Presented Abstracts

EXPOSURE-TARGETED MELPHALAN DOSING INDIVIDULIZATION IN PATIENTS WITH MULTIPLE MYELOMA UNDERGOING AUTOLOGOUS TRANSPLANT

Kyeongmin Kim1, Yizhen Guo1,2, Kasey Hill2, Nicole Abbott2, Donald J. Irby1, Craig C. Hofmeister3, Pritesh Patel5, Karen Sweiss4, and Mitch A. Phelps1,2

1Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 2Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 3Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 4Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL, 5Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL

BACKGROUND

High-dose melphalan (HDM) and autologous stem cell transplant is a standard of care in multiple myeloma. The standard HDM, melphalan dose of 200 mg/m2, yields a 5-fold variation in melphalan exposure which is associated with variability in drug responses or adverse drug reactions1. Therefore, HDM dose individualization is needed to improve clinical outcomes.

METHODS

We evaluated methods to perform HDM individualization. Data were obtained from a multicenter phase I trial (NCT04483206), where HDM was separated into an initial dose of 100 mg/m2 on Day -3 and a personalized dose on Day -1 to target a prespecified exposure (AUC0-inf) of 13-14 mg*hr/L. Seven blood samples were collected after each dose and melphalan AUC0-inf was estimated using non-compartment analysis (NCA) and non-linear mixed effect modeling (NONMEM) approaches. Per protocol, the Day -1 dose determination and target attainment assessment was based on NCA. In NONMEM approach, an in-house melphalan pharmacokinetic model was used and the performance of NONMEM was evaluated in post-hoc analysis.

RESULTS

Seven patients with a total of 95 blood samples were evaluated. Based on NCA, the total HDM dose was 140 (116-196) mg/m2, with 30.0% (2.04 – 42.2%) reduction from the standard dose of 200 mg/m2. The total AUC0-inf was 13.5 (12.8 – 13.9) mg*hr/L, with 6 patients achieving the target.  In NONMEM, the total AUC0-inf was well-correlated with NCA (R2=0.98). Compared with NCA, NONMEM approach would have resulted in a -0.57% (-9.89% – 4.77%) variation in total HDM dose and the same target attainment.

CONCLUSION

NCA and NONMEM methods were both sufficient to perform exposure-targeted HDM individualization. However, the performance could differ with missing or sparse samples. The source of variability remains to be investigated to further optimize HDM dose.

REFERENCE

  1. Nath, C. E. et al. Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. British Journal of Clinical Pharmacology 69, 484–497 (2010).

PHYSIOLOGICALLY-BASED MODELING OF IMMUNE CHECKPOINT INHIBITOR PHARMACOKINETICS AND TUMOR GROWTH INHIBITION

Kyeongmin Kim1, Yizhen Guo1, Bryan Remaily1, Trang T. Vu1, Justin Thomas1, Zhiliang Xie1, Latha Ganesan2, Dwight Owen3, Samuel K. Kulp1, Thomas A. Mace 4,5, Christopher C. Coss1,5, and Mitch A. Phelps1,5

1 Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 2 Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University, 3 Division of Medical Oncology, The Ohio State University James Comprehensive Cancer Center, 4 Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, The Ohio State University, 5 The Comprehensive Cancer Center, The Ohio State University

Recent clinical pharmacology studies of monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have revealed that elevated baseline clearance (CL) of ICI drugs is associated with shorter overall survival (OS) in patients with solid tumors and cancer-associated cachexia1. However, the underlying mechanisms linking outcomes to baseline CL in patients with cancer-associated cachexia are not known. Neonatal Fc receptor (FcRn) is well-known to protect antibodies from elimination, and Fc-γ-receptors (FcγRs) have also been identified lately for their association in the anti-tumor activity and clearance of antibodies2,3. Our group recently demonstrated elevated CL of pembrolizumab could be replicated in the murine CD2F1/C26 and C57BL/6/LLC models of cancer-associated cachexia4. Therefore, the aim of this study was to develop a physiologically based pharmacokinetics-pharmacodynamic (PBPK-PD) model capable of explaining the observed pembrolizumab CL and tumor growth inhibition in murine models of cachexia. A major feature of our model included incorporation of both FcRn and FcγRs and direct competition for binding between mAb drug and endogenous IgG, based on binding affinity data. The predictive performance of the PK model was evaluated against published mouse datasets. To date, no published PK model has incorporated competition between IgG mAb drug and endogenous IgG for binding both FcRn and FcγRs. Our novel model is guiding our experimental designs and has shed light on underlying mechanisms potentially contributing to the observed link between mAb drug CL and outcomes in our mouse models and in patients with cancer cachexia.

References

1. Turner DC, Kondic AG, Anderson KM, Robinson AG, Garon EB, Riess JW, et al. Pembrolizumab Exposure–Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance. Clin Cancer Res. American Association for Cancer Research; 2018;24:5841–9.

2. Oldham RJ, Mockridge CI, James S, Duriez PJ, Chan HTC, Cox KL, et al. FcγRII (CD32) modulates antibody clearance in NOD SCID mice leading to impaired antibody-mediated tumor cell deletion. J Immunother Cancer. BMJ Specialist Journals; 2020;8:e000619.

3. Jin H, D’Urso V, Neuteboom B, McKenna SD, Schweickhardt R, Gross AW, et al. Avelumab internalization by human circulating immune cells is mediated by both Fc gamma receptor and PD-L1 binding. OncoImmunology. Taylor & Francis; 2021;10:1958590.

4. Castillo AMM, Vu TT, Liva SG, Chen M, Xie Z, Thomas J, et al. Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans. JCSM Rapid Communications. 2021;4:232–44.

Elucidating the estrogen receptor subtype-dependent effects of estrogen receptor-β agonists on the hypothalamic-pituitary-gonadal axis

Gillian Mulcahy1, Samuel K. Kulp1, Mayu Fukuda1, Justin Thomas1, Tyler A. Wilson2, Chad Bennett2,3, Christopher C. Coss1,2,3

1College of Pharmacy, 2Medicinal Chemistry Shared Resource, 3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University

Background. The biological effects of estrogens are mediated by estrogen receptor (ER)α and ERβ, which act as ligand-activated transcription factors, and the membrane-bound G protein-coupled estrogen receptor 1 (GPER1). Selective activation of ERβ is expected to provide the beneficial effects of estrogen pharmacology without the unwanted side effects of estrogens that are primarily mediated through ERα. The OSUCCC Drug Development Institute supports a research program developing novel carborane-based selective ERβ agonists. The lead compound, OSU-ERb-12, shows high ERβ selectivity[1], favorable drug-like properties, and preclinical activity in ovarian cancer, breast cancer, and heart failure models[2-4]. In this study, we compared OSU-ERb-12 to LY500307, an advanced clinical stage selective ERβ agonist, in an in vivo bioassay in which urogenital tract (UGT) weight in male mice is an indicator of ERα-induced side effects resulting from altered feedback regulation of the hypothalamic-pituitary-gonadal axis. Methods. Twelve-week-old male ERαKO and ERβKO mice and wildtype (WT) littermates were randomized to groups (n=5) receiving OSU-ERb-12 at predicted ERβ-selective and nonselective doses (10, 100 mg/kg), LY500307 at reported ERβ-selective doses (0.5, 5.0 mg/kg), or vehicle once daily by oral gavage for 28 days. ERβ-selective and nonselective doses were previously determined via uterotrophic stimulation in estrogen-naïve, immature female mice[5]. At the end of study, UGT weights were measured, and blood was collected for serum luteinizing hormone measurements. Results. ERαKO, ERβKO and WT mice continue to be recruited to the study. Preliminary results show that in WT mice, OSU-ERb-12 reduced UGT weights at both of the tested dose levels. This effect appeared to persist in ERβKO mice, but was eliminated in ERαKO mice, suggesting that this effect is mediated by ERα. Consistent with previous observations, LY500307 reduced UGT weights in WT mice. Preliminary data suggest that this effect is dependent, at least in part, on the presence of ERα expression. Conclusions. Reductions in UGT weight by OSU-ERb-12 are mediated by ERα at both of the tested doses, suggesting ER isoform selectivity of OSU-ERb-12 may be age, sex, and model dependent. Similarly, reported ERβ-selective doses of LY500307 induced UGT side effects which also appear to involve ERα. Whether this sex tissue side effect results from modulation of the HPG axis will be informed by results of serum LH measurements.

  1. Sedlak, D., et al. J Med Chem, 2021. 64(13): p. 9330-9353.
  2. Rosenzweig, R., et al. Circ Heart Fail, 2022. 15(7): p. e008997.
  3. Datta, J., et al. Front Oncol, 2022. 12: p. 857590.
  4. Banerjee, A., et al. Cancers (Basel), 2022. 14(9).
  5. Jefferson, W.N., et al. J Chromatogr B Analyt Technol Biomed Life Sci, 2002. 777(1-2): p. 179-89.

This work was supported by the OSUCCC Drug Development Institute. Agents were synthesized in the Medicinal Chemistry Shared Resource and mice provided by the Target Validation Shared Resource (NCI/NIH P30CA016058).

USE OF MIXED-EFFECTS MODELING TO DEFINE CACHEXIA AND ITS IMPACT ON IMMUNE CHECKPOINT INHIBITOR DISPOSITION IN MURINE CANCER MODELS

Kyeongmin Kim1, Alyssa Marie M. Castillo1, Trang T. Vu1, Sophia G. Liva1,Min Chen1, Zhiliang Xie1, Justin Thomas1, Bryan Remaily1, Yizhen Guo1, Uma L. Subrayan1, Travis Costa2, Timothy H. Helms3, Donald J. Irby1, Dwight H. Owen4, Samuel K. Kulp1, Thomas A. Mace5,6, Mitch A. Phelps1,6 and Christopher C. Coss1,6

1 Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 2 Department of Biomedical Engineering, College of Engineering, The Ohio State University, 3 Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 4 Division of Medical Oncology, The Ohio State University James Comprehensive Cancer Center, 5 Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, The Ohio State University, 6 The Comprehensive Cancer Center, The Ohio State University

Recent clinical pharmacology studies have revealed that elevated clearance (CL) of monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies was associated with shorter overall survival (OS) in patients with solid tumors and evidence of cancer-associated cachexia. Turner et al. (2018) presented their analysis of OS for pembrolizumab-treated patients in advanced melanoma and non-small cell lung cancer (NSCLC), and they found that subjects with high pembrolizumab baseline clearance (CL0) had cachexia-related factors and showed decreased OS. Interestingly, the decreased OS was independent to pembrolizumab dose and exposure. Our group recently demonstrated elevated CL of the PD-1-targeted ICI, pembrolizumab, could be replicated in the murine C26 and LLC models of cancer-associated cachexia (Castillo et al., 2021), though elevated pembrolizumab CL was not observed in the non-cachectic MC38 tumor model. Though there are clinical factors (involuntary body weight loss, muscle and fat loss) and biomarkers (e.g. reduced serum albumin) associated with cachexia, there remains a poor understanding of the factors driving cachexia in patients and in animal models. Therefore, our goal is to understand the underlying mechanisms linking mAb ICI CL, anti-tumor efficacy, and cachexia, and we have sought to establish an objective measure of cachexia in our murine models. The aim of this study was to develop a mixed-effects pharmacokinetic (PK) model which can explain the difference in pembrolizumab CL between cachectic (colon carcinoma, C26; Lewis lung carcinoma, LLC), and non-cachectic (colon adenocarcinoma, MC38) mouse models. The model was able to predict pembrolizumab PK in individual mice, and it incorporated several covariates: murine IgG concentration, terminal fat weight, and Fcgrt expression. Moreover, the model was capable of explaining elevated pembrolizumab CL in the two cachectic cancer models (C26 and LLC) versus the tumor-free and the non-cachectic cancer model (MC38). This demonstrated the modeling approach serves as a means to identify factors impacting ICI mAb CL and may also enable a novel, objective definition of cachexia in mice.

Reference

  1. Turner DC, Kondic AG, Anderson KM, et al. Pembrolizumab Exposure–Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance. Clin Cancer Res. 2018;24(23):5841-5849.
  2. Castillo AM, Vu TT, Liva SG et al. Single-dose pembrolizumab in murine cancer-cachexia models replicates elevated catabolic pembrolizumab clearance in humans. JCSM Rapid Communications. doi: 10.1002/rco2.32 (Article in press)

Cancer-Associated Cachexia Alters the Pharmacokinetics of Extra-vascularly Administered Monoclonal Antibodies

Adeoluwa Adeluola1, Justin Thomas1, Lauren Granchie1, Thomas Tibbitts1, Bryan Remaily1, Min Hai1, Kyeongmin Kim1, Zhiliang Xie1, Samuel Kulp1, Mitch Phelps1,2, Christopher Coss1,2*

1Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, 43201, USA.; 2The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, 43201, USA.

Fc receptors play a critical role in the pharmacokinetics and efficacy of monoclonal antibody (mAb) therapies. For example, the neonatal Fc receptor (FcRn) prolongs the half-life of IgG-based mAbs by recycling these proteins and facilitates their transport across biological membranes. In cancer-associated cachexia, however, there is evidence to suggest that FcRn’s function is altered leading to faster clearance of IgG-based therapies in cachectic patients. We hypothesized that the alteration in FcRn’s function in cancer-associated cachexia is not limited to mAb elimination but would also affect the extravascular absorption of therapeutic mAbs. Consequently, we conducted a pharmacokinetic study that compared the rate of absorption and bioavailability of Pembrolizumab administered via IV, IP, and SC routes in cachectic and tumor-free mice. Plasma samples were obtained from treated mice over 8 days (1-192hrs) and analyzed for pembrolizumab concentration using ELISA techniques. mAb CL was elevated in all LLC TB mice relative to tumor free controls, irrespective of dose route.  However, cachexia-mediated inductions were smaller following extravascular IP and SC doses as compared to IV pembrolizumab administration, contrary to our initial hypothesis. Therefore, we conclude that FcRn’s altered function in cachexia may be limited to the central compartment. It is also possible that the increased clearance of pembrolizumab may be propagated by other Fc receptors that bind and internalize serum IgGs; however, this requires further investigation.

IDENTIFICATION OF THE ANDROGEN RECEPTOR SPLICE VARIANT DEPENDENT TRANSCRIPTOME IN HEPATOCELLULAR CARCINOMA

Emma J. Montgomery1, Anees M. Dauki2, PhD, Moray J. Campbell1,3, PhD, James S. Blachly4,5, MD, Esko A. Kautto4,6,7, Christopher C. Coss1,3, PhD.

1Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus OH. 2Gilead Sciences, Inc., Foster City, CA. 3Drug Development Institute, OSU Comprehensive Cancer Center, The Ohio State University, Columbus OH. 4Division of Hematology, College of Medicine, The Ohio State University, Columbus, OH.  5Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH. 6Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH. 7Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH.

Introduction: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and one of the most lethal forms of cancer worldwide.1 HCC is also highly sexually dimorphic with males having a 2-4 times higher risk of HCC occurrence than females regardless of the disease etiology.2 Based upon the discrepancy in HCC incidence between the sexes, the role of sex hormone receptors, such as the androgen receptor, in HCC progression has been investigated.3 Despite the evidence behind AR’s role in HCC lethality, clinical trials of anti-androgen therapy in HCC showed no significant clinical benefit.4 We recently reported the presence of abundant ligand-independent AR splice variants (AR-SVs) in HCC.5  AR-SVs are expressed in nearly 80% of HCC patients and may reach up to a quarter of their expressed AR, potentially reconciling abundant AR expression in HCC with the failure of anti-androgen therapy.  It is critical to characterize AR-SVs’ transcriptome in HCC as a first step toward understanding AR-SV action and the utility of therapeutically targeting AR-SVs in this lethal disease. 

Objectives: 1) Determine AR-SV’s effect on gene expression in HCC cell lines expressing AR isoforms in different cellular contexts. 2) Identify AR-SV dependent gene networks that may be associated with clinical outcomes in HCC.

Methods: HCC patient data and their AR-SV expression profiles was procured from TCGA. AR knockdown loss of function experiments were performed in two AR expressing HCC cell lines, SNU475 and HCCLM3, via AR siRNA. Knock down efficiency was validated by western blot. Paired end RNA-seq was performed followed by differential gene expression based upon cell line AR status. R & RStudio were used to visualize the DEGs. GSEA software from the Broad Institute was used to analyze gene set enrichment of the DEGs from RNA-Seq.

Results: AR-SVs commonly occur in many HCC patients and their contribution to patients’ composite AR expression is correlated with overall survival. RNA-seq indicates that AR-SVs are implicated in gene networks related to HCC progression and metastases.

Conclusions: These results indicate that higher AR-SV expression in HCC may lead to lower overall survival. Further, AR-SV modulation of gene expression may account for a portion of differential gene expression between patients varied levels of non-canonical AR transcript. Finally, AR-v7 modulation of gene expression related to epithelial mesenchymal transition (EMT) may be related to HCC progression and metastases.

References:

  1. Shang N, Wang H, Bank T, Perera A, Joyce C, Kuffel G, et al. Focal Adhesion Kinase and β-Catenin Cooperate to Induce Hepatocellular Carcinoma. Hepatology. 2019;70(5):1631–45.
  2. Kalra M, Mayes J, Assefa S, Kaul AK, Kaul R. Role of sex steroid receptors in pathobiology of hepatocellular carcinoma. World Journal of Gastroenterology. 2008 Oct 21;14(39):5945–61.
  3. Zhang H, Spencer K, Burley SK, Zheng XFS. Toward improving androgen receptor-targeted therapies in male-dominant hepatocellular carcinoma. Drug Discov Today. 2021 Jun;26(6):1539–46.
  4. Harding JJ, Kelley RK, Tan B, Capanu M, Do GK, Shia J, et al. Phase Ib Study of Enzalutamide with or Without Sorafenib in Patients with Advanced Hepatocellular Carcinoma. Oncologist. 2020 Dec;25(12):e1825–36.
  5. Dauki AM, Blachly JS, Kautto EA, Ezzat S, Abdel-Rahman MH, Coss CC. Transcriptionally Active Androgen Receptor Splice Variants Promote Hepatocellular Carcinoma Progression. Cancer Res. 2020 Feb 1;80(3):561–75.

DEVELOPMENT OF NICLOSAMIDE ANALOGS FOR TREATMENT OF ANDROGEN RECEPTOR POSITIVE HEPATOCELLULAR CARINCOMA

Emma J. Montgomery1, Enming Xing2, Anees M. Dauki3, PhD, Hanna Radomska1, PhD, Sam Kulp1, PhD, Lauren Granchie1, Mayu Fukuda1, Pui-Kai Li2 , PhD, Christopher C. Coss1, PhD.

1Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus OH. 2Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus OH. 3Gilead Sciences, Inc., Foster City, CA.

Introduction: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and the 4th leading cause of cancer death worldwide.1 HCC is also highly sexually dimorphic with males having a 2-4 times higher risk of HCC occurrence than females regardless of the disease etiology.2 Based upon the discrepancy in HCC incidence between the sexes, the role of sex hormone receptors, such as the androgen receptor (AR), in HCC progression has been investigated.3 Despite the evidence behind AR’s role in HCC lethality, clinical trials of anti-androgen therapy in HCC showed no significant clinical benefit.4 We recently reported the presence of abundant ligand-independent AR splice variants (AR-SVs) in HCC.5 Niclosamide is an anthelmintic drug that was identified in drugs screens for AR-V7 degrading and anti-HCC properties.6,7 Despite these features, niclosamide suffers from poor bioavailability by design resulting in dose limiting toxicities.8

Objective: 1) Identify and understand key functional groups of niclosamide for development of niclosamide analogs. 2) Develop niclosamide analogs improving bioavailability and limiting first pass metabolism.  

Methods: HCC and primary liver cell lines were treated with niclosamide analogs to determine efficacy in comparison to the parent compound. Toxicity studies were carried out in mice over a two-week span using a range of drug concentrations. Mouse pharmacokinetics studies to evaluate drug parameters were conducted through Charles River Laboratories.  

Results: Numerous niclosamide analogs were evaluated resulting in valine conjugated niclosamide improving bioavailability and a niclosamide analog with improved first pass metabolism and its valine conjugate. Leading analogs showed improved bioavailability without showing toxicities at higher doses.

Conclusions: Niclosamide is a drug showing key activity against AR and HCC that lends itself to treatment of AR/AR-SV positive HCC. Niclosamide analogs improve upon the parental drug by overcoming its bioavailability and dose limiting GI toxicity while shedding light on additional pathways for further improvement.

References:

  1. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nature Reviews Disease Primers. 2021 Jan 21;7(1):1–28.
  2. Kalra M, Mayes J, Assefa S, Kaul AK, Kaul R. Role of sex steroid receptors in pathobiology of hepatocellular carcinoma. World Journal of Gastroenterology. 2008 Oct 21;14(39):5945–61.
  3. Zhang H, Spencer K, Burley SK, Zheng XFS. Toward improving androgen receptor-targeted therapies in male-dominant hepatocellular carcinoma. Drug Discov Today. 2021 Jun;26(6):1539–46.
  4. Dauki AM, Blachly JS, Kautto EA, Ezzat S, Abdel-Rahman MH, Coss CC. Transcriptionally Active Androgen Receptor Splice Variants Promote Hepatocellular Carcinoma Progression. Cancer Res. 2020 Feb 1;80(3):561–75.
  5. Shafi AA, Yen AE, Weigel NL. Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacology & Therapeutics. 2013 Dec 1;140(3):223–38.
  6. Chen B, Wei W, Ma L, Yang B, Gill RM, Chua MS, et al. Computational Discovery of Niclosamide Ethanolamine, a Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells In Vitro and in Mice by Inhibiting Cell Division Cycle 37 Signaling. Gastroenterology. 2017 Jun 1;152(8):2022–36.
  7. Liu C, Lou W, Zhu Y, Nadiminty N, Schwartz CT, Evans CP, et al. Niclosamide Inhibits Androgen Receptor Variants Expression and Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer. Clin Cancer Res. 2014 Jun 15;20(12):3198–210.
  8. Schweizer MT, Haugk K, McKiernan JS, Gulati R, Cheng HH, Maes JL, et al. A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer. PLOS ONE. 2018 Jun 1;13(6):e0198389.

Greg Young

Abstract: Cancer cachexia (CC) is the unintentional loss of skeletal muscle and body mass which occurs in up to 80% of patients with late-stage cancer and causes up to 20% of cancer-associated death. Immune Checkpoint Inhibitors (ICIs) have shown to be a promising treatment for some cancers [1]. However, clinical data shows patients suffering from CC have a significantly poorer outcome with ICI treatment compared to non-cachectic patients. In addition to poor outcomes, cachectic patients have higher rates of ICI mAb drug clearance. Interestingly, worse prognosis has shown to be independent of drug dose, indicating that worse outcomes seen in cachectic patients is not due to lower drug exposure caused by faster clearance [2]. Instead, there is likely a common driver causing increased clearance, poor outcomes, and cachexia. Understanding the link between ICI clearance and cachexia may help identify likely responsive patients and to develop novel therapies to better treat cachectic patients. Investigating this link is often confounded due to the complex interplay between tumor and host in models of cancer cachexia. Specifically, separating the direct effects of the tumor from the effects of cachexia is challenging. To remove this confounder, we utilized a previously characterized Adeno-Associated Viruses (AAV) system [3]to transduce skeletal muscle in mice with Interleukin 6 or Activin A expression vectors. Both of these secreted, circulating factors are associated with cancer cachexia in patients and can drive cachectic changes in body composition in mice absent tumors. We found these tumor-free AAV treated mice had a similar loss in body fat and skeletal muscle mass as observed in tumor bearing cachexia models supporting the utility of this approach for follow-up mechanistic studies. Our future studies include investigating clearance of Pembrolizumab, an ICI mAb, in IL-6/Activin A treated mice versus empty vector controls. Additionally, we will isolate liver resident macrophages, which are thought to play a key role in monoclonal antibody clearance, from AAV treated mice to evaluate potential cachexia-mediated changes in their catabolic capacity for mAbs. Overall, this AAV model represents a robust method for examining the effects of cachexia without the influence of a tumor.

Min Hai, Tyler A. Wilson, Samuel K. Kulp, Hanna S. Radomska, Chad Bennett, Mitch A. Phelps, Christopher C. Coss. Preclinical dose selection strategy for a novel agent OSU-ERβ-12. Research Day, College of Pharmacy, The Ohio State University, 2023.

Min Hai, Kyeongmin Kim, Bryan Remaily, Justin Thomas, Trang T. Vu, Millennium Manna, Zhiliang Xie, Travis Costa, Yizhen Guo, Xiaokui Mo, Dwight H. Owen, Samuel K. Kulp, Thomas A. Mace, Christopher C. Coss and Mitch A. Phelps. Use of population pharmacokinetics model to identify cancer cachexia and its impact on pembrolizumab disposition in murine cancer models. 7th Annual Division Scientific Retreat Program, College of Pharmacy, The Ohio State University, 2022.

Bryan Remaily, Justin Thomas, Trang T. Vu, Kyeongmin Kim, Zhiliang Xie, Camille Stanton, Yizhen Guo, Travis Costa, Millennium Manna, Dwight H. Owen, Samuel K. Kulp, Latha P. Ganesan, Christopher C. Coss, Thomas A. Mace PhD, Mitch A. Phelps PhD (2022) Fc Gamma Receptor Role in Cachexia Mediated Increases in Immune Checkpoint Inhibitor Catabolism. The Ohio State College of Pharmacy Research Day, April 2023. Columbus, OH

Bryan Remaily, Trang T. Vu, Justin Thomas, Kyeongmin Kim, Zhiliang Xie, Yizhen Guo, Travis Costa, Millennium Manna, Riley Britt, Dwight H. Owen, Samuel K. Kulp, Latha P. Ganesan, Christopher C. Coss, Thomas A. Mace PhD, Mitch A. Phelps PhD (2022) Fc receptor modulation and potential impact on clearance of immune checkpoint inhibitors in cancer cachexia. American Society for Clinical Pharmacology and Therapeutics 2023 Annual Meeting, March 2023. Atlanta, GA

Bryan Remaily, Justin Thomas, Kyeongmin Kim, Trang T. Vu, Zhiliang Xie, Yizhen Guo, Travis Costa, Millennium Manna, Riley Britt, Dwight H. Owen, Samuel K. Kulp, Latha P. Ganesan, Christopher C. Coss, Thomas A. Mace PhD, Mitch A. Phelps PhD (2022) Endogenous Fc Receptor Expression Changes and Cancer Cachexia: Potential Impact Upon Immune Checkpoint Inhibitor Pharmacokinetics. Ohio State Comprehensive Cancer Center-James Pelotonia Institute for Immuno-Oncology Annual Immuno-Oncology Symposium, November 2022. Columbus, OH

Bryan Remaily, Alyssa Marie M. Castillo, Trang T. Vu, Sophia G. Liva, Min Chen, Zhiliang Xie, Justin Thomas, Bryan Remaily, Yizhen Guo, Travis Costa, Timothy H. Helms, Kyeongmin Kim, Samuel K. Kulp, Thomas A. Mace, Mitch A. Phelps & Christopher C. Coss (2021) Potential Role of Fc-gamma Receptors in Elevated Clearance of Immune Checkpoint Inhibitors. The Ohio State College of Pharmacy Research Day, March 2021. Columbus, OH

Peter D. Whooley, Elizabeth A. Handorf, Christopher C. Coss, Trang T. Vu, Bryan Remaily, Emma Montgomery, Pritish Iyer, Matthew Blau, Yana Chertock, Rishi Jain, Michael J. Hall (2022) Associations between body composition measurements (BCM) and phase 1 (P1) oncology clinical trial outcomes Journal of Clinical Oncology 2022 40:16_suppl, e18648-e18648. American Society for Clinical Oncology publication: e18648, June 2022

Justin Thomas, “Novel Agent OSU-ER𝛃-12 in Combination with Anti-PD1 Therapy Promotes Anti-Tumor Immune Action”; The Ohio State University College of Pharmacy Research Day; Columbus, OH; April 12, 2023

Justin Thomas, “Novel Agent OSU-ER𝛃-12 Selectively Inhibits Granulocytic Myeloid-Derived Suppressor Cell Proliferation in Tumor-Bearing Mice”; The Ohio State University College of Pharmacy Division of Pharmaceutics and Pharmacology Divisional Retreat; Dublin, OH; November 15, 2022

Justin Thomas, “The Neonatal Fc Receptor is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer”; The Ohio State University Hayes Graduate Research Forum; March 4, 2022 

Justin Thomas, “The Neonatal Fc Receptor is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer”; Society for Immunotherapy of Cancer (SITC) Conference; Washington DC; November 14, 2021

Justin Thomas, “The Neonatal Fc Receptor is Altered in Myeloid Immune Populations in Pancreatic Cancer”; The Ohio State University James Annual Scientific Meeting; Columbus, OH; October 12, 2021

Justin Thomas, “The Neonatal Fc Receptor is Altered in Myeloid Immune Populations in Pancreatic Cancer”; Cancer Cachexia Conference; Virtual; August 28, 2021