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Background: In an open-label, phase Ib dose-finding and dose-expansion study in pts with aRCC, AXI+PEMBRO was tolerable; objective response rate (ORR) was 73.1%, and median progression free survival (mPFS) was 20.9 months (Lancet Oncol. 2018;19:405-15). These planned exploratory analyses evaluated candidate biomarkers that may confer sensitivity/resistance to AXI+PEMBRO. Materials & Methods: Tumor tissue (de novo biopsy or archival), serum and whole blood samples were collected at baseline (BL). Biomarkers were chosen based on known angiogenesis/immunomodulation roles. Clinical outcomes included ORR and PFS. Comparisons for responders vs non-responders were made using Wilcoxon rank sum test. Comparisons of PFS for Results: 52 pts were treated. Tumor tissue, serum and whole blood samples were analyzed from 39 (75.0%), 51 (98.1%) and 52 (100%) pts, respectively. Immunohistochemical analysis of tumor tissue biomarkers revealed no significant associations between CD68, CD8 or PD-L1 levels at BL and ORR or PFS. However, pts whose tumor CD8 % positive cells was ≥median had a numerically longer PFS than pts whose CD8 % positive cells was Conclusions: In pts with aRCC, higher tumor levels of CD8 and serum levels of CXCL10 and CEACAM1 at BL may indicate potential sensitivity to AXI+PEMBRO treatment. Further validation of the value of these biomarkers in an independent cohort with a large sample size is warranted. Citation Format: Michael Atkins, Jean-Francois Martini, Elizabeth Plimack, David McDermott, Igor Puzanov, Mayer Fishman, Daniel Cho, Ulka Vaishampayan, Brad Rosbrook, Kathrine Fernandez, Jamal Tarazi, Saby George, Toni Choueiri. Axitinib in combination with pembrolizumab (AXI+PEMBRO) in patients (pts) with advanced renal cell carcinoma (aRCC): Analysis of immune-related biomarkers [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 CT093.

Renal cell carcinoma (RCC) is very difficult to treat as the cells are mostly resistant to many current therapies. Therefore, newer treatments including better ways of drug delivery are urgently needed to fight this malignant disease efficiently. The ongoing work was done by generating and characterizing RCC cells that are resistant to everolimus, a front-line mTOR-targeted therapy, and tested whether a class of CARP-1 functional mimetic (CFM) compounds inhibits parental and everolimus-resistant RCCs in combination with sorafenib. CFMs inhibited RCC cell viability in a dose-dependent manner that was comparable to everolimus treatments as well as the combination with sorafenib. CFM-4.16 inhibited viabilities of everolimus-resistant RCC cells, albeit CFM-4.16 combined with sorafenib was more effective than CFM-4.16 alone. CFM-dependent loss of RCC cell viabilities was due in part to reduced cyclin B1 levels, activation of pro-apoptotic, stress-activated protein kinases (SAPKs), and apoptosis. However, CFMs and sorafenib are hydrophobic, and their dose escalation for in vivo studies remains challenging. We addressed the solubility and delivery concerns of CFM-4.16 and sorafenib by utilizing a nanotechnology-based approach. Our data thus far revealed that we have been successful in overcoming the solubility concerns of CFM-4.16 and sorafenib by encapsulating it in water-soluble vitamin E TPGS-based micellar nanoformulation that enables high drug loading and affords its intravenous administration for animal testing. We also use our polymeric NPs formulation for in vitro efficacy in parental, wild-type and everolimus-resistant RCC. After confirming the anticancer activity of CFM-4.16-loaded nanoformulations in vitro, we finally examined the intravenous (i.v.) administration of the CFM-4.16-loaded polymeric NPs in a clinically relevant RCC mouse model. The CFM-4.16 formulation inhibited the viability of parental and everolimus-resistant RCC cells in vitro and suppressed the growth of parental A498 RCC-cell-derived xenografts (RCC animal model), in part by stimulating apoptosis. After optimizing its potency and biologic stability, we performed imaging of animal inoculated with RCC tumor and PDX model by conjugation with NIR dye. The results showed high binding affinity and specific tumor uptake, faster normal tissue clearance and less non-target organ uptake. These findings make CFM-4.16 an important potential therapeutic in combination with sorafenib using nanoformulation in the treatment of RCCs. Citation Format: Hashem O. Alsaab, Samaresh Sau, Vino T. Cheriyan, Ulka Vaishampayan, Arun K. Rishi, Arun K. Iyer. Tumor multifunctional targeting polymeric nanomicelles with polypharmacy payload for effective therapy and imaging of resistant renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4107.

Background: Dysregulated Wnt/β-catenin signaling has been linked to several cancers, including pancreatic cancer (PC) and colorectal cancer (CRC). WNT974 (formerly LGK974) - a first-in-class, selective, oral inhibitor of Porcupine (an O-acyltransferase required for Wnt activation and secretion) - has shown preclinical activity in tumor models with mutations upstream in the Wnt pathway. Furthermore, dysregulated Wnt signaling has been linked to T-cell exclusion in tumor tissue and resistance to immunotherapy, suggesting WNT974 may act synergistically with checkpoint inhibitors. Methods: This ongoing Phase I, open-label, dose-escalation and -expansion study (NCT01351103) is designed to determine the maximum tolerated dose and/or recommended dose for expansion, characterize the safety and tolerability, and assess preliminary antitumor activity, pharmacokinetic (PK), and pharmacodynamic properties of WNT974, alone or combined with PDR001 (spartalizumab, an anti-PD-1 antibody) in advanced/metastatic solid tumors. Here, we focus on preliminary biomarker analyses from the single-agent part of the study. The study initially enrolled pts with lobular breast cancer and melanoma and was later amended to enroll pts with triple negative breast cancer (TNBC), PC, and CRC, and those with tumors with genetic alterations upstream in the Wnt pathway. Pre and on-treatment skin and tumor tissue specimens were collected for RT-PCR analysis of AXIN2, a marker of Wnt pathway activity. NanoString gene expression was measured in a subset of pts using remnant RNA from the tumor samples, and chemokine and dendritic cell signatures were analyzed pre and on-treatment. Results: At the data cut-off date, March 2, 2017, 94 pts were enrolled. Median age was 58.5 years (range, 28-77), 43% were male, and the most common cancer types were PC (30%), melanoma (26%), and breast cancer (21%). Patients received single-agent WNT974 orally at doses of 5, 7.5, 10, 15, 20, 22.5, or 30 mg daily, 30 or 45 mg intermittently (4 days on, 3 days off), or 5 mg twice daily. Median duration of exposure was 4.9 weeks (range, 0.1-27.7). Safety, tolerability, and PK have previously been reported. AXIN2 expression in paired samples from skin and tumor showed evidence of Wnt pathway inhibition in all indications; this was not dose-dependent in the dose range studied. Immune signature analyses of a paired tumor sample subset (n=8) revealed an inverse association between change in AXIN2 expression and change in chemokine and activated dendritic cell signatures. Conclusions: Biomarker analyses show that WNT974 can potently inhibit Wnt pathway activity in skin and tumors. Immune signature data suggest that WNT974 treatment may promote T-cell recruitment into tumors, and support investigation of the combination of WNT974 with immunotherapy. The combination part of this study evaluating WNT974 combined with PDR001 (spartalizumab) is ongoing. Citation Format: Jordi Rodon, Guillem Argilés, Roisin M. Connolly, Ulka Vaishampayan, Maja de Jonge, Elena Garralda, Marios Giannakis, David C. Smith, Jason R. Dobson, Margaret McLaughlin, Abdelkader Seroutou, Yan Ji, Sinead Dolan, Jennifer Morawiak, Susan Moody, Filip Janku. Biomarker analyses from a phase I study of WNT974, a first-in-class Porcupine inhibitor, in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT175.

Renal Cell Carcinoma (RCC) contributes >90% of the most common form of kidney tumor and remains one of the ten leading causes of cancer death in the US. Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors have increased therapeutic possibilities for treating RCC. Although the impact on disease progression is encouraging, a substantial proportion of patients do not respond adequately, and therapy resistance almost inevitably occurs. Eventually, new strategies have emerged that include immunotherapy such as PD-1 inhibitor (Nivolumab) and the combination of chemo-immune therapy. Possibly, combination treatment aimed at different, non-related pathways may be advantageous. In this regard, we would like to come up with synergistic therapeutic strategies for nonresponsive, highly aggressive tumor types to tackle the current clinical challenges. We have worked on different RCCs tumor models that in general have a poor prognosis with conventional therapies. We also pursued different combination regimens, including drugs that work on the mTOR inhibition (everolimus), inhibit RTK-inhibitor or VEGFR (cabozantinib or sorafenib). Also, there is a critical need to develop safe and effective delivery vehicles that can carry the payload to the right target tissue and cell. Thus, different types of nanoparticles have been designed to deliver a variety of therapeutic agents to target hypoxic tumor microenvironment by using carbonic anhydrase-9 (CA9); FRα for targeting cancer epithelial cells; and FRβ for targeting tumor-associated macrophages (TAM) and combination delivery of RTK-inhibitor Cabozantinib (CB) and sorafenib with our own apoptosis inducer/CARP-1 protein activator CFM-4.16 (C4.16) for overcoming drug resistance and reprograming TAM for RCC therapy. The current work also focused on multimodal approaches, including (a) Optimization of hypoxia marker conjugated targeted polymer-lipid nano-formulation (PLNP) using copper-free click chemistry; (b) In vitro and in vivo pre-clinical testing of targeted -PLNP loaded with polypharmacy in inhibiting RCCs using mice bearing resistant RCCs and patient-derived xenografts (PDX). The results of efficacy and biodistribution of targeted PLNPs in animals bearing RCC xenografts and PDX model showed higher accumulation of drugs at tumor sites with higher tumor growth inhibition. Also, the targeted formulation showed high binding affinity and specific tumor uptake, faster normal tissue clearance, and less non-target organ uptake. These findings portent promising therapeutic potential of hypoxia-targeted -PLNPs for treating RCCs. Citation Format: Hashem O. Alsaab, Samaresh Sau, Vino T. Cheriyan, Rami Alzhrani, Ulka Vaishampayan, Arun K. Rishi, Arun K. Iyer. Tumor multicomponent targeting nano-micelles with synergistic combination to overcome drug resistance and reprogramming of macrophages in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3716.

Background: TMPRSS2-ERG fusions are highly prevalent in prostate cancer patients, where androgen responsive TMPRSS2 gene promoter fused with coding sequence of ERG transcription factor resulting in androgen mediated expression of ERG factor. Metastatic cancer patients harbor the TMPRSS2-ERG fusions and presence of fusions associate with poor overall survival. The association between ERG transcription factor and anti-androgen therapy (enzalutamide (arm A) vs. bicalutamide (arm B)) responsiveness was evaluated in a randomized trial in metastatic hormone sensitive prostate cancer (mHSPC). Methods: 40 of 71 patients had evaluable tissue from metastatic biopsy. 18 patients were on enzalutamide arm (A) and 22 patients were on bicalutamide arm (B). PSA was monitored monthly for first 7 months and then every 3 months. Total RNA was isolated from biopsy specimens, QPCR analysis was performed for ERG gene. A standard curve was developed with ERG expressing plasmid in QPCR experiment and the copy number of ERG was determined in the metastatic biopsies. Seven month PSA Response (SMPR) rates were calculated for the high and low subset categories of median-dichotomized ERG copy number. The odds of SMPR was modeled as a function of continuous ungrouped correlative via univariable logistic regression. Results: 15/40 patients had both pre and post treatment biopsies available. The mean ERG copy number was increased in post treatment biopsy in both arms (enzalutamide, n=10 and bicalutamide, n=5). The mean copy increased (pre= 8541 and post =9789) upon enzalutamide treatment and also increased (pre=17186 and post = 23368) upon bicalutamide treatment. SMPR rates show that low copy number patients responded better (19/20) compared to high copy number patients (14/20). In arm A response rate is 100% (18/18), whereas in arm B, low ERG copy number patients responded better (8/11) compared to high copy number patients (7/11). Finally, the SMPR odds ratio remained close to 1.000 even for large copy number increase. Selective ERG responsive gene expression levels were determined in metastatic biopsies and will be associated with clinical endpoints. Conclusions: Enzalutamide improved the likelihood of PSA remission in mHSPC and follow up is ongoing. Metastatic biopsy specimen analysis show that higher ERG copy number had a lower likelihood of PSA response with ADT and may serve as a prognostic or predictive marker, but further analysis is warranted. Citation Format: Sreenivasa R. Chinni, Ulka N. Vaishampayan, Lance K. Heilbrun, Louie Semaan, Daryn Smith, Dipenkumar Modi, Paul Monk, Shiela Tejwani, Guru Sonpavde, Kimberlee Dobson, Brenda Dickow, Elisabeth Heath, Joseph Fontana, Micheal L. Cher. Evaluation of ERG as a biomarker of responsiveness in a randomized trial of enzalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-309.

Background: In patients (pts) with mCRPC, bone metastases (mets) occur up to 80% of the time and are a significant cause of morbidity and mortality. Radium-223 dichloride (Ra-223) is a targeted α-emitter and extends overall survival (OS) in mCRPC pts with symptomatic bone mets. While several therapies, including Ra-223, have recently been approved for mCRPC, pts ultimately develop resistance and progressive disease. Therefore, there is a high unmet need for new treatments for mCRPC pts. Atezolizumab (atezo) is a humanized mAb that targets PD-L1 and blocks its interaction with its receptors, PD-1 and B7.1, which is expected to enhance T-cell responses and improve anti-tumor activity. A pre-clinical study found that tumor and dendritic cells have higher PD-L1 expression after ionizing radiation (IR) exposure and that combining anti-PD-L1 therapy with IR enhanced the inhibition of tumor growth. Radiotherapy leads to immune modulation and may help prime an immune response by releasing tumor-associated antigens that may target tumors distant from the local radiation field (i.e., abscopal effect). These data support the hypothesis that atezo + Ra-223 may be an effective therapy for CRPC pts with bone and soft tissue mets. Methods: A phase Ib clinical trial (NCT02814669) is being conducted to assess the safety and tolerability of atezo + Ra-223 in pts with mCRPC after progression on an androgen pathway inhibitor and to identify a recommended treatment schedule. Pts will have mCRPC with at least 2 bone mets and either measurable visceral (non-liver) mets or lymphadenopathy. Eligibility criteria include ECOG PS 0-1, progression on an androgen pathway inhibitor, and soft tissue disease amenable for serial biopsy. Exclusion criteria include small cell or neuroendocrine prostate cancer, autoimmune disease, eligible for and willing to receive treatment with taxanes, and prior treatment with Ra-223. Pts will receive atezo (840 mg q2w) and Ra-223 (55 kBq/kg q4w). The study includes a cohort phase, to evaluate a concurrent dosing regimen, and if safe and tolerable, a randomization phase to compare concurrent and staggered dosing. Regimens that are safe and tolerable may undergo expanded enrollment. A recommended schedule will be based on incidence of dose-limiting toxicities during first cycle of combination treatment. A preliminary assessment of efficacy will include ORR per RECIST v1.1, DOR, rPFS, OS, and PSA response rate. Approximately 45 pts will initially be enrolled in the United States. Citation Format: Lawrence Fong, Michael Morris, Andrew Armstrong, Daniel Petrylak, Ulka Vaishampayan, Ajjai Alva, Jean Hoffman-Censits, Indrani Sarkar, Susheela Carroll, Christina Schiff, Oliver Sartor. A phase Ib trial to study the safety and tolerability of atezolizumab with radium-223 dichloride in patients with metastatic castrate-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT031. doi:10.1158/1538-7445.AM2017-CT031

About 20% of non-castrated female domestic cats develop malignant mammary tumors with similar histopathology and disease progression as human breast cancer. Her2 over-expression is reported in 40-85% of feline mammary carcinomas, indicating this disease is particularly suited for testing Her2 DNA vaccination. To corroborate these findings, expression of Her2 was evaluated in 4 feline mammary tumors resected from three feline patients. Immunohistochemistry analysis with anti-human Her2 mAb showed regions of intense membrane staining in all four tumor samples, indicating high frequency of Her2 expression among feline mammary tumors and immune cross-reactivity of human and feline Her2. Feline mammary tumor lines K248 (Minke, et. al. 1991) and K12 (Modiano, et. al. 1991) both express Her2 as measured by flow cytometry, further demonstrating Her2 as a common antigen in feline mammary tumors. Feline Her2 cDNAs cloned from K248 and K12 (GenBank Accession JN990983) are identical to each other and show 93% sequence identity with human Her2. To test the feasibility of conducting DNA electrovaccination in cats, 3 pathogen-free domestic short hair cats between 1-2 years of age were injected i.m. in the biceps femoris of the hind legs or triceps of the front legs with vaccine DNA. Each cat received admix of 1.5mg of pE2Neu encoding a hybrid human Her2 and rat neu fusion protein and 1.5mg of feline pGM-CSF. Each injection site was subjected to electroporation with a NEPA21 electroporator, consisting of three 50msec 100V degenerating bipolar pulses. The vaccination was repeated at 3 week intervals and blood was drawn 2 weeks after each vaccination. Anti-human Her2 antibody was detected in the immune serum after 2 vaccinations, as demonstrated by binding to SKOV3 cells that over-express human Her2. After 4 vaccinations, anti-human Her2 antibody titers ranged from 50,000 to 200,000. Therefore, DNA electrovaccination is an effective means to induce immune response in cats. To test if immunization with heterologous pE2Neu induced cross-reactive antibody to self feline Her2, immune serum was incubated with 3T3/fHer2 cells that express feline Her2. Specific binding to 3T3/fHer2 was observed after 3 vaccinations at 1:100 serum dilutions. These results provide the first evidence that immune tolerance in cats to self Her2 is overcome by a hybrid DNA vaccine encoding a fusion protein of two heterologous genes: human Her2 and rat neu. This vaccine regimen is a candidate veterinary therapeutic agent and the insight gained from cat vaccination provides strong support for human vaccine trials. Citation Format: Heather M. Gibson, Richard Jones, Marie Piechocki, Joyce Reyes, Michele Sauerbrey, Ulka Vaishampayan, Wei-Zen Wei. Electrovaccination of domestic cats with a hybrid heterologous Her2 DNA vaccine overcomes immune tolerance to self Her2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 470. doi:10.1158/1538-7445.AM2013-470