Treatment Of Multiple Solid Tumors Research Articles

Th2 Cells Are Associated with Tumor Recurrence Following Radiation.

The curative treatment of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC), utilizes radiation. The outcomes for HPV/p16-negative HNSCC are significantly worse than HPV/p16-positive tumors, with increased radiation resistance leading to worse locoregional recurrence (LRR) and ultimately death. This study analyzed the relationship between immune function and outcomes following radiation in HPV/p16-negative tumors to identify mechanisms of radiation resistance and prognostic immune biomarkers. A discovery cohort of 94 patients with HNSCC treated uniformly with surgery and adjuvant radiation and a validation cohort of 97 similarly treated patients were utilized. Tumor immune infiltrates were derived from RNAseq gene expression. The immune cell types significantly associated with outcomes in the discovery cohort were examined in the independent validation cohort. A positive association between high Th2 infiltration and LRR was identified in the discovery cohort and validated in the validation cohort. Tumor mutations in CREBBP/EP300 and CASP8 were significantly associated with Th2 infiltration. A pathway analysis of genes correlated with Th2 cells revealed the potential repression of the antitumor immune response and the activation of BRCA1-associated DNA damage repair in multiple cohorts. The Th2 infiltrates were enriched in the HPV/p16-negative HNSCC tumors and associated with LRR and mutations in CASP8, CREBBP/EP300, and pathways previously shown to impact the response to radiation.

CSF1R inhibition reprograms tumor-associated macrophages to potentiate anti-PD-1 therapy efficacy against colorectal cancer

PD-1 blockade therapy has made great breakthroughs in treatment of multiple solid tumors. However, patients with microsatellite-stable (MSS) colorectal cancer (CRC) respond poorly to anti-PD-1 immunotherapy. Although CRC patients with microstatellite instability (MSI) or microsatellite instability-high (MSI-H) can benefit from PD-1 blockade therapy, there are still some problems such as tumor recurrence. Tumor-associated macrophages (TAMs), most abundant immune components in tumor microenvironment (TME), largely limit the therapeutic efficacy of anti-PD-1 against CRC. The CSF1/CSF1R pathway plays a key role in regulating macrophage polarization, and blocking CSF1R signaling transduction may be a potential strategy to effectively reprogram macrophages and remodel TME. Here, we found that increasing expression of CSF1R in macrophages predicted poor prognosis in CRC cohort. Furthermore, we discovered a novel potent CSF1R inhibitor, PXB17, which significantly reprogramed M2 macrophages to M1 phenotype. Mechanically, PXB17 significantly blocked activation of PI3K/AKT/mTORC1 signaling, resulting in inhibition of cholesterol biosynthesis. Results from 3D co-culture system suggested that PXB17-repolarized macrophages could induce infiltration of CD8+ T lymphocytes in tumors and improve the immunosuppressive microenvironment. In vivo, PXB17 significantly halted CRC growth, with a stronger effect than PLX3397. In particular, PXB17 potently enhanced therapeutic activity of PD-1 mAb in CT-26 (MSS) model and prevented tumor recurrence in MC-38 (MSI-H) model by promoting formation of long-term memory immunity. Our study opens a new avenue for CSF1R in tumor innate and adaptive anti-tumor immunomodulatory activity and suggests that PXB17 is a promising immunotherapy molecule for enhancing the efficacy of PD-1 mAb or reducing tumor recurrence of CRC.

Nivolumab and ipilimumab in combination with radiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck

BackgroundThe combination of nivolumab and ipilimumab has been approved for the treatment of multiple solid tumors. This was a phase I study investigating definitive radioimmunotherapy (RIT) with nivolumab and ipilimumab...

Abstract 5653: LCB97, an antibody drug conjugate (ADC) targeting a novel tumor antigen for the treatment of multiple solid tumors

Abstract LCB97 is an antibody-drug conjugate (ADC) directed against a novel tumor antigen, composed of monomethyl auristatin E (MMAE) as payload (DAR 4) and the humanized IgG1 antibody AFF4 generated by Elthera. AFF4 targets a novel antigen preferentially expressed in various solid tumors including pancreatic cancer, ovarian cancer, colon cancer, breast cancer and melanoma. LCB97 generated by using LCB’s ConjuAllTM technology with AFF4 showed potent cytotoxicity in various cancer cell lines including breast cancer (BC), ovarian cancer (OC), pancreatic cancer (PaC), small cell lung cancer (SCLC), colorectal cancer (CRC) and melanoma. LCB97 also showed excellent anticancer efficacy in several cell line-derived xenograft (CDX) models, including BC, CRC, OC and melanoma. Preliminary toxicity assessment in cynomolgus monkeys (an AFF4 cross reactive species) demonstrated that LCB97 was well tolerated within the estimated therapeutic index of ~20 for repeat dosing. In conclusion, LCB97, generated by combining theAFF4 monoclonal antibody of Elthera and the highly innovative ConjuAllTM platform technology of LegoChem Biosciences is a promising next-generation ADC for the treatment of various solid cancers, including BC, CRC, melanoma, OC and PaC. Citation Format: Yeojin Jeong, Gunther Spohn, Flavio Mehli, Chul-Woong Chung, Changsik Park. LCB97, an antibody drug conjugate (ADC) targeting a novel tumor antigen for the treatment of multiple solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5653.

Abstract 6254: The discovery and preclinical characterization of the SAM-competitive PRMT5 inhibitor UCT-000445

Abstract Protein arginine methyltransferase 5 (PRMT5) is a methyltransferase enzyme that symmetrically dimethylates arginine residues of histones, transcription elongation factors, translation regulators, and transcription factors like p53. It also regulates the activity of MAPK and PI3K signaling through methylation and activation of various receptor tyrosine kinases. As such, it has epigenetic effects that may be therapeutic in oncology. Successful clinical development of PRMT5 inhibitors will depend on upon utilizing this unique inhibitor modality and identifying those cancers with sensitivity to PRMT5 inhibition. By evaluating the potency and efficacy of several SAM-competitive, substrate-competitive, and MTA-cooperative PRMT5 inhibitors using a large (n>500), diverse panel of human cancer cell lines, we determined that the SAM-competitive inhibitor modality offers the best therapeutic potential thanks to its larger therapeutic window in vitro. This screening approach also identified several solid tumor histologies that were extremely sensitive to PRMT5 inhibition. Using our proprietary chemistry and by screening through the panel of human cancer cell lines, we identified UCT-000445, a SAM-competitive PRMT5 inhibitor with high selectivity over PRMT9 and good pharmacokinetic properties. Moreover, efficacy UCT-000445 is achieved regardless of MTAP gene status in histologies outside of hematological malignancies and including colon. UCT-000445 potently inhibits tumor growth in multiple human xenograft models of cancers, including but not limited to colon and lung cancers. The responses observed are durable upon cessation of treatment. Marked combined efficacy was also observed with standard of care treatment in these cancer types. UCT-000445 was well tolerated in vivo and using a CD-1 nude mouse model we found that while reticulocyte proliferation (a surrogate marker for bone marrow cytopenias) is abrogated by continuous treatment with UCT-000445, the use of intermittent dosing schedules overcomes this effect, while yielding equivalent efficacy. Our data with UCT-000445 indicate that SAM-competitive PRMT5 inhibitors may represent a novel and compelling therapeutic strategy for the treatment of multiple solid tumors. Citation Format: Martina S. McDermott, Neil A. O'Brien, Brendan O'Boyle, Michael Bartberger, Oliver C. Losón, Kevin Chau, Ella Schwab, Jenny Hong, Jiaying Zhou, Chuhong Hu, Tong Luo, Raul Ayala, John Glasby, Brian M. Stoltz, Dennis J. Slamon. The discovery and preclinical characterization of the SAM-competitive PRMT5 inhibitor UCT-000445 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6254.

Abstract OT2-16-01: ONCX-NAV-G201: A phase 2, basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors: Triple-negative breast cancer cohort (trial in progress)

Abstract Objective: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors. Cohort C will enroll triple-negative breast cancer (TNBC) patients. Background: Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aberrant NOTCH signaling is associated with chemotherapy resistance, tumor plasticity, enhanced metastatic potential, promotion of a cancer stem cell phenotype, and immune evasion. In TNBC, aberrant NOTCH expression is associated with poor prognosis, making targeting of this pathway an attractive therapeutic strategy. Additionally, NOTCH may mediate resistance to angiogenesis inhibition. While VEGF inhibitors are approved for the treatment of multiple solid tumors, observed anti-tumor activity is limited in breast cancer. Pre-clinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway targeting. We postulate that navicixizumab will demonstrate anticancer efficacy against TNBC. Methods: Eligible TNBC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 4 prior lines of standard therapy for metastatic disease, including immunotherapy (for PD-L1 positive TNBC patients), and sacituzumab govitecan. TNBC is defined as ER and PR < 1%, and HER2-negative (IHC 0, 1+, or 2+ and negative fluorescence in situ hybridization [FISH]). Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap™ ExTra with the Xerna TME Panel™ to classify patient samples into one of four tumor microenvironment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each TNBC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort C1) or in combination with paclitaxel (80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle) (Cohort C2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of < 5% and a 20% PFS rate at 4 months, with targets of 15% and 40% respectively considered promising for this study. Interim efficacy assessments will be at 10-patient increments following the time patients have had at least 1 post-baseline scan. Cohort continuation and future evaluation decisions will be guided by the boundaries identified by a sequential monitoring procedure. Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel™ biomarker subtypes. Citation Format: Amelia B. Zelnak, Heinz-Josef Lenz, Kerry Culm, Lukas Makris, Valerie Chamberlain Santos, Hagop Youssoufian, Colleen Mockbee, Kathy D. Miller. ONCX-NAV-G201: A phase 2, basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors: Triple-negative breast cancer cohort (trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-01.

The Immune Checkpoint Landscape in Tumor Cells of Pancreatic Ductal Adenocarcinoma.

Immune checkpoint therapy (ICT) has shown promising potential in the treatment of multiple solid tumors. However, the role of ICT in pancreatic ductal adenocarcinoma (PDAC) remains limited. Patterns of immune checkpoints (ICs) in PDAC represent the basis for establishing a potent ICT. The aim of this study is to create a profile of IC expression and its prognostic relevance in cancer cells of PDAC. Therefore, tumor cells from peripheral and central tissue microarray (TMA) spots from histologically confirmed PDAC of 68 patients after tumor resection were investigated in terms of expressions of TIM3, IDO, B7H4, LAG3, VISTA, and PD-L1 using immunohistochemistry. The presence of the respective ICs was compared to overall survival (OS). The presence of VISTA and PD-L1 significantly correlates with shorter OS (median OS: 22 months vs. 7 months and 22 months vs. 11 months, respectively, p < 0.05). For the presence of TIM3, IDO, B7H4, and LAG3, no difference in OS was observed (p > 0.05). The analysis of OS of combined subgroups for VISTA and PD-L1 (VISTA and PD-L1 neg., VISTA pos. and PD-L1 neg., VISTA neg. and PD-L1 pos., and VISTA and PD-L1 pos.) yielded overall statistical significance difference (p = 0.02). These results suggest that the presence of VISTA and PD-L1 is of prognostic relevance and potentially qualifies them as targets for ICT.

Immune Checkpoint Inhibitors and Novel Immunotherapy Approaches for Breast Cancer.

To critically review the existing evidence on immune checkpoint inhibitors (ICIs) in early-stage and metastatic breast cancer and discuss emerging strategies in the different breast cancer subtypes. Immunotherapy has become one of the major milestones in contemporary oncology, revolutionizing the treatment of multiple solid tumors. ICI agents combined with chemotherapy have demonstrated significant efficacy in both early-stage and metastatic triple-negative breast cancer. However, only a subgroup of patients responds to those agents and some associated toxicities, although infrequent, can be life-disabling. Emerging data from immunotherapy studies in advanced hormone receptor-positive (HR +) breast cancer as well as HER2-positive disease are arising with mixed results. Although breast cancer has not classically been considered a hot tumor, ICIs have proven to be effective in a subset of breast cancer patients. However, much remains to be learned, and the identification of new biomarkers beyond PD-L1 expression is essential not only to improve the efficacy of ICI but also to identify patients who can avoid them, together with their toxicities and costs.

Abstract PO-020: Heating up immune cold pancreatic adenocarcinoma with bioengineered immunotherapy remodels tumor microenvironment and prevents metastasis in vivo

Abstract Background: Immunotherapy has resulted in a paradigm shift in the treatment of multiple solid tumors. Still, immunotherapy in unselected pancreatic ductal adenocarcinoma (PDAC) patients has been disappointing. This failure is likely multifactorial and associated with a high immunosuppressive and desmoplastic tumor microenvironment (TME). This unique TME in PDAC leads to various immune escape mechanisms employed by the tumor. While this could be overcome by therapy involving IL12 (or other cytokines) alone, they often fail due to immune-related adverse effects (irAEs). On the other hand, bioengineered collagen-binding domain-linked IL-12 (CBD-IL12; T- cell stimulant that delivers IL12 to collagen-rich regions) is effective in other cancers in pre-clinical settings. Here, we hypothesise that different immune (cold/hot) and collagen content in mice determines their treatment efficacy and irAEs to CBD-IL12 or combination immunotherapy. Methods: Three (7947, 7784 and 2334) out of 12 syngeneic orthotopic models of PDAC were classified into immune “hot” (immunehot) or “cold” (immunecold) with varying collagen levels (collagenhigh or collagenlow) using cross-species statistical inference (in silico analysis). Mice were treated with vehicle or two bioengineered treatment arms – CBD-IL-12 or CBD-IL-12 + anti-PD1. Tumor growth and metastasis was assessed in an interventional trial. Transcriptome profiling was performed on harvested tumors. Results: As predicted by in silico analyses, our in vivo experiments confirmed 7947 syngeneic model as immune cold (immunecold) and resistant to selected stimulatory (GITR) and inhibitory (anti-PD1 or anti-CSF1R+anti-PD1) immunotherapies. To improve the immunotherapy in this immunecold model, we utilised the opportunity that this model has increased collagen (collagenhigh), hence, treating them with CBD-IL12 or combination with anti-PD1 therapy may provide improved treatment efficacy and reduce irAEs. Remarkably, the treatments prevented distant metastasis to the liver by significantly reducing tumor burden (p&amp;lt;0.05) and toxicity. The mechanistic analysis demonstrated a cascade of TME changes, including increased CD8 T cells and MHCII+ myeloid cell-based antigen presentation in the treated tumors compared to the control. This increased antigen presentation was associated with macrophage repolarisation from M2 to M1. This was not the case in two other immunecold/collagenlow or immunehot/collagenhigh models. Conclusion: Our integrated strategy to pre-select mouse models based on their TME (immune/collagen) profiles improves personalised bioengineered immunotherapy response in immune cold PDAC. Furthermore, the added benefit of preventing metastasis is rather promising and warrants further investigation in aggressive disease like PDAC. Citation Format: Chanthirika Ragulan, Patrick Varun Lawrence, Hari Ps, Krisha Desai, Jun Ishihara, Anguraj Sadanandam. Heating up immune cold pancreatic adenocarcinoma with bioengineered immunotherapy remodels tumor microenvironment and prevents metastasis in vivo [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-020.

Cellulose Nanofiber-Based Hydrogels Embedding 5-FU Promote Pyroptosis Activation in Breast Cancer Cells and Support Human Adipose-Derived Stem Cell Proliferation, Opening New Perspectives for Breast Tissue Engineering.

The structure and biocompatibility analysis of a hydrogel based on cellulose nanofibers (CNFs) combined with alginate/pectin (A.CNF or P.CNF) and enriched with 1% or 5% 5-FU revealed more favorable properties for the cellular component when pectin was dispersed within CNFs. 5-Fluorouracil (5-FU) is an antimetabolite fluoropyrimidine used as antineoplastic drug for the treatment of multiple solid tumors. 5-FU activity leads to caspase-1 activation, secretion and maturation of interleukins (IL)-1, IL-18 and reactive oxygen species (ROS) generation. Furthermore, the effects of embedding 5-FU in P.CNF were explored in order to suppress breast tumor cell growth and induce inflammasome complex activation together with extra- and intracellular ROS generation. Exposure of tumor cells to P.CNF/5-FU resulted in a strong cytotoxic effect, an increased level of caspase-1 released in the culture media and ROS production—the latter directly proportional to the concentration of anti-tumor agent embedded in the scaffolds. Simultaneously, 5-FU determined the increase of p53 and caspase-1 expressions, both at gene and protein levels. In conclusion, P.CNF/5-FU scaffolds proved to be efficient against breast tumor cells growth due to pyroptosis induction. Furthermore, biocompatibility and the potential to support human adipose-derived stem cell growth were demonstrated, suggesting that these 3D systems could be used in soft tissue reconstruction post-mastectomy.

Stem cell properties of GT101, a tumor infiltrating lymphocyte (TIL) product with multiple indications.

e14506 Background: Tumor infiltrating lymphocyte (TIL) is a kind of adoptive T cell therapy that has demonstrated clinical benefits in several types of solid tumors. GT101 is an autologous TIL therapy for the treatment of multiple solid tumors. Previous studies showed that in vitro expansion resulted in over 80% terminally differentiated effector T cells in the final TIL products, which may show good cytotoxicity but weak capability of persistence and proliferation in vivo. Herein we present phenotype and function characterization of our TIL product GT101 with a focus on its stemness attributes. Methods: We have produced more than 30 batches of GT101 TIL samples from 10 different cancer indications and analyzed their proliferation, cytokine production and phenotype at preREP and/or REP stage. Results: GT101 products keep a consistent T cell phenotype and good proliferation capacity, and are capable of secreting large amounts of cytokines after stimulation by anti-CD3/CD28 antibody, reflecting its good functionality. The residues in the final products, such as feeder cells and tumor cells, are below the detection limit. In contrast to equivalent TIL products previously reported across the world, we find that GT101 features a manufacturing process that preserves the stem cell characteristics of T cells. Analysis of all the 30 GT101 TIL samples demonstrates that the average percentage of central memory T cells (Tcm) and naïve T cells is 40-50% and 10-20% respectively in both CD8+ and CD4+ populations at the end of preREP stage. Meanwhile, CD8+TCF1+ cells are close to 50%, mainly in the form of PD-1-. In the phase of REP, the stemness of T cell is still well maintained—the average proportion of both Tcm and naïve T cells only decreases by about 5%, and that of CD8+TCF1+ cells down by about 10%. Conclusions: In general, GT101 demonstrates good stemness with a higher percentage of Tcm and TCF1+ than equivalent products previously reported across the world, suggesting better performance in persistence and proliferation in clinic.

Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia.

BackgroundImmune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand/receptor interactions that determine the function of T cells in AML.MethodsTo analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem/progenitor cells and paired bone marrow (BM)-infiltrating CD4+ and CD8+ T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of PAC1.ResultsWe observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8+ T cells and partially in CD4+ T cells, due to pathological chromatin remodeling via histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of PAC1, as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8+ T cells.ConclusionsOur results suggest that CD8+ T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML.

Abstract PS19-22: Fatty acid synthase enzyme as a mediator of obesity-induced breast cancer

Abstract INTRODUCTION: Breast cancer accounts for nearly 40,000 deaths annually with the overall prognosis worsened if the patient is obese. Reprogramming of lipid metabolism in cancer is an established hallmark and contributes to tumorigenesis and drug-resistance. The fatty acid synthase enzyme (FASN) is overexpressed in multiple solid and hematopoietic tumors and its expression is associated with tumor grade as well as resistance to therapy. Targeted therapies against the fatty acid synthase enzyme (FASN) are currently in phase II of clinical trials for the treatment of multiple solid tumors. Previously, our lab has shown enhanced expression of FASN in breast cancer cells exposed to obese sera as well as increased sensitivity to the FASN inhibitor, TVB-3166. The obese phenotype is characterized by increased circulating bioactive growth factors and hormones, such as insulin, estrogen, and insulin-like growth factor 1 (IGF-1), that are ligands for the insulin (IR) and insulin-like growth factor receptor-1 (IGF-1R). Activation of these receptors can lead to downstream signaling through the PI3K-Akt-mTOR pathway that mediates lipogenic gene expression through various transcription factors. Of these transcription factors, sterol regulatory element-binding protein-1 (SREBP-1), drives FASN gene expression and is activated downstream of both Akt and mTORC1. HYPOTHESIS: We hypothesize that obesity-induced breast cancer progression is mediated through an SREBP dependent overexpression of FASN. METHODS: MCF-7 cells were exposed to obese or non-obese sera and subjected to quantitative RT-PCR for FASN expression. MTT and colony-forming assays using both MCF-7 and T-47D breast cancer cells conditioned in 2% obese and 2% non-obese sera as well as treated with and without a FASN inhibitor (TVB-3166) were utilized to determine cell survival and viability in response to FASN inhibition. FASN expression in obesity-induced breast cancer was investigated by treating MCF-7 cells with either insulin or SREBP processing inhibitor (Betulin) and subjected to chIP-qPCR against anti-SREBP or normal rabbit IgG. RESULTS: In response to obese sera exposure, there was a nearly 3-fold increase (p=.010) in FASN expression compared to non -obese control. Obese sera exposure increased sensitivity and decrease cell viability to TVB-3166 treatment compared to non-obese sera. ChIP-qPCR against anti-SREBP showed an increase in FASN expression upon treatment with insulin compared to normal rabbit IgG control. This increase in FASN expression was attenuated upon treatment with the SREBP processing inhibitor, Betulin. CONCLUSION: The overexpression of FASN contributes to obesity-induced breast cancer aggression and is regulated by an insulin-SREBP-FASN signaling axis. Citation Format: Bryan Mcclellan, Tommy Pham, Brittany Harlow, Gabby Lee, Duan Quach, Christopher Jolly, Andrew Brenner, Linda deGraffenried. Fatty acid synthase enzyme as a mediator of obesity-induced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-22.

Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats.

Cisplatin is used widely for the treatment of multiple solid tumors. Cisplatin-induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin-induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug-drug interaction between lansoprazole and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin-induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. The in vivo rat study showed that concomitant lansoprazole significantly ameliorated cisplatin-induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole ameliorated cisplatin-induced nephrotoxicity by inhibiting rOCT2-mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin-induced nephrotoxicity.

Predicting Paclitaxel Disposition in Humans With Whole-Body Physiologically-Based Pharmacokinetic Modeling.

Paclitaxel is a commonly used drug in the treatment of multiple solid tumors, including cancers of the breast, lung, and ovaries. Despite the established exposure–pharmacodynamic relationships for paclitaxel, treatment is associated with wide interindividual pharmacokinetic variability that leads to unpredictability of the agent's clinical activity and toxicity. We hypothesized that physiologically‐based modeling approaches could be employed to predict the human pharmacokinetics of paclitaxel following administration of the approved Cremophor‐based formulation (Taxol). The model was developed from tissue distribution studies performed in mice and applied to plasma concentration‐time data obtained in adult cancer patients receiving Taxol at the approved dose and schedule (175 mg/m2 by a 3‐hour intravenous infusion), taking into account interspecies differences in physiological parameters. The final model adequately captured the observed concentrations in patients and allowed prediction of paclitaxel distribution profiles in multiple target organs and can be applied to further refine the chemotherapeutic treatment with a clinically important agent.

1195P - Safety, efficacy, and immune effects of intratumoral tilsotolimod in patients with refractory solid tumours: Updated results from ILLUMINATE-101

BackgroundTilsotolimod, a synthetic toll-like receptor 9 (TLR9) agonist, modulates the tumor immune microenvironment and has antitumor activity as monotherapy in preclinical models. In the ILLUMINATE-204 phase I/II study of tilsotolimod in combination with ipilimumab in patients with refractory melanoma, increased antitumor immune activity was observed in injected and uninjected tumors at 24hours following tilsotolimod treatment. The ILLUMINATE-101 phase Ib study explored the safety, efficacy, and immune effects of tilsotolimod monotherapy in multiple solid tumors. MethodsAdults with histologically or cytologically confirmed diagnosis of cancer not amenable to curative therapies received intratumoral tilsotolimod in doses escalating from 8mg to 32mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced melanoma were enrolled into an expansion cohort at the 8-mg dose, the recommended phase II dose established for melanoma. Objectives included characterizing safety and efficacy, and immunological assessment. Blood samples and tumor biopsies of injected and distal lesions were obtained at baseline and 24hours post treatment for immune analyses. ResultsAs of May 6 2019, 54 patients have been enrolled, including 38 patients into the dose evaluation portion and 16 patients into the melanoma expansion cohort. No dose-limiting toxicities were observed. The most common treatment-related adverse events were fever, fatigue, and chills. Within 24hours, fresh tumor biopsies showed increased gene expression for multiple immune checkpoint pathways, increased IFN gamma levels, activation of the type 1 IFN pathway, and upregulation of MHC class I and II, compared to pretreatment biopsies. Of 43 evaluable patients, 15 (35%) had a RECIST v1.1 disease assessment of stable disease (duration 1.2 to 11.1 months, 1 patient ongoing). ConclusionsTilsotolimod was well tolerated and induced robust alterations in the tumor microenvironment, including immune checkpoint upregulation, activation of dendritic cells, and induction of Type 1 IFN signaling. A phase II study of tilsotolimod in combination with nivolumab and ipilimumab has been initiated for the treatment of multiple solid tumors (ILLUMINATE-206; NCT03865082). Clinical trial identificationNCT03052205. Editorial acknowledgementTed Everson, Idera Pharmaceuticals, Inc. Legal entity responsible for the studyIdera Pharmaceuticals, Inc. FundingIdera Pharmaceuticals, Inc. DisclosureH. Babiker: Advisory / Consultancy: Endocyte; Advisory / Consultancy: Celgene. V. Subbiah: Advisory / Consultancy: Idera Pharmaceuticals; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: Loxo Oncology. S. Rahimian: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. C. Haymaker: Research grant / Funding (institution): Idera Pharmaceuticals. C. Bernatchez: Research grant / Funding (institution): Idera Pharmaceuticals. G. Bindra: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. I. Iverson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. S. Chunduru: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. A. Diab: Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: Nektar Therapeutics; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy: Jounce Therapeutics; Honoraria (self): Novartis; Advisory / Consultancy: Idera. All other authors have declared no conflicts of interest.

Abstract 2753: The molecular basis of blocking the TIM-3 checkpoint with the LY3321367 mAb in cancer immunotherapy

Abstract The anti-T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) antibody LY3321367 is a promising immune-checkpoint inhibitor that is being clinically tested for the treatment of multiple solid tumors (NCT03099109). LY3321367 was phenotypically selected from a large set of phage library Fabs that are TIM-3 binders. Tim3 has multiple protein and non-protein binding partners; hence, we attempt in this study to deconvolute the molecular mechanism of action of LY3321367. Surprisingly, LY3321367 in ELISA assays partially blocks the TIM-3/GAL-9 complex but does not block the TIM-3/CEACAM-1 complex. We also utilized X-ray crystallography to solve the structure the LY3321367-Fab complex with the IgV domain of TIM-3 at 2.0Å resolution. After solving the unbound structure of the LY3321367-Fab, we demonstrated that its CDRs do not undergo any conformational changes upon binding human TIM-3. The structural alignment of the human TIM-3/LY3321367-Fab complex with the available murine TIM-3 structure unexpectedly suggests that the 6.0Å epitope of LY3321367 overlaps the phosphatidylserine (PS) binding site on TIM-3. Consequently, we developed a cell-based assay to demonstrate that LY3321367 completely blocks the binding of soluble human TIM-3 to PS displayed on the surface of Campothecin-treated DO11.10 cells. Our structural results suggest an important role for PS in TIM-3 biology which is blocked by LY3321367. When combined with the partial blocking of GAL-9, the structural data of LY3321367 suggests that the binding sites of PS and GAL-9 may be proximal to each other on TIM-3. Citation Format: Jaafar N. Haidar, Stephen Antonysamy, Sneha Mathew, Lan Wu, Yi Zhang, Margaret C. Kearins, Leyi Shen, J. Michael Sauder, David Schaer, Kyla E. Driscoll, Michael Kalos. The molecular basis of blocking the TIM-3 checkpoint with the LY3321367 mAb in cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2753.

Abstract SY33-01: Improving immunotherapy of cancer by normalizing tumor vessels

Abstract SY33-01: Improving immunotherapy of cancer by normalizing tumor vessels

MiR-30b-5p attenuates oxaliplatin-induced peripheral neuropathic pain through the voltage-gated sodium channel Nav1.6 in rats

Oxaliplatin is a third-generation derivative of platinum that is effective in the treatment of multiple solid tumors. However, it can cause peripheral neuropathic pain, and the molecular mechanisms of this effect remain unknown. We induced a model of peripheral neuropathic pain in rats by intraperitoneally injecting them with oxaliplatin twice a week for 4.5 weeks. We found that both the mRNA and protein expression levels of Nav1.6 (encoded by the gene Scn8a) increased while the miR-30b-5p (shorthand for miR-30b) expression decreased in the dorsal root ganglion (DRG) of treated rats. Using TargetScan and miRanda predictive software, we discovered that Scn8a was a major target of miR-30b. Moreover, we found that miR-30b negatively regulated Scn8a by binding to the Scn8a 3′UTR in PC12 cells. In addition, Nav1.6 and miR-30b were colocalized in the DRG neurons of naive rats. Overexpression of miR-30b using an miR-30b agomir attenuated neuropathic pain induced by oxaliplatin and inhibited both the mRNA and protein expression levels of Nav1.6 both in vitro and in vivo. Conversely, the inhibition of miR-30b with an miR-30b antagomir resulted in neuropathic pain and an increase in the expression of Nav1.6. More importantly, overexpression of miR-30b inhibited the proliferation of LS-174t cells (Colorectal cancer cells). These data suggest that miR-30b contributes to oxaliplatin-induced chronic neuropathic pain through Nav1.6 downregulation and could be a novel therapeutic target for the treatment of oxaliplatin-induced neuropathic pain as a side effect of chemotherapy in cancer patients.

EPR19-74: Risk of Cabozantinib-Associated Gastrointestinal and Hepatic Toxicities in Patients With Metastatic Solid Tumors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Cabozantinib is an oral inhibitor of multiple tyrosine kinases and is used in treatment of multiple solid tumors, targeting several pathways such as vascular endothelial growth factor signaling pathway and proto-oncogenes MET, KIT, RET. These pathways are implicated in several tumor development and progression. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities among patients with metastatic solid tumors treated with cabozantinib. Methods: MEDLINE, EMBASE databases, and meeting abstracts from inception to September 2018 were queried. Phase 3 RCTs that mention GI and elevation of liver enzymes as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: We included 4 phase 3 RCTs with a total of 2,703 patients with various solid tumors. The study arm used cabozantinib while the control arm utilized everolimus or placebo or prednisone. The relative risks of all-grade side effects were as follows: diarrhea, 2.495 (95% CI: 2.149–2.897, P&lt;.0001); nausea, 1.849 (95% CI: 1.649–2.072; P&lt;.0001); vomiting, 2.335 (95% CI: 1.724–3.163; P&lt;.0001); stomatitis, 4.541 (95% CI: 0.908–22.696; P=.065); dysgeusia, 4.428 (95% CI: 2.67–7.343; P&lt;.0001); elevated AST, 2.002 (95% CI: 1.331–3.011; P=.001); and elevated ALT, 1.988 (95% CI: 0.936–4.222; P=.074). The RR of high-grade side effects were as follows: diarrhea, 5.913 (95% CI: 3.655–9.566; P&lt;.0001); nausea, 3.098 (95% CI: 1.266–7.581; P=.013); vomiting, 1.298 (95% CI: 0.395–4.265; P=.668); stomatitis, 3.837 (95% CI: 0.749–19.665; P=.107); dysgeusia, 1.522 (95% CI: 0.159–14.574; P=.716); elevated AST, 1.733 (95% CI: 1.101–2.728; P=.018); and elevated ALT, 2.489 (95% CI: 1.164–5.326; P=.019). Conclusion: The risk of developing all grades of diarrhea, nausea, elevated AST, and any-grade vomiting, dysgeusia as well as high-grade elevated ALT, was high in cabozantinib group. Timely recognition and providing good supportive care will enhance patients’ quality of life.