoma to prevent recurrence.
Authors: Myers John W , Herbert Garth S , Clifton Guy T , Vreeland Timothy J , Brown Tommy A , Peace Kaitlin M. , Greene Julia M , Jackson Doreen O , Hale Diane F , Berry John S , Faries Mark B. , Peoples George Earl
Published: February 2018

TPS201

Background: Melanoma is a potentially lethal skin malignancy; patients with stage III/IV resected disease have a recurrence rate of 50-90%. Adjuvant checkpoint inhibitor immunotherapy decreases the risk of recurrence but also causes significant immune-related toxicity. Vaccines are a promising strategy for patients with high risk melanoma. The optimal time to intervene may be in the adjuvant setting after attaining a disease-free state through standard of care therapies. Our strategy uses autologous tumor lysate (TL) in a yeast cell wall particle (YCWP) to load dendritic cells (DC) ex vivo. The tumor lysate particle loaded dendritic cell (TLPLDC) vaccine is then given to prevent melanoma recurrences. An alternate vaccine delivery method that we are evaluating utilizes the tumor lysate particle-only (TLPO) technique, in which tumor lysate is loaded into capped YCWP and injected intradermally, allowing an in vivo uptake by the patient’s dendritic cells. Methods: We are performing a prospective, randomized, blinded, placebo-controlled phase IIb trial in patients with resected stage III/IV melanoma who have been rendered disease-free but remain at high risk of recurrence. The study will utilize the TLPLDC strategy vs placebo (2:1) in 120 patients, followed by a bridging study of TLPO vs TLPLDC (2:1) in 60 patients. Both TLPLDC and TLPO inoculations will be monthly x3, followed by boosters at 6, 12, and 18 months. Primary endpoints will be disease free survival (DFS) at 24 months in the TLPLDC arm, and overall safety in the TLPO arm. We have completed enrollment in the phase IIb portion of the study. Clinical trial information: NCT02301611.
Phase 1/2 study of safety/efficacy using trabectedin, ipilimumab, and nivolumab as first-line treatment of advanced soft tissue sarcoma (STS).
Authors: Gordon Erlinda Maria , Chua-Alcala Victoria S. , Kim Katherine , Tseng William W. , Quon Doris M , Chawla Sant P
Published: February 2018

TPS46

Background: Sarcoma cells are most immunogenic at the onset of cancer when the immune system can recognize and destroy them. Hence, immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To investigate the maximum tolerated dose of trabectedin, an alkylating agent, when given sequentially with ipilimumab, a CTLA4 inhibitor, and nivolumab, a PD-1 inhibitor, in advanced STS, (2) To investigate the objective response rate (ORR), progression free survival (PFS) and overall survival (OS) , and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: Forty patients ≥18 years of age with advanced STS will be enrolled. This is a phase 1/2 study using a defined dose of ipilimumab (1 mg/kg i.v. q 12 weeks), nivolumab (3 mg/kg i.v. q 2 weeks), and escalating doses of trabectedin (1.0, 1.3, 1.5 mg/m2 i.v. q 3 weeks). I. Dose Escalation Phase 1 (previously treated patients): The study will employ the standard “cohort of three” design. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. II. Expansion Phase 2 (previously untreated patients): An additional 22-28 patients will receive trabectedin at the MTD and defined doses of ipilimumab and nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients may continue treatment until significant disease progression or unacceptable toxicity occurs. Statistical Considerations: NIH CTCAE v4.03 and RECIST v1.1 will be used. Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. The analyses of all study objectives will be descriptive and hypothesis generating, for planning Phase 2/3 studies. Clinical trial information: NCT 03138161.
Testosterone nadir and PSA recurrence-free survival in men with intermediate and high-risk localized prostate cancer undergoing definitive radiotherapy and androgen deprivation therapy.
Authors: Alex Bryant , McKay Rana R. , Kader A. Karim , Parsons J Kellogg , Einck John Paul , Kane Christopher J. , Mundt Arno James , Murphy James Don , Rose Brent Shane
Published: February 2018

100

Background: There is limited data on the relationship between testosterone level during androgen deprivation and clinical outcomes of localized prostate cancer treated with hormone therapy and radiation therapy (RT). Here we investigate the association between testosterone nadir during androgen deprivation therapy and prostate-specific antigen (PSA) response and survival. Methods: Using a nationwide Veterans Affairs database, we identified 899 patients with intermediate- or high-risk localized prostate adenocarcinoma diagnosed between 2000 and 2015 and treated with gonadotropin-releasing hormone agonists and RT. All patients had total testosterone measurements while receiving hormone therapy and between 6 weeks and 6 months after the start of hormone therapy. Using univariable and multivariable models we examined the effect of testosterone nadir on 3-month post-treatment PSA, PSA recurrence-free survival, and prostate cancer-specific survival. Multivariable models included age at diagnosis, Gleason score, tumor stage, anti-androgen therapy, hormone therapy duration, comorbidity, BMI, and pre-treatment PSA. Results: Of the 899 patients with testosterone data, 481 patients had a testosterone nadir of < 20 ng/dL, 305 had a nadir between 20 and 49 ng/dL, and 113 had a nadir ≥50 ng/dL. Higher testosterone nadir was associated with higher 3-month post-treatment PSA on univariable (Spearman rho = 0.22, p < 0.001, n = 651) and multivariable (ß = 0.03, 95% CI 0.01-0.05, p = 0.004) analysis. In multivariable Cox regression, higher testosterone nadir was associated with an increased risk of PSA recurrence (hazard ratio [HR] 1.43 per 10-fold increase in testosterone nadir, 95% CI 1.07-1.90, p = 0.01, n = 715) but not prostate cancer-specific mortality (HR 1.45, 95% CI 0.87-2.42, p = 0.16, n = 891). Conclusions: Higher nadir testosterone levels in intermediate- or high-risk localized prostate cancer patients undergoing hormone therapy is associated with higher 3-month post-treatment PSA and inferior PSA recurrence-free survival, though there was no significant effect on prostate cancer-specific mortality.
Can post-operative prostate fossa radiation be omitted in patients with high-risk features using a genomic classifier?
Authors: Marascio Joseph Anthony , Bloom Matthew , Hurwitz Mark , Gomella Leonard G. , Lallas Costas D. , Trabulsi Edouard John , Mann Mark , Mark James Ryan , Calvaresi Anne , Kelly W. Kevin , Hoffman-Censits Jean H. , Godwin James Luke , Dicker Adam , Den Robert Benjamin
Published: February 2018

101

Background: At our institution, based upon the AUA/ASTRO guidelines, discussion of adjuvant radiation therapy (ART) for patients with adverse pathologic features (APF) (pT3/positive margins) occurs in a multidisciplinary setting. We had previously offered ART to approximately 50% of these patients. We describe our evaluation of Decipher genomic testing to select patients to offer observation following prostatectomy (RP). Methods: Since March 2014, patients at Thomas Jefferson University with APF and undetectable post-operative PSA underwent Decipher genomic testing. Collectively, we decided to offer observation with salvage radiation therapy (SRT) for patients with low or intermediate risk Decipher scores. The primary outcome of this analysis was biochemical progression free survival (bPFS) with failure defined as a PSA ≥0.1 ng/mL. Results: From March of 2014 through September of 2016, 47 patients met the above criteria. The median patient age was 64 and median follow up was 16 months. Median pre-treatment PSA was 6.0 ng/mL (2.94 to 22.7 ng/mL). With regard to pathologic stage: 19% had T2c, 68% had T3a, and 13% had T3b disease. Pathologic Gleason grouping was 6%, 49%, 34%, 6%, and 4% for groups 1-5, respectively. 51% of patients had positive margins, 36% had lymph-vascular space invasion, and 53% had perineural invasion. Four patients received ART and 1 patient was lost to follow up after his initial visit. Of the remaining 42 patients, 3 patients experienced biochemical failure at 8, 27, and 44 months. Conclusions: This is the first prospective report utilizing Decipher genomic testing to stratify men with undetectable PSA and adverse pathologic features into an observation cohort following RP. Despite the stringency of our definition of biochemical failure, our observed bPFS was 87% at 3 years. Historically, in an unselected population the 3 year bPFS was 90% in those receiving ART and 65% in those receiving SRT. While these initial findings are promising, longer follow up is warranted. Our findings demonstrate the utility of genomic classifiers in patient selection and provide a safe approach to reducing over treatment in the post RP setting.
Clinical outcomes following biochemical recurrence among patients with Gleason score 9-10 prostate adenocarcinoma.
Authors: Sandler Kiri A , Chu Fang-I , Ciezki Jay P. , Stock Richard , Merrick Gregory Stephen , Demanes David Jeffrey , Spratt Daniel Eidelberg , Abu-Isa Eyad I. , Pomerantz Mark , Ross Ashley , Tran Phuoc T. , Nguyen Paul L. , Wedde Trude Baastad , Lilleby Wolfgang , Krauss Daniel , Alam Ridwan , Steinberg Michael L. , Horwitz Eric M. , King Christopher R. , Kishan Amar Upadhyaya
Published: February 2018

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Background: Patients with Gleason score (GS) 9-10 prostate cancer (PCa) have a high risk of early biochemical recurrence (BCR). Salvage therapy options differ depending on the upfront management strategy. Patients who received upfront surgery (RP) may be curable with salvage external beam radiation therapy (EBRT). However those who underwent EBRT or EBRT with a brachytherapy boost (EBRT+BT) are less likely to receive local salvage therapy and are commonly treated with androgen deprivation therapy (ADT). In this study, we examine the risk of distant metastases (DM) and prostate-cancer specific mortality (PCSM) among patients with GS 9-10 PCa who had BCR following RP, EBRT, or EBRT+BT. Methods: 712 patients with GS 9-10 PCa treated between 2000-2013 at 12 institutions who had BCR were included (346 RP, 282 EBRT, 84 EBRT+BT). Time to DM and PCSM were compared between groups using Cox proportional hazards models with propensity score adjustment. Propensity scores were calculated using age, T-stage, PSA, and GS. Results: In patients who had a BCR, incidence rates of DM and PCSM after RP were 40% and 28%. Rates after EBRT were 60% and 46% and after EBRT+BT were 49% and 31%. Median times to DM and PCSM were 3.5 and 4.9 years after RP, 3.7 and 5.1 years after EBRT, and 3.3 and 6.8 years after EBRT+BT. The rates of local salvage RT and systemic salvage therapy among RP patients were 38% and 59%, respectively. Local and systemic salvage rates were 5% and 31% for EBRT patients and 5% and 28% for EBRT+BT patients. EBRT patients had a shorter time interval to DM compared with RP (HR 1.4, p = .02) and EBRT+BT (HR 1.9, p < .01). EBRT patients also had a shorter time interval to PCSM compared with RP (HR 1.5, p = .02). Conclusions: Among patients with GS 9-10 PCa who experience BCR after definitive management, those treated with EBRT have a shorter time interval to DM and PCSM compared with RP and EBRT+BT. While this analysis is confounded by the differential thresholds for diagnosing a BCR after different modalities, it does suggest that outcomes following BCR after EBRT+BT and RP are similar. It also suggests that extreme dose escalation delays the onset of DM and PCSM even after BCR, when compared with conventionally-dosed EBRT alone.
Shared decision making for prostate cancer screening: Reality or farce?
Authors: Pucheril Daniel , Fletcher Sean A. , Zlatev Dimitar V. , Mossanen Matthew , Ingham Matthew D. , Chang Steven Lee , Kibel Adam S. , Trinh Quoc-Dien
Published: February 2018

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Background: A core tenant of major cancer society guidelines regarding prostate cancer screening (PSAS) is that providers discuss both the advantages and disadvantages of screening with eligible patients in a shared decision making (SDM) process. We sought to determine contemporary trends of SDM in regards to PSAS. Methods: Consistent with the AUA guidelines for PSAS, data was abstracted from the 2012-2016 Behavioral Risk Factor Surveillance System for men 55-69, without a personal history of prostate cancer, and having answered all questions within the PSAS module. PSAS occurred if a man had a PSA test within the last two years for reasons other than "a prostate problem” or “prostate cancer”. SDM occurred if the respondent was informed about both advantages and disadvantages of PSAS by a health professional. Descriptive statistics were generated for demographic covariates by year. The Chi-Square test was used to compare the distribution of covariate proportions amongst years. Separate multivariable regression models were built to identify independent predictors of both receipt of PSA screening and SDM. Results: A weighted estimate of 56.7 million men (n = 138,492) met inclusion criteria. Reported rates of PSAS decreased each year (56.7% in 2012 to 52.6% in 2014 to 49.1% in 2016, p < 000.1). There were no significant changes in rates of SDM (p = 0.82); in all three years, less than one-third of respondents reported SDM. After controlling for known confounders, possession of a personal physician (OR 2.24,95%CI 2.02-2.48), receipt of information regarding the advantages of PSAS (OR 3.93, 95%CI 3.63-4.26), and receiving a physician recommendation to undergo PSAS (OR 7.78, 95%CI 7.25-8.35) were most strongly associated with odds of undergoing PSAS. Odds of reporting participation in SDM were strongest amongst black respondents (2.09 95%CI 1.92-2.28) and those who received a physician recommendation to undergo PSAS (OR 4.64, 95%CI 4.32-4.99). Conclusions: Despite recommendations that physicians engage patients in a SDM process, our findings suggest that less than a third of patients are advised of both the advantages and disadvantages of PSAS. With the likely revision of the USPSTF PSAS recommendation to Grade C, a renewed effort towards SDM is needed.
Active surveillance of prostate cancer in African-Americans during the MRI era.
Authors: Bloom Jonathan , Gold Samuel , Hale Graham R. , Rayn Kareem , Valera Vladimir , Mehralivand Sherif , Wood Brad J. , Turkbey Baris , Parnes Howard L. , Pinto Peter A.
Published: February 2018

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Background: Many patients with low-risk prostate cancer are encouraged by their physicians to pursue active surveillance (AS). AS has increasingly been utilized, however there remains anxiety by patients and their physicians that more aggressive disease will be missed and allowed to progress. African-American (AA) patients may present with more aggressive disease and higher rates of upgrading at the time of radical prostatectomy. Due to these factors, physicians may be hesitant to recommend AS to AA patients. We examined the role of AS in these patients in the era of MRI targeted biopsies. Methods: A prospectively maintained database was queried for all patients who underwent an MRI guided fusion biopsy from 2007 to 2016 and chose AS as their primary management strategy. Patents with Gleason Group (GG) 1 or 2 were eligible. Patients were then followed with yearly PSA, exam, MRI and biopsy if warranted. MRI Fusion biopsies were reviewed to determine any GG progression. Results: A total of 19 AA and 143 non-AA patients were reviewed with median follow up times of 31.63 (15.42 -89.50) and 30.87 (3.45 – 99.85) months, respectively. AA and non-AA patients had similar baseline PSA values (6.08 ± 2.93 vs. 5.89 ± 4.23, p = 0.85), proportion of GG 1 (15.89% vs 21.68%, p = 0.55) and PSA density (0.103 ± 0.041 vs. 0.123 ± 0.041, p = 0.36. However, AA patients did present at an earlier age (58.89 ± 6.64 vs. 63.69 ± 6.64, p = 0.004). A total of 8/19 (42.1%) AA and 46/143 (32.2%) non-AA had GG upgrading while on AS, p = 0.34. The median time until progression for AA and non-AA patients was 60.76 and 77.42 months, p = 0.68. Conclusions: In our study, AA men did begin AS at an earlier age than non-AA men. While both groups had statistically similar rates of progression, the relative risk of progression was higher in the AA cohort during this time period. Therefore, in the era of MRI and fusion biopsies we are better able to detect upgrading and somewhat mitigate the the risks associated with upgrading during AS irrespective of race but larger studies are needed to determine whether there are meaningful differences in the rates of progression between AA and non-AA men. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH.
Development of prostate-specific antigen (PSA) screening nomograms for 15-year prediction of prostate cancer diagnosis (PCDx), mortality (PCM), and all-cause mortality (ACM).
Authors: Brooks Michael Austin , Carlsson Sigrid V. , Zajichek Alexander , Chagin Kevin M. , Hugosson Jonas , Kattan Michael W. , Stephenson Andrew J.
Published: February 2018

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Background: Recommendations for PSA screening encourage shared decision making between patients and providers, rather than population-based screening. Nomograms provide individualized risk predictions potentially enhancing informed decisions to undergo screening. Our objective was to develop PSA screening nomograms using demographic and follow-up data from two large randomized screening trials: the Göteborg Screening Trial ( Lancet Oncol. 2010;11:725-32) and Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial ( N Engl J Med. 2009;360:1310-9). The endpoints of the models were PCDx, PCM, and ACM at 15 years. Methods: Patients with screening prior to trial entry were excluded, leaving 59,951 total subjects: 19,899 and 40,052 from Göteborg and PLCO, respectively. Demographic information including age, family history of PCDx, ethnicity, Charlson Comorbidity Index, marital status, education, and control vs. screening arm were used as predictive variables. If screened, baseline PSA was used as an additional continuous variable. Models for ACM were first developed, then models predicting PCDx and PCM using competing risk analysis. Predictive accuracy was assessed using the concordance index (c-index) and calibration plots. Results: On multivariable analysis, all variables were significant (P < 0.05) for predicting at least one outcome. Nomograms predicting PCDx, PCM, and ACM demonstrated reasonable discrimination: c-index 0.60, 0.65, 0.70, respectively. When a single baseline PSA was included, discriminative accuracy improved for PCDx and PCM, but remained the same for ACM: c-index 0.78, 0.74, 0.69, respectively. Estimates were well-calibrated for all endpoints. Conclusions: Using demographic information, we developed PSA screening nomograms, with good discrimination and calibration in predicting all three outcomes. A single baseline PSA improved nomogram discrimination substantially for PCDx and PCM. We will study the implementation of these nomograms into clinic practice to aid decisions for previously unscreened patients, or whether to continue PSA screening for patients with a known prior PSA.