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BackgroundIntratumoral immunotherapies are being tested in different solid tumors. They trigger local and systemic responses.1 2 BO-112 is a double stranded RNA nanoplexed with polyethyleneimine (PEI), which mimics a viral infection and mobilizes the immune system.In preclinical models and in a first in human clinical trial BO-112 activated dendritic cells, induced CD-8 infiltration, apoptosis and enhancement of immunogenic cell death and achieved an objective response in 2 out of 10 patients with melanoma with primary resistance to antiPD-1.3 4MethodsIn this phase 2 study, BO-112 plus pembrolizumab is evaluated in patients with advanced melanoma, who have developed progressive disease while on or within 12 weeks after anti-PD1/PD-L1 based therapy (either as first line or as adjuvant treatment). BO-112 is administered intratumorally once weekly in 1 to 8 tumor lesions, total dose 1 to 2 mg, for the first 7 weeks and thereafter every three weeks; pembrolizumab 200 mg is administered intravenously every three weeks. Overall response rate (ORR) is analyzed as primary endpoint by independent reviewer. Secondary objectives include disease control rate (DCR), duration of response and progression free survival (PFS); response assessment is done by RECIST 1.1 and iRECIST; in addition, CD-8 and PD-L1 IHC, NGS, itRECIST and radiomics signatures are prospectively assessed. Key eligibility criteria include cutaneous or mucosal melanoma with known BRAF status; at least one lesion RECIST 1.1 measurable and amenable for IT injection. Enrollment has been completed on 26th August.ResultsWith 26 evaluable patients with a first response assessment, seven have progressive disease (PD), five have partial response (PR) and fourteen patients show stable disease (SD). Preliminary ORR is 19.2% and DCR is 73.1% at week 8. Three patients with PR at week 8 have undergone a second assessment at week 16, with further decrease in sum of diameters (SOD) in both injected and non-injected lesions. Three out of five patients with SD and a second assessment maintain SD, showing a decrease in SOD in two cases (figure 1). In addition, two patients with only skin lesions have a pathological complete response. CD8 and PD-L1 have increased in 8 and 7 out of 13 patients with paired biopsies, being related with clinical benefit (figure 2).Abstract 961 Figure 1Swimmer plot, efficacy data for evaluable patients undergoing at least one response assessmentAbstract 961 Figure 2Immunohistochemistry data for CPS and CD8 data from paired biopsiesConclusionsDespite these data being preliminary, there is a trend for benefit in terms of ORR and also in long lasting stable diseases. BO-112 is able to increase PD-L1 expression in tumor cells and increase CD8-T cell infiltrates.AcknowledgementsMerck, Pivotal SLU, Quibim radiomics, Pangaea laboratories, all participating sites and patientsTrial RegistrationNCT04570332ReferencesAznar MA, Planelles L, Perez-Olivares M, et al. Immunotherapeutic effects of intratumoral nanoplexed poly I:C. J Immunother Cancer. 2019 May 2;7(1):116.5. Hamid O, Ismail R, Puzanov I. Intratumoral immunotherapy-update 2019. The Oncologist 2020;25:e423–438.Márquez-Rodas I, Longo F, Rodríguez-Ruiz M, et al. Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors. Sci Transl Med 2020 Oct 14;12(565):eabb0391.Kalbasi A, Tariveranmoshabad M, Hakimi K, Kremer S, et al. A. Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma. Sci Transl Med 2020 Oct 14;12(565):eabb0152.Ethics ApprovalThe study obtained ethics approval by Spanish Health Agency (AEMPS), on 11th December 2020, and French Health Agency (ANSM) on 27th January 2021; study obtained approval from two Ethics Committee: Vall D’Hebron, Barcelona, Spain on 7th December 2020 (number 467), and Centre Léon Bérard, Lyon, France, CPP 20.11.10.38825 on 11th February 2021.For each study patient, written informed consent is obtained prior to any protocol-related activities. As part of this procedure, the principal investigator or one of his/her associates must explain orally and in writing the nature, duration, and purpose of the study, and the action of the study drug in such a manner that the patient is aware of the potential risks, inconveniences, or adverse effects that may occur. They should be informed that the patient may withdraw from the study at any time. They will receive all information that is required by the regulatory authorities and ICH guidelines. The ICF has been signed by the patient and a copy provided to them.ConsentN/A

Protocol tittle: Study of BO-112 with pembrolizumab for colorectal or gastric/GEJ cancer with liver metastasis.Background: Gastric (GC), oesophagogastric junction (EGJC) and colorectal tumors (CRC) with microsatellite stability (MSS) are poorly responders to PD(L)-1 inhibition, due to low CD8+ T cell infiltration and PD-L1 expression. Therefore, modulation of the tumor microenvironment (TME) could increase disease control. In these tumors the presence of liver lesions is difficult to control because of the hepatic immune tolerance. Control of the hepatic disease could increase survival.BO-112 is a non-coding dsRNA agonist of TLR3, MDA5 and RIG-I which activates the innate and adaptative immune response, inducing apoptosis and immunogenic cell death, with a local and a systemic effect. A prior Phase I trial showed that the combination of pembrolizumab and intratumoral (IT) BO-112 has a good safety profile and encouraging activity. Study design: This is a single arm phase IIa trial to assess the efficacy of intrahepatic IT BO-112 and iv pembrolizumab in 3W cycles in patients with MSS CRC, GC or EGJ tumors. Up to 69 patients with at least one liver lesion and 2 prior lines for CRC and 1 for GC/EGJC will be enrolled. Primary endpoints: ORR and related TEAEs ≥ grade 3. Secondary endpoints: ORR (iRECIST), PFS, 6-months OS and safety. Exploratory endpoint: Changes in TME (PD-L1 expression and CD8+ T cell infiltration) from baseline to C2D1.Results: A total of 11 CRC and 7 GC/EGJC patients were enrolled since July 2020. This abstract focuses on the CRC patients´ biomarker expression. These patients had low PD-L1 CPS (combined positive score) expression and CD8+ T cell infiltration with a median value of 5 and 4%, respectively, in the TME at baseline. Following two IT BO-112 injections, an important increase in PD-L1 expression and CD8+ T cell infiltration was observed in 5 and 7 patients, respectively. PD-L1 CPS median value increased to 37.9 while CD8+ T cell infiltration median values raised to 12.9%.Conclusions: A meaningful increase in PD-L1 expression and CD8+ T cell infiltration was achieved in MSS CRC patients after one cycle of BO-112-pembrolizumab. Table 1.Baseline characteristics and TME changesBaseline characteristicsCRC N=11Demographics-Sex-Male-Female-Age (mean, range)7 (63.6%)4 (36.4%)55 (38-74)Location of primary tumor-Right colon-Left colon2 (36.4%)7 (63.6%)Presence of extrahepatic disease-No-YesLocation of the extrahepatic disease-Lungs-Lymph nodes-Ohers (bone, adrenal gland, peritoneum, pancreas)2 (18.2%)9 (81.8%)6 (54.5%)5 (45.5%)1 (9.1%)Molecular characteristics:-MMR status-MSS-KRAS-Wild type-Mutant -PD-L1-CPS Citation Format: Mariano Ponz-Sarvisé, Elena Élez, Andrés Muñoz, Marc Van den Eynde, Antonio Gaetano Rampoldi, Alain Hendlisz, Hans Prenen, Mercedes Rodríguez, María Teresa Cano, Marya Chaney, Helena Escuin, Vanesa Pons, Marisol Quintero, Andrés Cervantes. Phase IIa open-label clinical study of intratumoural administration of BO-112 in combination with pembrolizumab in subjects with liver metastasis from colorectal cancer or gastric/gastro-oesophageal junction cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT192.

Background Several breast cancer (BC) trials have adopted pathological complete response (pCR) as a surrogate marker of long-term treatment efficacy. In patients with luminal subtype, pCR seems less important for outcome prediction. BC is a heterogeneous disease, which is evident in residual tumors after neoadjuvant-chemotherapy (NAC). This study evaluates changes in Ki67 in relation to disease-free survival (DFS) and overall survival (OS) in patients without pCR. Subjects, Materials, and Methods Four hundred thirty-five patients with stage IIA–IIIC BC without pCR after standard NAC with anthracycline and paclitaxel were analyzed. We analyzed the decrease or lack of decrease in the percentage of Ki67-positive cells between core biopsy samples and surgical specimens and correlated this value with outcome. Results Twenty-five percent of patients presented with luminal A-like tumors, 45% had luminal B-like tumors, 14% had triple-negative BC, 5% had HER2-positive BC, and 11% had triple-positive BC. Patients were predominantly diagnosed with stage III disease (52%) and high-grade tumors (46%). Median Ki67 level was 20% before NAC, which decreased to a median of 10% after NAC. Fifty-seven percent of patients had a decrease in Ki67 percentage. Ki67 decrease significantly correlated with better DFS and OS compared with no decrease, particularly in the luminal B subgroup. Multivariate analysis showed that nonreduction of Ki67 significantly increased the hazard ratio of recurrence and death by 3.39 (95% confidence interval [CI] 1.8–6.37) and 7.03 (95% CI 2.6–18.7), respectively. Conclusion Patients without a decrease in Ki67 in residual tumors after NAC have poor prognosis. This warrants the introduction of new therapeutic strategies in this setting. Implications for Practice This study evaluates the change in Ki67 percentage before and after neoadjuvant chemotherapy (NAC) and its relationship with survival outcomes in patients with breast cancer who did not achieve complete pathological response (pCR). These patients, a heterogeneous group with diverse prognoses that cannot be treated using a single algorithm, pose a challenge to clinicians. This study identified a subgroup of these patients with a poor prognosis, those with luminal B-like tumors without a Ki67 decrease after NAC, thus justifying the introduction of new therapeutic strategies for patients who already present a favorable prognosis (luminal B-like with Ki67 decrease).

BackgroundBO-112 is a nanoplexed form of polyinosinic:polycytidylic acid that acting on toll-like receptor 3 (TLR3), melanoma differentiation-associated protein 5 (MDA5) and protein kinase RNA-activated (PKR) elicits rejection of directly injected transplanted tumors, but has only modest efficacy against distant untreated tumors. Its clinical activity has also been documented in early phase clinical trials. The 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulator of interferon genes (STING) agonist shows a comparable pattern of efficacy when used via intratumoral injections.MethodsMice subcutaneously engrafted with bilateral MC38 and B16.OVA-derived tumors were treated with proinflammatory immunotherapy agents known to be active when intratumorally delivered. The combination of BO-112 and DMXAA was chosen given its excellent efficacy and the requirements for antitumor effects were studied on selective depletion of immune cell types and in gene-modified mouse strains lacking basic leucine zipper ATF-like transcription factor 3 (BATF3), interferon-α/β receptor (IFNAR) or STING. Spatial requirements for the injections were studied in mice bearing three tumor lesions.ResultsBO-112 and DMXAA when co-injected in one of the lesions of mice bearing concomitant bilateral tumors frequently achieved complete local and distant antitumor efficacy. Synergistic effects were contingent on CD8 T cell lymphocytes and dependent on conventional type 1 dendritic cells, responsiveness to type I interferon (IFN) and STING function in the tumor-bearing host. Efficacy was preserved even if BO-112 and DMXAA were injected in separate lesions in a manner able to control another untreated third-party tumor. Efficacy could be further enhanced on concurrent PD-1 blockade.ConclusionClinically feasible co-injections of BO-112 and a STING agonist attain synergistic efficacy able to eradicate distant untreated tumor lesions.

Intratumoral therapies, especially Toll-like receptor agonists, can trigger both the innate and adaptive immune systems. BO-112 is a nanoplexed form of polyinosinic:polycytidylic acid (poly I:C) that induces local and systemic immunotherapeutic effects in mouse models. In a multicenter phase 1 clinical trial, repeated intratumoral administrations of BO-112 induced an increase in tumor cell necrosis and apoptosis, as well as augmented immune reactivity according to gene expression profiling. The first three cohorts receiving BO-112 as a monotherapy resulted in a recommended dose of 1 mg that could be safely repeated. Two grade 3 to 4 adverse reactions in the form of reversible thrombocytopenia were reported. In a fourth cohort of 28 patients with tumors that had primary resistance to anti-programmed cell death protein-1 (PD-1), the combination of intratumoral BO-112 with nivolumab or pembrolizumab was also well tolerated, and 3 patients (2 with melanoma and 1 with renal cell carcinoma) achieved partial responses, with 10 more patients having stable disease at 8 to 12 weeks. Thus, local BO-112 combined with a systemic anti-PD-1 agent might be a strategy to revert anti-PD-1 resistance.

Background: BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI), that acts as an agonist to toll-like receptor 3 and targets the cytosolic helicase melanoma differentiation-associated gene 5 and retinoic acid-inducible gene I. By mimicking the effect of a viral infection, it mobilizes the immune system, including activation of dendritic cells, CD8 T-cell infiltration, induction of interferons (IFNs), induction of apoptosis and enhancement of immunogenic cell death. Clinical data are available from the first-in-human study (NCT02828098) which evaluated single intratumoral (IT) BO-112 (Part 1; N = 16) and the combination of IT BO-112 with pembrolizumab or nivolumab (Part 2; N = 28). Part 2 showed an ORR of 11% and DCR of 46% in patients with multiple tumor types. Of them, 2 out of 10 (20%) patients with melanoma resistant to anti PD-1 achieved a partial response. Safety profile of BO-112, both as single agent and in combination with anti-PD-1, is manageable and currently characterized by Grade 1 fever and other flu-like symptoms. A phase 2 clinical study of IT BO-112 in combination with pembrolizumab in patients with liver metastases from colorectal or gastric/gastro-esophageal junction cancer patients is currently ongoing. Methods: Phase 2, single arm, open label study of IT BO-112 in combination with pembrolizumab in patients with advanced and/or metastatic melanoma that have progressed on anti-PD-1-containing treatment (NCT04570332). BO-112 will be administered once weekly (QW) in 1 to 8 tumor lesions, total dose 1-2 mg (depending on the number of injected lesions), for the first 7 weeks and then once every three weeks (Q3W); pembrolizumab 200 mg will be administered Q3W. Key eligibility criteria include histologically confirmed, unresectable cutaneous or mucosal melanoma with known BRAF status. Patients must have progressed on or after treatment with an anti-PD-1/L1 mAb. At least one lesion RECIST 1.1 measurable and amenable for weekly IT injection is needed. Primary efficacy variable is ORR by RECIST 1.1, assessed by independent central radiologist (by QUIBIM Precision platform). Secondary efficacy variables include clinical activity in terms of DCR, DOR, PFS, OS, iRECIST, safety and PKs. Exploratory objectives include itRECIST and evaluation of tumor microenvironment (by Pangaea laboratory). A 1-sided alpha of 4.19% and power of 81.8% are used. A total of 40 patients will be enrolled. If less than 8 patients out of 40 have ORR, the study will not meet the statistical bar. Study was approved on 14 December in Spain; enrollment is open; two sites are active as of 18 December 2020. Nineteen sites (12 in Spain and 7 in France) are planned to be activated. Citation Format: Iván Márquez-Rodas, Miguel Fernández de Sanmamed Gutiérrez, María González Cao, Ana M. Arance, Alfonso Berrocal, Eduardo Castañon, Sofía España, Pablo Cerezuela-Fuentes, Juan F. Rodríguez-Moreno, Pilar López Criado, Juana Oramas, Luis de la Cruz Merino, Stéphane Dalle, Caroline Dutriaux, Julie Charles, Caroline Robert, Brigitte Dréno, Henri Montaudié, Philippe Saiag, Javier Sánchez-López, María Rojas, Helena Escuin-Ordinas, Vanesa Pons Sanz, Sonia Maciá, Marisol Quintero. Phase 2 clinical study to evaluate the efficacy and safety of intratumoral BO-112 in combination with pembrolizumab in patients with advanced melanoma that have progressive disease on anti-PD-1-based therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT233.

Background: BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine. By mimicking a viral infection, it mobilizes the immune system, including activation of dendritic cells, CD8 T-cell infiltration, induction of interferons, and enhancement of immunogenic cell death. Intratumoral (IT) BO-112 has been tested both alone and in combination with anti-PD-1 therapies in a phase I trial (NCT02828098), which showed an overall response rate (ORR) of 11% and disease control rate (DCR) of 46% in patients with multiple tumor types and a tolerable safety profile. While anti-PD1 therapies have shown promise in select subtypes of soft tissue sarcoma (STS), their overall efficacy in STS has been limited. We hypothesize that BO-112, in combination with radiotherapy (RT), may reverse resistance to anti-PD1 therapy in a subset of patients with STS. Methods: This is an exploratory phase I study of IT BO-112 in combination with nivolumab in patients with STS planning to undergo neoadjuvant RT (NCT04420975) and surgery. BO-112 at a dose of 1 mg will be administered intratumorally on days 1, 8 and 15; nivolumab 240 mg will be administered intravenously on days 8 and 22. Patients will receive 5 fractions of neoadjuvant RT between day 8 and 12, followed by surgical resection between days 26 and 50. Twenty patients with newly diagnosed high grade histologically confirmed STS of the extremity, trunk or retroperitoneum amenable for IT injection will be included. Allowed histological subtypes are undifferentiated pleomorphic sarcoma, myxofibrosarcoma, leiomyosarcoma, dedifferentiated liposarcoma and synovial sarcoma.The primary objective is to explore the safety of BO-112 in combination with nivolumab in patients undergoing preoperative RT. The study includes stopping rules based on the frequency of dose limiting toxicities. As an exploratory single arm pilot study results will be reported using purely descriptive statistics. Tumor and blood specimens collected at baseline, at each IT BO-112 injection, and surgery will allow evaluation of the dynamic changes in tumor immune infiltration, T cell receptor repertoire, and tumor necrosis. These dynamic changes, along with putative biomarkers, such as baseline tumor mutational load, copy number alterations, tumor immune composition, tumor and immune gene expression signatures, and PD-L1 expression, will be related to individual subject tumor responses. The 2-year rate of local recurrence and distant metastasis will also be assessed. This study began accrual in December 2020 and is open. Citation Format: Anusha Kalbasi, Fritz C. Eilber, Arun Singh, Bartosz Chmielowski, Nicholas Bernthal, Brooke Crawford, Joseph G. Crompton, Varand Ghazikhanian, Leanne Seeger, Kambiz Motamedi, Michael L. Douek, Carol Felix, Vincent Basehart, Helena Escuin-Ordinas, Marisol Quintero, Sonia Macia. A phase I study of intratumoral BO-112 and nivolumab for resectable soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT221.

Introduction: BO-112 is an analogue of double-stranded viral RNA which is an agonist of TLR3, RIG-1 and MDA5. It is currently in phase II clinical development, being administered intratumorally (IT), in combination with checkpoint inhibitors. It has been administered through different tumor locations, including liver metastases. Liver metastases constitute a challenging setting, with a proven negative impact on prognosis in those patients treated with immunotherapy independently of the tumor type but especially in those tumors considered as cold. Liver has a particular microenvironment, due to its continuous exposure to nonself-antigens. In order to deal with those antigens arising from the gut via the portal circulation, the liver must strike a balance between tolerating them and exhibiting some degree of antimicrobial effect. This microenvironment shows low level expression of antigen presenting cells, impaired to prime T cells. As a result, it is challenging to respond to exposed antigens, what may eventually prevent protective immune responses. A viral infection mimic induced by BO-112 results in upregulation of genes involved in T-cell homing and migration. This rationale provide support for the potential of IT BO-112 administration into liver metastases. Besides, PD-L1 induced upregulation in response to BO-112, suggests the need to combine treatment with an anti-PD-1/PD-L1 agent. Methods: BO-112 has been injected intratumorally into the liver in 16 patients so far at two different studies: a phase I trial (NCT02828098, which included initially patients with solid tumors being treated with BO-112 monotherapy and, through subsequent amendment, in combination with anti PD-1 drugs in patients having developed progressive disease on these therapies, being treated with BO-112 plus the same checkpoint inhibitor) and a phase II study (NCT04508140), which is including patients with liver metastases from colorectal (CRC) or gastroesophageal (GE) origin, receiving IT BO-112 plus pembrolizumab. A new phase II in patients with metastatic melanoma will start enrollment shortly and will also allow injection of liver metastases (NCT04570332). New unpublished data: Tumor biopsy results from phase 1 study (NCT02828098) showed increased expression of gene signatures for IFN, CD8 T-cell activation, CTL effector function and tumor inflammation. Changes in CD8 lymphocytes infiltration of the tumor microenvironment (TME) and PD-L1 expression in the injected liver metastases from CRC and GE tumors will be presented as part of an independent abstract sharing NCT04508140 preliminary results. Conclusions: Liver is a challenging organ to achieve clinical benefit in terms of response; however, with IT BO-112 being administered in liver metastases from different tumors, there is a change in the TME with an increase in key biomarkers, which may overcome primary or secondary resistance to systemic immunotherapy. Citation Format: Marisol Quintero, Vanesa Pons, Sonia Maciá, María Rojas, Javier Sánchez López, Desiree Kanters, Helena Escuin-Ordinas, Mark Branum, Juan M. Funes, Mercedes Pozuelo, Mike Doherty. BO-112 as a modifier of the tumor microenvironment for liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1790.

TPS9586 Background: Intratumoral immunotherapies are gaining interest in oncology, particularly in melanoma. These therapies, however, have faced some issues. For instance, standard response criteria do not accurately describe tumor burden, and responses may differ for injected/non injected lesions. Besides, target lesions may become non evaluable. Biomarkers provide interesting information for these therapies. In addition, some radiomic signatures have been associated with CD-8 infiltration. BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI) that mimics a viral infection, mobilizing the immune system and changing tumor microenvironment. Clinical data are available from a first-in-human study, which showed ORR of 11% and DCR of 46% in patients who had developed progressive disease on immunotherapy. In patients with melanoma, this ORR was 20%. A phase 2 clinical study of BO-112 with pembrolizumab in patients with liver metastases from digestive tumors is ongoing. Both studies brought up data regarding how some biomarkers are increased after a single dose of BO-112 and correlated with responses. In this phase II study in patients with pretreated melanoma (NCT04570332), we will prospectively assess CD-8 and PD-L1 by immunohistochemistry, which will be compared with multi-parametric radiologic findings and correlated with clinical benefit. In addition, retrospective DNA sequencing will be performed. This kind of exploratory analysis in intratumoral immunotherapies might be key to identify predictive and prognostic factors. Methods: Phase 2, single arm, open label study of BO-112 with pembrolizumab in patients with advanced melanoma. BO-112 is administered once weekly (QW) in 1 to 8 tumor lesions, total dose 1-2 mg (depending on the number of injected lesions), for the first 7 weeks and then once every three weeks (Q3W); pembrolizumab 200 mg will be administered Q3W. Key eligibility criteria: advanced cutaneous or mucosal melanoma; patients must have progressed on or after treatment with an antiPD-1/L1 mAb; at least one measurable lesion amenable for weekly IT injection. Primary efficacy variable is ORR by RECIST 1.1, assessed by independent central radiologist (QUIBIM Precision platform). A 1-sided alpha of 4.19% and power of 81.8% are used. If less than 8 patients out of 40 have ORR, the study will not meet the statistical bar. Secondary endpoints include clinical activity by RECIST1.1 and iRECIST, overall survival, safety and PKs. Exploratory objectives include itRECIST and evaluation of CD-8 and PD-L1 expression by immunohistochemistry (Pangaea laboratory), which will be correlated with radiomic signatures (first order and second order) from standard-of-care computed tomography (CT) images. Enrollment is open and 1 of planned 40 patients has been enrolled. Nineteen sites are planned to participate. Clinical trial information: NCT04570332.

Background BO-112 is a dsRNA (poly I:C) formulated with polyethylenimine, that upon Intratumoral (IT) injection acts by activating TLR3, RIG-1 and MDA-5. This induces immunogenic cell death and potentiate systemic therapy with checkpoint inhibitors in animal models. In patients (pts), single-agent BO-112 IT increases necrosis, apoptosis and expression of pro-immune genes in solid cancers, with a manageable safety. 1 mg was the dose combined with anti-PD-1 in the current clinical trial (NCT02828098). Methods BO-112 was combined with anti PD-1 in 28 pts with solid tumors primarily resistant to anti PD-1 (nivolumab or pembrolizumab). A lesion >1 cm amenable to IT injection was required. 28 pts were treated with 1 mg IT BO-112 qw x 2 or 3 doses before continuing the previous anti PD-1 combined with BO-112, until progression, limiting toxicity or up to 1y. Pre & post BO-112 biopsies from injected lesion were analysed. Response was first assessed by RECIST 1.1 at week 8-12. Results BO-112 related AEs and biological effects at interim analysis are summarized in the table. The combination was well tolerated. No deaths were associated with BO-112. Of 18 evaluable pts for response, at first assessment: 2 have achieved an objective partial response (PR) (1 melanoma and 1 renal carcinoma), with 1 of them continuing treatment; 11 patients had stable disease (SD); 5 patients progressed (PD). Additionally 6 patients progressed prior to the first evaluation, 3 died before efficacy assessments and 1 received palliative radiotherapy and was considered not evaluable. Table . 100P All G3-5 TEAEs (%) G3-4 BO-112 related TEAEs (%) Necrosis (D > 5%) (%)* CD8+ T cell infiltrate (D > 5%) (%)* *evaluable All N = 28 18 (64) 1 (4) 10 (50) 7 (35) Melanoma N = 10 7 (70) 0 5 (56) 4 (44) Non-Small lung cancer N = 13 8 (62) 1 (8) 3 (38) 1 (13) Other N = 5 3 (60) 0 2 (67) 2 (67) Conclusion BO-112 combined with anti PD-1 shows a manageable safety profile, direct antitumor effects and innate and adaptive immune system activation. Efficacy analyses suggest potential to reverse primary resistance to anti-PD1 treatment. Studies in other indications, including combination with radiotherapy, are planned. Clinical trial identification NCT02828098. Legal entity responsible for the study Bioncotech Therapeutics. Funding Bioncotech Therapeutics. Disclosure I. Marquez-Rodas: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bioncotech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Regeneron; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Non-remunerated activity/ies: Biosequence; Research grant / Funding (institution): Idera. P. Lopez-Casas: Full / Part-time employment: Bioncotech. M. Martin: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Tahio; Advisory / Consultancy: Pharmamar; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Daiichi. D. Tersago: Full / Part-time employment: Bioncotech. M. Quintero: Full / Part-time employment, Officer / Board of Directors: Bioncotech. I. Melero: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Alligator; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Genentech; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: Tusk; Advisory / Consultancy: Numab; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: F Star; Advisory / Consultancy: Bayer; Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.

Extracapsular nodal spread is a major prognostic indicator in head and neck cancer. Nitric oxide (NO), primarily produced by the enzyme inducible NO synthase (iNOS), has a large number of actions in cancer biology, but no studies have investigated its possible role in extracapsular spread or tumor invasion.Immunochemistry was used to study iNOS expression in 48 patients with either extracapsular or encapsulated metastasis. In vitro invasion assays were performed using H357 (an oral squamous cell carcinoma cell line) using the iNOS inhibitor drug, 1400 W.iNOS expression was significantly associated with extracapsular spread, with 22/27 cases showing positive iNOS expression compared with 8/21 cases in the encapsulated group (p = .01). Invasion of H357 cells was inhibited by 1400 W at concentrations of 100 microM and 1 mM (p = .002, p = .003).iNOS protein seems to be associated with extracapsular spread and invasion in head and neck cancer. Further studies are required to understand this role more fully.

The indirect and direct cost of occupational musculoskeletal disorders (MSDs) cause a significant burden on the health system, and lower back pain (LBP) is associated with a significant portion of MSDs. In Australia, there is a high prevalence of MSDs for health care workers, such as nurses. Two digital human models (DHMs) Siemens JACK and imk EMA were used to investigate if hospital bed pushing, a simple task and hazard that is commonly associated with LBP, can be validly simulated and ergonomically assessed in a virtual environment. While JACK and EMA have implemented a range of common physical work assessment methods, the simulation of a dynamic task such as bed pushing remains a challenge due to the complex interface between the environment, object, interface and other factors, which can only be insufficiently modelled. In addition, it was found that both human simulation systems present limitations that need to be considered during the interpretation of the results. This research highlights the limitations in the DHMs studied and the need for further research in the area. In particular, the implementation of legacy two dimensional, low resolution ergonomic methods in an analytic, high resolution three dimensional software system is critically reflected.

Background: Hypoxia is a common feature of many cancers. It contributes to local and systemic tumour progression as well as potentially compromising radiotherapy and chemotherapy. Hypoxia-inducible factor 1α (HIF-1α) is an essential component in changing the transcriptional response of tumours under hypoxia. It targets the transcription of over 60 genes involved in many aspects of cancer biology including cell survival, glucose metabolism, cell invasion and angiogenesis. Methods: In this review, we discuss the relevant literature on HIF-1α with specific emphasis on oral cancer. We also present some of our preliminary data on HIF-1α in oral cancer. Results: Although there are a few conflicting reports of its prognostic significance, over expression of HIF-1α seems to play an adverse role in the malignant progression of head and neck cancer by facilitating the adaptation of cells to hypoxia as well as contributing to the invasive properties and angiogenesis in these tumours. Conclusions: HIF-1α has an important role to play in pathophysiology of oral cancer, both under normal and hypoxic conditions. The pharmacological manipulation of HIF-1α has marked effects on tumour growth, and it could prove to be an important target for drug therapy, both in oral cancer and in other hypoxia-dependent disease states.

Hypoxia is a common feature of many cancers. It contributes to local and systemic tumour progression as well as potentially compromising radiotherapy and chemotherapy. Hypoxia-inducible factor 1 (HIF-1) is an essential component in changing the transcriptional response of tumours under hypoxia. It targets the transcription of over 60 genes involved in many aspects of cancer biology including cell survival, glucose metabolism, cell invasion and angiogenesis. Over-expression of HIF-1 has been associated with increased patient mortality in several cancer types including breast, stomach, cervical, endometrial and ovarian cancers. The pharmacological manipulation of HIF-1 has marked effects on tumour growth, and it could prove to be an important target for drug therapy, both in cancer and in other hypoxia-dependent disease states.